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Masouri MM, Ebrahimi R, Noori S. An Updated Systematic Review and Meta-Analysis on the Efficacy and Safety of Metformin as Add-on Therapy to Insulin in Patients With Type 1 Diabetes. Endocrinol Diabetes Metab 2025; 8:e70060. [PMID: 40512873 PMCID: PMC12165280 DOI: 10.1002/edm2.70060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2025] [Revised: 04/05/2025] [Accepted: 05/15/2025] [Indexed: 06/16/2025] Open
Abstract
INTRODUCTION This study aims to perform an updated meta-analysis evaluating the efficacy and safety of metformin adjunct therapy in type 1 diabetes mellitus (T1DM) patients. METHOD Cochrane, PubMed and Embase were searched for randomised controlled trials (RCTs) that reported the efficacy and safety of metformin in T1DM patients. Statistical analyses were performed using STATA software. RESULTS Twenty-nine placebo-controlled RCTs enrolling 2051 T1DM patients were included. Adolescents experienced a notable reduction in total insulin daily dose (TIDD) (mean difference [MD] = -0.61 [95% confidence interval (CI): -1.02, -0.20] units/kg per day) and levels of haemoglobin A1c (HbA1c) (MD = -0.45 [95% CI: -0.79, -0.11]), total cholesterol (TC) (MD = -0.78 [95% CI: -1.54, -0.02]), and low-density lipoprotein (LDL) (MD = -0.69 [95% CI: -1.36, -0.02]) at 3 months of follow-up with metformin. In adults, metformin significantly reduced Body Mass Index (BMI) (MD = -0.71 [95% CI: -1.23, -0.19]), TIDD (MD = -0.44 [95% CI: -0.73, -0.16]), and levels of HbA1c (MD = -0.70 [95% CI: -1.10, -0.30]) and TC (MD = -0.60 [95% CI: -1.09, -0.10]) at 6 months. The risk of gastrointestinal adverse events (GIAEs) was significantly higher in both adolescents (Relative Risk [RR] = 1.74 [95% CI: 1.38, 2.21]) and adults (RR = 3.24 [95% CI: 1.49, 7.02]). All of the above had p-values less than 0.05. The metformin group showed no differences in BMI Z-score, high-density lipoprotein (HDL) level, or diabetic ketoacidosis (DKA) risk. No statistical difference was identified for any of the outcomes at other follow-up endpoints. CONCLUSIONS Metformin may reduce TIDD and levels of HbA1c, TC, triglycerides (TG), and LDL in T1DM adolescents. BMI, TIDD, and levels of HbA1c and TC may decrease in adults. Moreover, it may raise the risk of GIAEs in both age groups.
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Affiliation(s)
| | - Rasoul Ebrahimi
- School of MedicineShahid Beheshti University of Medical SciencesTehranIran
| | - Shokoofe Noori
- Department of BiochemistryFaculty of Medicine, Shahid Beheshti University of Medical SciencesTehranIran
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Azar S, Maroun Abou Jaoude N, Kędzia A, Niechciał E. Barriers to Type 1 Diabetes Adherence in Adolescents. J Clin Med 2024; 13:5669. [PMID: 39407728 PMCID: PMC11477045 DOI: 10.3390/jcm13195669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 08/26/2024] [Accepted: 09/14/2024] [Indexed: 10/20/2024] Open
Abstract
Background: Adolescence is a particularly crucial period of physical, emotional, and social development and adaptation, rendering these formative years rather challenging for individuals with chronic conditions like type 1 diabetes (T1D). Despite rapid improvement in diabetes therapies, adolescents with T1D are characterized by poorer adherence to treatment regimens compared with other pediatric age groups. Insufficient adherence is strongly related to low diabetes control, increasing morbidity, and risk for premature mortality. This study aimed to provide a comprehensive overview of adolescents' most common barriers to T1D adherence, stressing the need for a deep and comprehensive understanding of these barriers. The complexity of these barriers is underscored by the diverse factors contributing to poor T1D adherence in adolescents. Methods: A narrative review was conducted, surveying four databases (PubMed, Scopus, EMBASE, and Web of Science) for full-text articles in the English language published up to June 2024. All studies related to barriers to T1D adherence in adolescents were considered. The literature was selected using selection and exclusion criteria and extracted and organized using Mendeley. Exclusion criteria included studies with insufficient data and non-peer-reviewed articles. This review revealed that adolescents face numerous obstacles to T1D adherence related to psychological factors, flux in family dynamics, perceived social pressures, therapy-related factors, transitioning responsibility, risk-taking behaviors, and pubertal changes. Conclusions: Navigating the adaptations to the different aspects of T1D, from treatment to complications and adolescents' personal growth, effectively requires a thorough understanding of the barriers of a treatment regimen that patients at this critical age face.
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Affiliation(s)
| | | | | | - Elżbieta Niechciał
- Department of Pediatric Diabetes, Clinical Auxology and Obesity, Poznan University of Medical Sciences, Szpitalna Street 27/33, 60-572 Poznan, Poland; (S.A.); (N.M.A.J.); (A.K.)
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Abstract
PURPOSE OF REVIEW This review provides the most recent update of metformin, a biguanide oral antihyperglycemic drug used as a first-line treatment in type 2 diabetes mellitus. RECENT FINDINGS Metformin continues to dominate in the world of antidiabetics, and its use will continue to rise because of its high efficiency and easy availability. Apart from type 2 diabetes, research is exploring its potential in other conditions such as cancer, memory loss, bone disorders, immunological diseases, and aging. Metformin is the most prescribed oral antidiabetic worldwide. It has been in practical use for the last six decades and continues to be the preferred drug for newly diagnosed type 2 diabetes mellitus. It reduces glucose levels by decreasing hepatic glucose production, reducing intestinal glucose absorption, and increasing insulin sensitivity. It can be used as monotherapy or combined with other antidiabetics like sulfonylureas, DPP-4 inhibitors, SGLT-2 inhibitors, or insulin, improving its efficacy. Metformin can be used once or twice daily, depending on requirements. Prolonged usage of metformin may lead to abdominal discomfort, deficiency of Vitamin B12, or lactic acidosis. It should be used carefully in patients with renal impairment. Recent studies have explored additional benefits of metformin in polycystic ovarian disease, gestational diabetes mellitus, cognitive disorders, and immunological diseases. However, more extensive studies are needed to confirm these additional benefits.
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Oza C, Mondkar S, Shah N, More C, Khadilkar V, Khadilkar A. A Pilot Study to Assess Effect of Metformin Therapy on Prevention of Double Diabetes in Indian Adolescents with Type-1 Diabetes. Indian J Endocrinol Metab 2023; 27:201-207. [PMID: 37583410 PMCID: PMC10424107 DOI: 10.4103/ijem.ijem_46_23] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/08/2023] [Accepted: 03/21/2023] [Indexed: 08/17/2023] Open
Abstract
Introduction Increased prevalence of metabolic syndrome in Indian adolescents owing to the obesity epidemic leads to double diabetes (DD), which is associated with an increased risk of complications in type-1 diabetes (T1D). Metformin may be a useful intervention for the prevention and treatment of insulin resistance in T1D. We conducted this pilot randomized controlled trial with the objective of investigating the effect of metformin on insulin sensitivity in Indian adolescents with T1D. Method This pilot randomized controlled trial was performed on 59 participants with T1D aged 10-19 years distributed uniformly by gender and puberty across two groups with a 3-month intervention period. The intervention group received metformin (weight less than 60 kg received 500 mg twice daily and more than 60 kg received 1 gm twice daily) and non-metformin group received standard of care for diabetes. Anthropometric, clinical details, biochemistry and insulin sensitivity indices (ISI) were evaluated using standard protocols at baseline and endline. Result 22.2% of subjects from non-metformin group and 12.5% from metformin group were at the risk of the development of DD. The odds ratio and relative risk for the development of DD in non-metformin subjects were 2.0 and 1.4, respectively, as compared to participants in metformin group. The mean improvement in ISI ranged from 1.4% to 4.6% in participants on metformin as opposed to deterioration of -2% to -14.1% in non-metformin group. On performing the paired sample t-test, the reduction in ISI in non-metformin group was significant. Conclusion Metformin may prevent deterioration in insulin sensitivity in Indian adolescents with T1D.
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Affiliation(s)
- Chirantap Oza
- Department of Growth and Pediatric Endocrinology, Cowasji Jehangir Medical Research Institute, Pune, Maharashtra, India
| | - Shruti Mondkar
- Department of Growth and Pediatric Endocrinology, Cowasji Jehangir Medical Research Institute, Pune, Maharashtra, India
| | - Nikhil Shah
- Department of Growth and Pediatric Endocrinology, Cowasji Jehangir Medical Research Institute, Pune, Maharashtra, India
- Department of Paediatrics, Cloudnine Hospital, Mumbai, Maharashtra, India
| | - Chidvilas More
- Department of Growth and Pediatric Endocrinology, Cowasji Jehangir Medical Research Institute, Pune, Maharashtra, India
| | - Vaman Khadilkar
- Department of Health Sciences, Savitribai Phule Pune University, Pune, Maharashtra, India
- Department of Growth and Pediatric Endocrinology, Senior Paediatric Jehangir Hospital, Pune, Maharashtra, India
| | - Anuradha Khadilkar
- Department of Growth and Pediatric Endocrinology, Cowasji Jehangir Medical Research Institute, Pune, Maharashtra, India
- Department of Growth and Pediatric Endocrinology, Senior Paediatric Jehangir Hospital, Pune, Maharashtra, India
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Xu L, Wang W, Song W. A combination of metformin and insulin improve cardiovascular and cerebrovascular risk factors in individuals with type 1 diabetes mellitus. Diabetes Res Clin Pract 2022; 191:110073. [PMID: 36075464 DOI: 10.1016/j.diabres.2022.110073] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 08/14/2022] [Accepted: 08/31/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND This study aims to further clarify whether the addition of metformin to insulin treatment improve cardiovascular and cerebrovascular risk factors in individuals with T1DM. METHODS Electronic databases were searched for randomized controlled trials in which the efficacy and safety of metformin were compared with those of a placebo for risk factors of cardiovascular and cerebrovascular disease among individuals with T1DM, and a meta-analysis was conducted. RESULTS Thirteen cardiovascular studies were identified. In the metformin group, mean carotid intimal media thickness was significantly reduced by 0.03 mm, ascending aortic pulse wave velocity by 6.3 m/s, descending aortic wall shear stress by 1.77 dyn/cm2 (P = 0.02), insulin daily dose by 0.05 U/kg/d, body weight by 2.27 kg, fat-free mass by 1.32 kg, body mass index by 0.58 kg/m2, hip circumference by 0.29 m, and low-density lipoprotein by 0.16 mmol/L, all above are P < 0.05. In the metformin group, flow-mediated dilation was increased by 1.29 %, glucose infusion rate/insulin by 18.22 mg/(kg⋅min)/μIU/μL, and waist-to-hip ratio by 0.02, all above are P < 0.00001. The metformin group showed no differences in blood pressure, reactive hyperemia index, waist circumference, triglyceride, total cholesterol, high-density lipoprotein cholesterol, or body mass index Z score. For cerebrovascular studies were identified. But none of them had a risk factor assessment. CONCLUSIONS Metformin can ameliorate cardiovascular and cerebrovascular risk factors through non-hypoglycemic multiple pathways in individuals with T1DM.
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Affiliation(s)
- Linlin Xu
- The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wei Wang
- The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Wei Song
- The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China.
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Liu Y, Chen H, Li H, Li L, Wu J, Li H. Effect and Safety of Adding Metformin to Insulin Therapy in Treating Adolescents With Type 1 Diabetes Mellitus: An Updated Meta-Analysis of 10 Randomized Controlled Trials. Front Endocrinol (Lausanne) 2022; 13:878585. [PMID: 35707462 PMCID: PMC9190285 DOI: 10.3389/fendo.2022.878585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 04/20/2022] [Indexed: 11/24/2022] Open
Abstract
BACKGROUND The role of metformin in the treatment of adolescents with type 1 diabetes mellitus (T1DM) remains controversial. We conducted this updated meta-analysis to generate a comprehensive assessment regarding the effect and safety of metformin in treating adolescents with T1DM. METHODS We systematically searched PubMed, Embase, and the Cochrane Central Registry of Controlled Trials (CENTRAL) from their inception to November 2021 to identify randomized controlled trials evaluating the efficacy of metformin in the treatment of adolescents with T1DM. The primary outcome was the HbA1c level, and secondary outcomes included the body mass index (BMI), total insulin daily dose (TIDD) (unit/kg/d), hypoglycemia events, diabetes ketoacidosis (DKA) events, and gastrointestinal adverse events (GIAEs). Statistical analysis was conducted using RevMan 5.4 and STATA 14.0. RESULTS Ten studies enrolling 539 T1DM adolescents were included. Results suggested that metformin significantly decreased the HbA1c level at 12 months (mean difference [MD])=-0.50, 95% confidence interval [CI]=-0.61 to -0.39, P < 0.01); BMI (kg/m2) at 3 months (MD=-1.05, 95%CI=-2.05 to -0.05, P=0.04); BMI z-score at 6 months (MD=-0.10, 95%CI=-0.14 to -0.06, P<0.01); and TIDD at 3 (MD=-0.13, 95%CI=-0.20 to -0.06, P<0.01), 6 (MD=-0.18, 95%CI=-0.25 to -0.11, P<0.01), and 12 (MD=-0.42, 95%CI=-0.49 to -0.35, P<0.01) months but significantly increased the risk of hypoglycemia events (risk ratio [RR]=3.13, 95%CI=1.05 to 9.32, P=0.04) and GIAEs (RR=1.64, 95%CI=1.28 to 2.10, P<0.01). For remaining outcomes at other time points, no statistical difference was identified. Sensitivity analysis confirmed the robustness of all pooled results. CONCLUSIONS The use of metformin might result in decreased BMI (kg/m2), BMI z-score, and TIDD and increased risk of hypoglycemia events and GIAEs in adolescents with T1DM. However, future studies are required to further confirm the optimal dose and duration of metformin therapy.
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Affiliation(s)
- Ying Liu
- Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu, China
- Center of Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Hongbo Chen
- Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Hui Li
- Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Liman Li
- Center of Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Jin Wu
- Department of Pediatrics, West China Second Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
| | - Hong Li
- Center of Translational Medicine, Key Laboratory of Birth Defects and Related Diseases of Women and Children of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, China
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Sheikhy A, Eydian Z, Fallahzadeh A, Shakiba M, Hajipour M, Alaei M, Mosallanejad A, Saneifard H. Benefits of metformin add-on insulin therapy (MAIT) for HbA1c and lipid profile in adolescents with type 1 diabetes mellitus: preliminary report from a double-blinded, placebo-controlled, randomized clinical trial. J Pediatr Endocrinol Metab 2022; 35:505-510. [PMID: 35249270 DOI: 10.1515/jpem-2021-0704] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Accepted: 02/13/2022] [Indexed: 11/15/2022]
Abstract
OBJECTIVES Metabolic control during puberty is impaired in Type 1 Diabetes Mellitus (T1DM) patients due to increased insulin resistance. Metformin is one of the oral medications typically used in type 2 diabetes mellitus to reduce insulin resistance. We aimed to examine the effect of metformin on glycemic indices and insulin daily dosage in adolescents with T1DM. METHODS The present clinical trial was carried out on 50 adolescents aged 10-20 years with T1DM referred to the Endocrinology Clinic of Mofid Children's Hospital in Tehran for nine months. The patients were randomly divided into two groups. In the first group, metformin was added to insulin therapy, while the second group continued routine insulin therapy combined with placebo. Hemoglobin A1c (HbA1c), weight, BMI, insulin dosage, and blood pressure were measured at the beginning of the study and repeated every three months. Serum lipid profile, creatinine, blood urea nitrogen, and liver enzymes were also measured twice: At the beginning and end of the study (after nine months). RESULTS The HbA1c level (p<0.001) and insulin dosage (p=0.04) were lower in the metformin group than in the placebo group after nine months. Daily insulin dosage variability was significantly lower in the metformin recipient group (p=0.041). Serum triglyceride, cholesterol, and creatinine were significantly lower in the metformin arm than in the placebo arm (p<0.05). However, metformin did not affect LDL, HDL, liver enzymes, and BUN. CONCLUSIONS Adjunctive metformin therapy reduces insulin dosage by inhibiting insulin resistance and weight gain. It helps decrease daily insulin dosage variability, which may prevent hypoglycemia. Also, metformin reduces creatinine, preventing renal failure in the long term.
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Affiliation(s)
- Ali Sheikhy
- Research Department, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.,Non-Communicable Disease Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Zahra Eydian
- Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Aida Fallahzadeh
- Research Department, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran.,Non-Communicable Disease Research Center, Endocrinology and Metabolism Population Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Marjan Shakiba
- Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahmoud Hajipour
- Pediatric Gastroenterology, Hepatology and Nutrition Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadreza Alaei
- Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Asieh Mosallanejad
- Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hedyeh Saneifard
- Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Pediatric Gastroenterology, Hepatology and Nutrition Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Elbarbary NS, Ismail EAR, Ghallab MA. Effect of metformin as an add-on therapy on neuregulin-4 levels and vascular-related complications in adolescents with type 1 diabetes: A randomized controlled trial. Diabetes Res Clin Pract 2022; 186:109857. [PMID: 35351535 DOI: 10.1016/j.diabres.2022.109857] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/06/2022] [Accepted: 03/24/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Inflammation is closely associated with atherosclerosis and plays a crucial role in the development of cardiovascular disease. Metformin sensitizes body cells to insulin, which may cause a reduction of atherogenic lipid fractions. Low neuregulin-4 (Nrg-4) levels, an adipokine, are linked to obesity, insulin resistance, impaired glucose tolerance and type 2 diabetes. OBJECTIVES We assessed the effect of oral supplementation with metformin on glycemic control, neuregulin-4 levels and carotid intima media thickness (CIMT) as a marker for subclinical atherosclerosis in adolescents with type 1 diabetes mellitus (T1DM) and microvascular complications. METHODS This randomized placebo-controlled trial included 80 type 1 diabetic patients with microvascular complications who were randomly divided to receive either 24 weeks of metformin 500 mg/day or matching placebo. Fasting blood glucose (FBG), HbA1c, C-reactive protein (CRP), urinary albumin creatinine ratio (UACR), lipid profile, Nrg-4 and CIMT were assessed at baseline and study end. RESULTS Both groups were well-matched as regards baseline clinical and laboratory data (p greater than 0.05). After 24-weeks, metformin therapy for the intervention group resulted in a significant decrease of HbA1c, CRP, UACR, total cholesterol and CIMT while Nrg-4 levels were increased compared with baseline levels (p < 0.001) and with placebo group(p < 0.001). Baseline Nrg-4 levels were negatively correlated to FBG, HbA1c, total cholesterol, CRP and CIMT. Metformin was well-tolerated. CONCLUSIONS Oral metformin supplementation once daily for 24 weeks as an adjuvant therapy to intensive insulin in pediatric T1DM was safe and effective in improving glycemic control, dyslipidemia and Nrg-4 levels; hence, it decreased inflammation, microvascular complications and subclinical atherosclerosis.
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Ciężki S, Kurpiewska E, Bossowski A, Głowińska-Olszewska B. Multi-Faceted Influence of Obesity on Type 1 Diabetes in Children - From Disease Pathogenesis to Complications. Front Endocrinol (Lausanne) 2022; 13:890833. [PMID: 35784568 PMCID: PMC9243381 DOI: 10.3389/fendo.2022.890833] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Accepted: 05/13/2022] [Indexed: 01/08/2023] Open
Abstract
The prevalence of overweight and obesity among youth patients with diabetes type 1 is increasing. It is estimated, that even up to 35% of young patients with this type of diabetes, considered so far to be characteristic for slim figure, are overweight or even obese. General increase of obesity in children's population complicates differential diagnosis of the type of diabetes in youths. Coexistence of obesity has clinical implications for all stages of diabetes course. It is confirmed that obesity is the risk factor for autoimmune diabetes, and is connected with the earlier onset of diabetes in predisposed patients. Many diabetic patients with obesity present additional risk factors for macroangiopathy, and are recognised to present metabolic syndrome, insulin resistance, and typical for diabetes type 2 - polycystic ovary syndrome, or non-alcoholic fatty liver disease. The prevalence of obesity rises dramatically in adolescence of diabetic child, more often in girls. It has negative impact on metabolic control, glycaemic variability and insulin demand. The risk for microangiopathic complications increases as well. The treatment is difficult and includes not only insulinotherapy and non-pharmacological trials. Recently treatment of insulin resistance with biguanids, and treatment with typical for type 2 new diabetes drugs like GLP-1 analogues, SGLT-2 receptor inhibitors, or even cases of bariatric surgery also has been reported.
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Wang DD, Mao YZ, He SM, Chen X. Analysis of Time Course and Dose Effect From Metformin on Body Mass Index in Children and Adolescents. Front Pharmacol 2021; 12:611480. [PMID: 33981216 PMCID: PMC8107689 DOI: 10.3389/fphar.2021.611480] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Accepted: 03/01/2021] [Indexed: 01/07/2023] Open
Abstract
The purpose of this study was to analyze the time course and dose effect from metformin on body mass index (BMI) in children and adolescents by model-based meta-analysis (MBMA). Searching randomized controlled trial (RCT) studies of metformin on BMI in children and adolescents. The change rates of BMI from baseline values were used as indicator of evaluating metformin efficacy. A total of 18 RCT studies, 1,228 children and adolescents, were included for analysis, including patients with obesity, patients with type 1 diabetes mellitus, patients with nonalcoholic fatty liver, and patients with precocity. In order to achieve better effect of metformin on BMI in children and adolescents, the present study recommended that for patients with obesity, 1,000 mg/day metformin was required for at least 15.2 weeks and 60.8 weeks to achieve the plateau of metformin effect; for patients with type 1 diabetes mellitus, 1,000 mg/day metformin was required for at least 25.2 weeks and 100.8 weeks to achieve the plateau of metformin effect; for patients with nonalcoholic fatty liver, 1,000 mg/day metformin was required for at least 6.57 weeks and 26.28 weeks to achieve the plateau of metformin effect; for patients with precocity, 425 mg/day metformin was required for at least 12.4 weeks and 49.6 weeks to achieve the plateau of metformin effect. It was the first time to analyze the time course and dose effect from metformin on BMI and to recommend dosage and duration of treatment for metformin in children and adolescents with different disease types.
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Affiliation(s)
- Dong-Dong Wang
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, China
| | - Yi-Zhen Mao
- Department of Endocrinology, Xuzhou Central Hospital, Xuzhou, China
| | - Su-Mei He
- Department of Pharmacy, The Affiliated Suzhou Science and Technology Town Hospital of Nanjing Medical University, Suzhou, China
| | - Xiao Chen
- Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, Xuzhou, China.,Department of Pharmacy, The People's Hospital of Jiangyin, Jiangyin, China.,Department of Pharmacy, Children's Hospital of Fudan University, Shanghai, China
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11
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The use of metformin as an add-on therapy to insulin in the treatment of poorly controlled type 1 diabetes mellitus in adolescents. Metabol Open 2021; 9:100080. [PMID: 33598651 PMCID: PMC7868998 DOI: 10.1016/j.metop.2021.100080] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/12/2021] [Accepted: 01/19/2021] [Indexed: 12/21/2022] Open
Abstract
The aim of this integrative literature review was to evaluate the efficacy and safety of Metformin as an add-on therapy to insulin in poorly controlled overweight adolescents with type 1 diabetes mellitus. The research problem centered on providing optimum disease management during the most critical growth period and reducing the potential for cardiovascular-related morbidity and mortality in the future. The findings suggested that Metformin, in conjunction with insulin therapy, helped patients to achieve better metabolic control. The quality of metabolic control varied between studies according to differences in study design, exclusion and inclusion criteria, and methods. Adjunctive Metformin therapy has a positive effect on diabetes management, treatment, and prevention of cardiovascular-related complications with a minimal risk of side effects. Suggestions for further exploration of the research results and clinical implications are included in the review.
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Drzewoski J, Hanefeld M. The Current and Potential Therapeutic Use of Metformin-The Good Old Drug. Pharmaceuticals (Basel) 2021; 14:122. [PMID: 33562458 PMCID: PMC7915435 DOI: 10.3390/ph14020122] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/02/2021] [Accepted: 02/02/2021] [Indexed: 02/07/2023] Open
Abstract
Metformin, one of the oldest oral antidiabetic agents and still recommended by almost all current guidelines as the first-line treatment for type 2 diabetes mellitus (T2DM), has become the medication with steadily increasing potential therapeutic indications. A broad spectrum of experimental and clinical studies showed that metformin has a pleiotropic activity and favorable effect in different pathological conditions, including prediabetes, type 1 diabetes mellitus (T1DM) and gestational diabetes mellitus (GDM). Moreover, there are numerous studies, meta-analyses and population studies indicating that metformin is safe and well tolerated and may be associated with cardioprotective and nephroprotective effect. Recently, it has also been reported in some studies, but not all, that metformin, besides improvement of glucose homeostasis, may possibly reduce the risk of cancer development, inhibit the incidence of neurodegenerative disease and prolong the lifespan. This paper presents some arguments supporting the initiation of metformin in patients with newly diagnosed T2DM, especially those without cardiovascular risk factors or without established cardiovascular disease or advanced kidney insufficiency at the time of new guidelines favoring new drugs with pleotropic effects complimentary to glucose control. Moreover, it focuses on the potential beneficial effects of metformin in patients with T2DM and coexisting chronic diseases.
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Affiliation(s)
- Józef Drzewoski
- Central Teaching Hospital of Medical University of Lodz, 92-213 Lodz, Poland
| | - Markolf Hanefeld
- Medical Clinic III, Department of Medicine Technical University Dresden, 01307 Dresden, Germany;
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March CA, Becker DJ, Libman IM. Nutrition and Obesity in the Pathogenesis of Youth-Onset Type 1 Diabetes and Its Complications. Front Endocrinol (Lausanne) 2021; 12:622901. [PMID: 33828529 PMCID: PMC8021094 DOI: 10.3389/fendo.2021.622901] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Accepted: 02/15/2021] [Indexed: 12/15/2022] Open
Abstract
Since the 1980s, there has been a dramatic rise in the prevalence of overweight and obesity in pediatric populations, in large part driven by sedentary lifestyles and changing dietary patterns with more processed foods. In parallel with the rise in pediatric obesity in the general population, the prevalence of overweight and obesity has increased among children and adolescents with type 1 diabetes. Adiposity has been implicated in a variety of mechanisms both potentiating the risk for type 1 diabetes as well as exacerbating long-term complications, particularly cardiovascular disease. Treatment options targeting the unique needs of obese pediatric patients, both before and after diagnosis of type 1 diabetes, are limited. In this review, we discuss the history of the epidemiology of the obesity epidemic in the context of pediatric type 1 diabetes, highlight the possible role of obesity in type 1 diabetes pathogenesis and review the concept of "double diabetes". The impact of obesity at and after diagnosis will be discussed, including noted differences in clinical and biochemical markers, lipid abnormalities, and long-term cardiovascular complications. Finally, we will review the existing literature on pharmacologic and nutritional interventions as potential treatment strategies for youth with coexisting type 1 diabetes and obesity.
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Lin C, Cai X, Yang W, Lv F, Nie L, Ji L. Age, sex, disease severity, and disease duration difference in placebo response: implications from a meta-analysis of diabetes mellitus. BMC Med 2020; 18:322. [PMID: 33190640 PMCID: PMC7667845 DOI: 10.1186/s12916-020-01787-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2020] [Accepted: 09/17/2020] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND The placebo response in patients with diabetes mellitus is very common. A systematic evaluation needs to be updated with the current evidence about the placebo response in diabetes mellitus and the associated factors in clinical trials of anti-diabetic medicine. METHODS Literature research was conducted in Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies published between the date of inception and June 2019. Randomized placebo-controlled trials conducted in type 1and type 2 diabetes mellitus (T1DM/T2DM) were included. Random-effects model and meta-regression analysis were accordingly used. This meta-analysis was registered in PROSPERO as CRD42014009373. RESULTS Significantly weight elevation (effect size (ES) = 0.33 kg, 95% CI, 0.03 to 0.61 kg) was observed in patients with placebo treatments in T1DM subgroup while significantly HbA1c reduction (ES = - 0.12%, 95% CI, - 0.16 to - 0.07%) and weight reduction (ES = - 0.40 kg, 95% CI, - 0.50 to - 0.29 kg) were observed in patients with placebo treatments in T2DM subgroup. Greater HbA1c reduction was observed in patients with injectable placebo treatments (ES = - 0.22%, 95% CI, - 0.32 to - 0.11%) versus oral types (ES = - 0.09%, 95% CI, - 0.14 to - 0.04%) in T2DM (P = 0.03). Older age (β = - 0.01, 95% CI, - 0.02 to - 0.01, P < 0.01) and longer diabetes duration (β = - 0.02, 95% CI, - 0.03 to - 0.21 × 10-2, P = 0.03) was significantly associated with more HbA1c reduction by placebo in T1DM. However, younger age (β = 0.02, 95% CI, 0.01 to 0.03, P = 0.01), lower male percentage (β = 0.01, 95% CI, 0.22 × 10-2, 0.01, P < 0.01), higher baseline BMI (β = - 0.02, 95% CI, - 0.04 to - 0.26 × 10-2, P = 0.02), and higher baseline HbA1c (β = - 0.09, 95% CI, - 0.16 to - 0.01, P = 0.02) were significantly associated with more HbA1c reduction by placebo in T2DM. Shorter diabetes duration (β = 0.06, 95% CI, 0.06 to 0.10, P < 0.01) was significantly associated with more weight reduction by placebo in T2DM. However, the associations between baseline BMI, baseline HbA1c, and placebo response were insignificant after the adjusted analyses. CONCLUSION The placebo response in diabetes mellitus was systematically outlined. Age, sex, disease severity (indirectly reflected by baseline BMI and baseline HbA1c), and disease duration were associated with placebo response in diabetes mellitus. The association between baseline BMI, baseline HbA1c, and placebo response may be the result of regression to the mean.
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Affiliation(s)
- Chu Lin
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Xiaoling Cai
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
| | - Wenjia Yang
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Fang Lv
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China
| | - Lin Nie
- Department of Endocrinology and Metabolism, Beijing Airport Hospital, Beijing, China
| | - Linong Ji
- Department of Endocrinology and Metabolism, Peking University People's Hospital, No.11 Xizhimen South Street, Xicheng District, Beijing, 100044, China.
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15
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Soliman A, De Sanctis V, Alaaraj N, Hamed N. The clinical application of metformin in children and adolescents: A short update. ACTA BIO-MEDICA : ATENEI PARMENSIS 2020; 91:e2020086. [PMID: 32921782 PMCID: PMC7717009 DOI: 10.23750/abm.v91i3.10127] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Accepted: 07/02/2020] [Indexed: 12/25/2022]
Abstract
Metformin is a widely used drug that results in clear benefits in relation to glucose metabolism and diabetes-related complications. The global increase in the prevalence of obesity among children and adolescents is accompanied by the appearance and increasing prevalence of insulin resistance, prediabetes, and type 2 diabetes mellitus (T2DM). In addition, children, and adolescents with premature pubarche and polycystic ovary have considerable degree of insulin resistance. The insulin sensitizing actions of metformin encouraged many investigators and physician to use it as the key drug in these conditions for both prevention and treatment. However, long term-controlled studies are still required to assess the degree and duration of effectiveness and safety of using metformin. This review tries to update physicians about the main and the new therapeutic perspectives of this drug.
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Affiliation(s)
- Ashraf Soliman
- Department of Pediatrics, Division of Endocrinology, Hamad General Hospital, Doha, Qatar.
| | - Vincenzo De Sanctis
- Pediatric and Adolescent Outpatient Clinic, Quisisana Hospital, Ferrara, Italy.
| | - Nada Alaaraj
- Department of Pediatrics, Division of Endocrinology, Hamad General Hospital, Doha, Qatar.
| | - Noor Hamed
- Department of Pediatrics, Division of Endocrinology, Hamad General Hospital, Doha, Qatar.
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16
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Liu YS, Chen CN, Chen ZG, Peng Y, Lin XP, Xu LL. Vascular and metabolic effects of metformin added to insulin therapy in patients with type 1 diabetes: A systematic review and meta-analysis. Diabetes Metab Res Rev 2020; 36:e3334. [PMID: 32390336 DOI: 10.1002/dmrr.3334] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 04/08/2020] [Accepted: 04/30/2020] [Indexed: 01/15/2023]
Abstract
BACKGROUND The incidence of type 1 diabetes mellitus (T1DM) is increasing among youth worldwide, translating to an increased risk ofearly-onset cardiovascular disease (CVD). Mounting studies have shown that metformin may reduce maximal carotidintima-media thickness (cIMT), improve insulin resistance and metabolic control in subjects with T1DM, and thus, may extend cardioprotective benefits. This systematic review and meta-analysis was performed to assess the efficacy and safety of metformin added to insulin therapy on reducing CVD risks and improving metabolism in T1DM. METHODS PubMed, EMBASE, and the Cochrane Library were systematically searched for randomized controlled trials (RCTs) that compared metformin and insulin combination (duration ≥3 months) to insulin treatment alone in T1DM. Data were expressed as weighted/standardized mean differences (MDs/SMDs) for continuous outcomes and risk ratios (RRs) for dichotomous outcomes, along with 95% confidence intervals (CIs). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to evaluate the overall certainty of the evidence. RESULTS Nineteen RCTs (n = 1540) met the eligibility criteria. Metformin treatment significantly reduced carotid artery intima-media thickness (MD -0.06 mm [95% CI -0.88, -0.28], P < .001). Though no significant difference was found in insulin sensitivity (SMD 2.21 [95% CI -1.88, 6.29], P = .29), the total daily insulin dosage (SMD -0.81 [95% CI -1.25, -0.36], P < .001) along with traditional CVD risk factors showed improvement by better glycaemic control, partial lipid profiles, diastolic blood pressure, and limited weight gain, with neutral effect on diabetic ketoacidosis, lactic acidosis, and hypoglycaemia. However, metformin therapy increased the incidence of gastrointestinal adverse events. CONCLUSIONS Metformin with insulin has the potential to retard the progression of atherosclerosis and provides better metabolic control in patients with T1DM, and thus, providing a potential therapeutic strategy for patients with T1DM on reducing CVD risks.
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Affiliation(s)
- Ying-Shan Liu
- Shenzhen Hospital, Southern Medical University, Shenzhen, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Chu-Na Chen
- Shenzhen Hospital, Southern Medical University, Shenzhen, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Zhen-Guo Chen
- Shenzhen Hospital, Southern Medical University, Shenzhen, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Yu Peng
- Nanfang Hospital, Southern Medical University, Guangzhou, China
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Xiao-Pu Lin
- Nanfang Hospital, Southern Medical University, Guangzhou, China
- The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Ling-Ling Xu
- Shenzhen Hospital, Southern Medical University, Shenzhen, China
- The Third School of Clinical Medicine, Southern Medical University, Guangzhou, China
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Abstract
PURPOSE OF REVIEW Obesity is increasing in prevalence among patients with type 1 diabetes (T1D) and is associated with insulin resistance and increased cardiovascular risk. The management of obesity in this population is complicated by defects in pancreatic islet hormone secretion and the effects of exogenous insulin treatment. Here, we review the effects of antiobesity medications and adjunct-to-insulin medications on body weight in T1D. RECENT FINDINGS There is a profound evidence gap around the use of drugs for the treatment of obesity in T1D since systematic studies have not been performed in this population. Adjunctive-to-insulin therapy with certain antihyperglycemic agents leads to modest weight loss and reductions in insulin dose in T1D. However, only pramlintide has been approved in the United States for clinical use as adjunctive therapy in T1D. SUMMARY The growing prevalence of obesity in T1D has created an unmet need for safe and effective therapies to treat overweight and obesity in this population. Currently, antiobesity medications are used off-label for the treatment of patients with T1D. Additional studies are needed to understand the role of these medications in the management of obesity in patients with T1D.
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Affiliation(s)
- Anna Casu
- AdventHealth, Translational Research Institute
| | - Anika Bilal
- AdventHealth, Translational Research Institute
| | - Richard E Pratley
- AdventHealth, Translational Research Institute
- AdventHealth Diabetes Institute, Orlando, Florida, USA
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18
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Sadeghi A, Mousavi SM, Mokhtari T, Parohan M, Milajerdi A. Metformin Therapy Reduces Obesity Indices in Children and Adolescents: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. Child Obes 2020; 16:174-191. [PMID: 32068434 DOI: 10.1089/chi.2019.0040] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Purpose: Few studies have summarized findings for the effect of metformin on obesity indices. Therefore, we aimed to conduct a systematic review and meta-analysis on the effect of metformin on obesity indices among children and adolescents. Methods: Relevant articles published up to September 2018 were searched in SCOPUS, Medline, and Google Scholar using appropriate keywords. All clinical trials that examined the effect of metformin on obesity indices in children and adolescents were included. Results: Overall, 38 studies, including 2199 participants (39.75% male and 60.25% female), were included. The pooled results indicated that metformin significantly reduced BMI [weighted mean difference (WMD): -1.07 kg/m2; 95% confidence interval (CI): -1.43 to -0.72]. Same findings were found for waist circumference (WC) (WMD: -1.93 cm; 95% CI: -2.69 to -1.16). Metformin also reduced body weight in all participants (WMD: -2.51 kg; 95% CI: -3.14 to -1.89). Moreover, it reduced body fat mass in patients with overweight or obesity (WMD: -1.90%; 95% CI: -3.25 to -0.56) and chronic diseases (WMD: -1.41%; 95% CI: -2.23 to -0.58), but not among those with growth problems. Metformin therapy did not affect lean body mass (LBM) in patients with overweight or obesity and growth problems; however, it reduced LBM in patients with chronic diseases (WMD: -1.49 kg; 95% CI: -2.69 to -0.30). Conclusions: We found a significant reduction in BMI, body weight, WC, and fat mass following administration with metformin. However, the effect of metformin on LBM was not significant. Further studies are required to confirm these findings.
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Affiliation(s)
- Alireza Sadeghi
- Students' Scientific Research Center, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran.,Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Seyed Mohammad Mousavi
- Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Tahereh Mokhtari
- Department of Nutrition and Integrative Physiology, College of Health, University of Utah, Salt Lake City, UT
| | - Mohammad Parohan
- Department of Cellular and Molecular Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Alireza Milajerdi
- Students' Scientific Research Center, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran.,Department of Community Nutrition, School of Nutritional Sciences and Dietetics, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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19
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Yang D, Yan J, Deng H, Yang X, Luo S, Zheng X, Lv J, Liang W, Hong M, Wu Z, Yao B, Weng J, Xu W. Effects of Metformin Added to Insulin in Adolescents with Type 1 Diabetes: An Exploratory Crossover Randomized Trial. J Diabetes Res 2020; 2020:7419345. [PMID: 33457425 PMCID: PMC7785393 DOI: 10.1155/2020/7419345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 12/08/2020] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND To comprehensively assess the effects of metformin added to insulin on metabolic control, insulin sensitivity, and cardiovascular autonomic function in adolescents with type 1 diabetes. MATERIALS AND METHODS This was an exploratory, crossover, randomized trial conducted in adolescents with type 1 diabetes aged 12-18 years old. Participants were randomly received metformin (≤1000 mg/d) added to insulin for 24 weeks followed by insulin monotherapy for a subsequent 24 weeks or vice versa. Blood pressure, body mass index, insulin dose, estimated insulin sensitivity, glycated hemoglobin A1c (HbA1c), and lipid profiles were measured, with a 72-hour continuous glucose monitoring and 24-hour Holter monitoring performed at baseline, 24, and 50 weeks for the assessments of glucose variability and heart rate variability. RESULTS Seventeen patients with mean ± SD age 14.4 ± 2.3 years, body mass index 18.17 ± 1.81 kg/m2, median (IQR) diabetes duration 4.50 (3.58, 6.92) years, and HbA1c 9.0% (8.5%, 9.4%) were enrolled. The between-group difference in HbA1c of 0.28% (95% CI -0.39 to 0.95%) was not significant (P = 0.40). Changes in body mass index, insulin dose, blood pressure, lipid profiles, and estimated insulin sensitivity were similar for metformin add-on vs. insulin monotherapy. Glucose variability also did not differ. Compared with insulin monotherapy, metformin add-on significantly increased multiple heart rate variability parameters. CONCLUSIONS Metformin added to insulin did not improve metabolic control or glucose variability in lean/normal-weight adolescents with type 1 diabetes. However, metformin added to insulin significantly increased heart rate variability, suggesting that metformin might improve cardiovascular autonomic function in this population.
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Affiliation(s)
- Daizhi Yang
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
- Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Jinhua Yan
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
- Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Hongrong Deng
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
- Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Xubin Yang
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
- Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Sihui Luo
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of USTC, Division of Life Sciences of Medicine, University of Science and Technology of China, Anhui 230026, China
| | - Xueying Zheng
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of USTC, Division of Life Sciences of Medicine, University of Science and Technology of China, Anhui 230026, China
| | - Jing Lv
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
| | - Wen Liang
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
- Department of Endocrinology and Metabolism, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, China
| | - Mengjie Hong
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
- Department of Cardiovascular Medicine, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen 518107, China
| | - Zekai Wu
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
- Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Bin Yao
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
- Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
| | - Jianping Weng
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of USTC, Division of Life Sciences of Medicine, University of Science and Technology of China, Anhui 230026, China
| | - Wen Xu
- Department of Endocrinology and Metabolism, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China
- Guangdong Provincial Key Laboratory of Diabetology, Guangzhou 510630, China
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20
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Bjornstad P, Schäfer M, Truong U, Cree-Green M, Pyle L, Baumgartner A, Garcia Reyes Y, Maniatis A, Nayak S, Wadwa RP, Browne LP, Reusch JEB, Nadeau KJ. Metformin Improves Insulin Sensitivity and Vascular Health in Youth With Type 1 Diabetes Mellitus. Circulation 2019; 138:2895-2907. [PMID: 30566007 DOI: 10.1161/circulationaha.118.035525] [Citation(s) in RCA: 101] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND Cardiovascular disease is the leading cause of mortality in type 1 diabetes mellitus (T1DM) and relates strongly to insulin resistance (IR). Lean and obese adolescents with T1DM have marked IR. Metformin improves surrogate markers of IR in T1DM, but its effect on directly measured IR and vascular health in youth with T1DM is unclear. We hypothesized that adolescents with T1DM have impaired vascular function and that metformin improves this IR and vascular dysfunction. METHODS Adolescents with T1DM and control participants underwent magnetic resonance imaging of the ascending (AA) and descending aorta to assess pulse wave velocity, relative area change, and maximal (WSSMAX) and time-averaged (WSSTA) wall shear stress. Participants with T1DM also underwent assessment of carotid intima-media thickness by ultrasound, brachial distensibility by DynaPulse, fat and lean mass by dual-energy x-ray absorptiometry, fasting laboratories after overnight glycemic control, and insulin sensitivity by hyperinsulinemic-euglycemic clamp (glucose infusion rate/insulin). Adolescents with T1DM were randomized 1:1 to 3 months of 2000 mg metformin or placebo daily, after which baseline measures were repeated. RESULTS Forty-eight adolescents with T1DM who were 12 to 21 years of age (40% body mass index [BMI] ≥90th percentile; 56% female) and 24 nondiabetic control participants of similar age, BMI, and sex distribution were enrolled. Adolescents with T1DM demonstrated impaired aortic health compared with control participants, including elevated AA and descending aorta pulse wave velocity, reduced AA and descending aorta relative area change, and elevated AA and descending aorta WSSMAX and WSSTA. Adolescents with T1DM in the metformin versus placebo group had improved glucose infusion rate/insulin (12.2±3.2 [mg·kg-1·min-1]/μIU/μL versus -2.4±3.6 [mg·kg-1·min-1]/μIU/μL, P=0.005; 18.6±4.8 [mg·lean kg-1·min-1]/μIU/μL versus -3.4±5.6 [mg·lean kg-1·min-1]/μIU/μL, P=0.005) and reduced weight (-0.5±0.5 kg versus 1.6±0.5 kg; P=0.004), BMI (-0.2±0.15 kg/m2 versus 0.4±0.15 kg/m2; P=0.005), and fat mass (-0.7±0.3 kg versus 0.6±0.4 kg; P=0.01). Glucose infusion rate/insulin also improved in normal-weight participants (11.8±4.4 [mg·kg-1·min-1]/μIU/μL versus -4.5±4.4 [mg·kg-1·min-1]/μIU/μL, P=0.02; 17.6±6.7 [mg·lean kg-1·min-1]/μIU/μL versus -7.0±6.7 [mg·lean kg-1·min-1]/μIU/μL, P=0.02). The metformin group had reduced AA WSSMAX (-0.3±0.4 dyne/cm2 versus 1.5±0.5 dyne/cm2; P=0.03), AA pulse wave velocity (-1.1±1.20 m/s versus 4.1±1.6 m/s; P=0.04), and far-wall diastolic carotid intima-media thickness (-0.04±0.01 mm versus -0.00±0.01 mm; P=0.049) versus placebo. CONCLUSIONS Adolescents with T1DM demonstrate IR and impaired vascular health compared with control participants. Metformin improves IR, regardless of baseline BMI, and BMI, weight, fat mass, insulin dose, and aortic and carotid health in adolescents with T1DM. Metformin may hold promise as a cardioprotective intervention in T1DM. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov . Unique identifier: NCT01808690.
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Affiliation(s)
- Petter Bjornstad
- Division of Pediatric Endocrinology (P.B., M.C.-G., L.P., A.B., Y.G.R., K.J.N.), University of Colorado School of Medicine, Aurora
| | - Michal Schäfer
- Division of Pediatric Cardiology (M.S., U.T.), University of Colorado School of Medicine, Aurora
- Department of Bioengineering, University of Colorado Anschutz Medical Campus, Aurora (M.S.)
| | - Uyen Truong
- Division of Pediatric Cardiology (M.S., U.T.), University of Colorado School of Medicine, Aurora
| | - Melanie Cree-Green
- Division of Pediatric Endocrinology (P.B., M.C.-G., L.P., A.B., Y.G.R., K.J.N.), University of Colorado School of Medicine, Aurora
| | - Laura Pyle
- Division of Pediatric Endocrinology (P.B., M.C.-G., L.P., A.B., Y.G.R., K.J.N.), University of Colorado School of Medicine, Aurora
| | - Amy Baumgartner
- Division of Pediatric Endocrinology (P.B., M.C.-G., L.P., A.B., Y.G.R., K.J.N.), University of Colorado School of Medicine, Aurora
| | - Yesenia Garcia Reyes
- Division of Pediatric Endocrinology (P.B., M.C.-G., L.P., A.B., Y.G.R., K.J.N.), University of Colorado School of Medicine, Aurora
| | | | - Sunil Nayak
- Department of Pediatrics (S.N.), University of Colorado School of Medicine, Aurora
- Pediatric Endocrine Associates, Greenwood Village, CO (S.N.)
| | - R Paul Wadwa
- Barbara Davis Center for Diabetes (R.P.W.), University of Colorado School of Medicine, Aurora
| | - Lorna P Browne
- Division of Radiology (L.B.), University of Colorado School of Medicine, Aurora
| | - Jane E B Reusch
- Division of Endocrinology, Rocky Mountain Regional VAMC, Aurora, CO (J.E.B.R.)
| | - Kristen J Nadeau
- Division of Pediatric Endocrinology (P.B., M.C.-G., L.P., A.B., Y.G.R., K.J.N.), University of Colorado School of Medicine, Aurora
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21
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Leggett C, Giles L, Anderson JJA, Doogue M, Couper J, Pena AS. Adherence to metformin is reduced during school holidays and weekends in children with type 1 diabetes participating in a randomised controlled trial. Arch Dis Child 2019; 104:890-894. [PMID: 31079072 DOI: 10.1136/archdischild-2018-316303] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 03/16/2019] [Accepted: 04/24/2019] [Indexed: 11/04/2022]
Abstract
BACKGROUND Non-adherence to treatment in childhood chronic illness has serious consequences for health and healthcare costs. Accurate detailed objective data on adherence are minimal in this age group. OBJECTIVE To evaluate medication adherence using electronic monitoring systems in children with type 1 diabetes (T1D). DESIGN A cohort study of 90 T1D children (aged 13.6±2.5 years, 41 males) from two paediatric diabetes clinics, participated in a 12-month double-blind, randomised, placebo-controlled trial (1:1 allocation). This cohort provided 28 336 days of study observations; 7138 school holiday and 8875 weekend/public holiday days. METHOD Adherence to intervention (metformin (n=45) or placebo (n=45)) was measured objectively by Medication Event Monitoring Systems (MEMS) including proportion of medication doses taken and daily adherence patterns and by tablet count at 3, 6 and 12 months. The trial was completed in June 2015. RESULTS There was an average (SD) of 363.3 (42) days of MEMS observations available for each study participant (94.1 (12.6) school holiday days and 117.1 (13.4) weekend/public holiday days). Adherence reduced during school holidays (adjusted OR (aOR) 0.81; 95% CI 0.72 to 0.91; p<0.001) and during weekends/public holidays (aOR 0.74; 95% CI 0.69 to 0.80; p<0.001). Adverse effects to the intervention did not affect overall adherence (aOR 0.77; 95% CI 0.3 to 2.01; p=0.6). Age, gender, body mass index, diabetes duration, insulin dose, HbA1c (Haemoglobin A1c) or socioeconomic status did not predict adherence. CONCLUSION Medication adherence was reduced during school holidays and on weekends in children with T1D. Clinical characteristics including socioeconomic status and the presence of adverse effects did not predict adherence. TRIAL REGISTRATION NUMBER ACTRN12611000148976.
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Affiliation(s)
- Catherine Leggett
- SA Pharmacy, Women's and Children's Hospital, North Adelaide, South Australia, Australia
| | - Lynne Giles
- School of Public Health, University of Adelaide, Robinson Institute, Adelaide, South Australia, Australia
| | - Jemma Jay Angela Anderson
- Endocrinology and Diabetes Department, Women's and Children's Hospital, North Adelaide, South Australia, Australia.,Discipline of Paediatrics, University of Adelaide, Robinson Research Institute, Adelaide, South Australia, Australia
| | - Matthew Doogue
- Department of Medicine, University of Otago, Christchurch, New Zealand
| | - Jennifer Couper
- Endocrinology and Diabetes Department, Women's and Children's Hospital, North Adelaide, South Australia, Australia.,Discipline of Paediatrics, University of Adelaide, Robinson Research Institute, Adelaide, South Australia, Australia
| | - Alexia Sophie Pena
- Endocrinology and Diabetes Department, Women's and Children's Hospital, North Adelaide, South Australia, Australia.,Discipline of Paediatrics, University of Adelaide, Robinson Research Institute, Adelaide, South Australia, Australia
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22
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Cree-Green M, Bergman BC, Cengiz E, Fox LA, Hannon TS, Miller K, Nathan B, Pyle L, Kahn D, Tansey M, Tichy E, Tsalikian E, Libman I, Nadeau KJ. Metformin Improves Peripheral Insulin Sensitivity in Youth With Type 1 Diabetes. J Clin Endocrinol Metab 2019; 104:3265-3278. [PMID: 30938764 PMCID: PMC6584133 DOI: 10.1210/jc.2019-00129] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 03/27/2019] [Indexed: 02/08/2023]
Abstract
CONTEXT Type 1 diabetes in adolescence is characterized by insulin deficiency and insulin resistance (IR), both thought to increase cardiovascular disease risk. We previously demonstrated that adolescents with type 1 diabetes have adipose, hepatic, and muscle IR, and that metformin lowers daily insulin dose, suggesting improved IR. However, whether metformin improves IR in muscle, hepatic, or adipose tissues in type 1 diabetes was unknown. OBJECTIVE Measure peripheral, hepatic, and adipose insulin sensitivity before and after metformin or placebo therapy in youth with obesity with type 1 diabetes. DESIGN Double-blind, placebo-controlled clinical trial. SETTING Multi-center at eight sites of the T1D Exchange Clinic Network. PARTICIPANTS A subset of 12- to 19-year-olds with type 1 diabetes (inclusion criteria: body mass index ≥85th percentile, HbA1c 7.5% to 9.9%, insulin dosing ≥0.8 U/kg/d) from a larger trial (NCT02045290) were enrolled. INTERVENTION Participants were randomized to 3 months of metformin (N = 19) or placebo (N = 18) and underwent a three-phase hyperinsulinemic euglycemic clamp with glucose and glycerol isotope tracers to assess tissue-specific IR before and after treatment. MAIN OUTCOME MEASURES Peripheral insulin sensitivity, endogenous glucose release, rate of lipolysis. RESULTS Between-group differences in change in insulin sensitivity favored metformin regarding whole-body IR [change in glucose infusion rate 1.3 (0.1, 2.4) mg/kg/min, P = 0.03] and peripheral IR [change in metabolic clearance rate 0.923 (-0.002, 1.867) dL/kg/min, P = 0.05]. Metformin did not impact insulin suppression of endogenous glucose release (P = 0.12). Adipose IR was not assessable with traditional methods in this highly IR population. CONCLUSIONS Metformin appears to improve whole-body and peripheral IR in youth who are overweight/obese with type 1 diabetes.
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Affiliation(s)
- Melanie Cree-Green
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Center for Women’s Health Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Bryan C Bergman
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Eda Cengiz
- Yale School of Medicine University, New Haven, Connecticut
| | - Larry A Fox
- Nemours Children’s Specialty Care, Jacksonville, Florida
| | - Tamara S Hannon
- Division of Pediatric Endocrinology and Diabetology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
| | - Kellee Miller
- Jaeb Center for Health Research, Tampa, Florida
- Correspondence and Reprint Requests: Kellee Miller, PhD, Jaeb Center for Health Research, 15310 Amberly Drive, Tampa, Florida 33647. E-mail:
| | | | - Laura Pyle
- Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Department of Biostatistics and Informatics, Colorado School of Public Health, University of Anschutz Medical Campus, Aurora, Colorado
| | - Darcy Kahn
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Michael Tansey
- Stead Family Department of Pediatrics, Endocrinology and Diabetes, University of Iowa, Iowa City, Iowa
| | - Eileen Tichy
- Yale School of Medicine University, New Haven, Connecticut
| | - Eva Tsalikian
- Stead Family Department of Pediatrics, Endocrinology and Diabetes, University of Iowa, Iowa City, Iowa
| | - Ingrid Libman
- Children’s Hospital of Pittsburgh at University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Kristen J Nadeau
- Division of Pediatric Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Center for Women’s Health Research, University of Colorado Anschutz Medical Campus, Aurora, Colorado
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, Colorado
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23
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Hafez M, Musa N, Elbehairy S, Atty SA, Elbarbary M, Amin M. Effect of metformin on clinical and biochemical hyperandrogenism in adolescent girls with type 1 diabetes. J Pediatr Endocrinol Metab 2019; 32:461-470. [PMID: 31005950 DOI: 10.1515/jpem-2018-0430] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 03/07/2019] [Indexed: 12/31/2022]
Abstract
Background Hyperandrogenism with or without polycystic ovarian syndrome is seen in adolescents with type 1 diabetes (T1D), especially those with suboptimal control. Objective To assess the effect of metformin on hyperandrogenism and ovarian function in adolescents with T1D. Methods This prospective study included 28 T1D females showing signs of hyperandrogenism. History taking (detailed diabetes history and menstrual history) and anthropometric measurements (weight, height, body mass index [BMI], waist and hip circumference) were initially performed, and then the patients were assessed for the manifestations of hyperandrogenism (acne, hirsutism as well as pelvic ultrasound [U/S] for ovarian morphology). Biochemical evaluation for ovulation (progesterone assessment during the luteal phase), sex steroids (estradiol, testosterone, dehydroepiandrosterone sulfate [DHEAS] and androstenedione), prolactin, glycemic control (hemoglobin A1c [HbA1c]) and gonadotropin levels (follicle stimulating hormone [FSH] and luteinizing hormone [LH]) was done. Patients were subjected to 500 mg metformin twice daily orally for 1 year, and then the patients were re-evaluated for clinical and biochemical parameters. Results Metformin therapy resulted in a significant reduction in weight (p = 0.001), BMI (p = 0.002), acne (p = 0.008), hirsutism score (0.007), LH (p = 0.008), testosterone (p < 0.001) and androstenedione levels (p = 0.028) in adolescent girls with T1D. Regarding menstrual irregularities, there was a significant reduction in the number of patients with oligomenorrhea (68%) with a p value of <0.001. However, there were no significant reduction in the daily insulin requirements (p = 0.782) or HbA1c (p = 0.068). Nausea and/or abdominal pain were the commonly reported side effects of metformin (64%). Conclusions Metformin as an insulin sensitizing agent improved the BMI and cycle regularity together with clinical and biochemical hyperandrogenism in T1D adolescent girls. However, it did not improve their glycemic control.
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Affiliation(s)
- Mona Hafez
- Department of Pediatric Endocrinology, DEMPU, Cairo University, Cairo, Egypt
| | - Noha Musa
- Assistant Professor of Pediatric Endocrinology, Diabetes, Endocrine and Metabolism Pediatric Unit, Pediatric Department, Cairo University,Cairo 12111, Egypt, Phone: +2 01225304041
| | - Shaimaa Elbehairy
- Department of Pediatric Endocrinology, DEMPU, Cairo University, Cairo, Egypt
| | - Sahar Abdel Atty
- Department of Chemical Pathology, DEMPU, Cairo University, Cairo, Egypt
| | - Menna Elbarbary
- Pediatric Ultrasonography Unit, Children Hospital, Cairo University, Cairo, Egypt
| | - Maha Amin
- Department of Pediatric Endocrinology, DEMPU, Cairo University, Cairo, Egypt
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24
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Sabet S, Condren ME, Boston AF, Doak LC, Chalmers LJ. Evolving Pharmacotherapeutic Strategies for Type 1 Diabetes Mellitus. J Pediatr Pharmacol Ther 2018; 23:351-361. [PMID: 30429688 DOI: 10.5863/1551-6776-23.5.351] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Despite pharmacotherapeutic advancements in the management of type 1 diabetes mellitus during the past several decades, patients struggle to achieve glycemic goals. Additionally, hypoglycemia, especially in extremes of age, decreases quality of life. The lack of optimal glycemic control and risk for hypoglycemia are multifactorial. Nevertheless, endeavors aiming to develop pharmacotherapeutic options with enhanced pharmacokinetic, pharmacodynamic, and clinical profiles continue. This review article discusses recent ventures in 3 categories of insulin, non-insulin, and glucagon products.
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25
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Gloaguen E, Bendelac N, Nicolino M, Julier C, Mathieu F. A systematic review of non-genetic predictors and genetic factors of glycated haemoglobin in type 1 diabetes one year after diagnosis. Diabetes Metab Res Rev 2018; 34:e3051. [PMID: 30063815 DOI: 10.1002/dmrr.3051] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 07/20/2018] [Accepted: 07/23/2018] [Indexed: 12/13/2022]
Abstract
Type 1 diabetes (T1D) results from autoimmune destruction of the pancreatic βcells. Although all T1D patients require daily administration of exogenous insulin, their insulin requirement to achieve good glycaemic control may vary significantly. Glycated haemoglobin (HbA1c) level represents a stable indicator of glycaemic control and is a reliable predictor of long-term complications of T1D. The purpose of this article is to systematically review the role of non-genetic predictors and genetic factors of HbA1c level in T1D patients after the first year of T1D, to exclude the honeymoon period. A total of 1974 articles published since January 2011 were identified and 78 were finally included in the analysis of non-genetic predictors. For genetic factors, a total of 277 articles were identified and 14 were included. The most significantly associated factors with HbA1c level are demographic (age, ethnicity, and socioeconomic status), personal (family characteristics, parental care, psychological traits...) and features related to T1D (duration of T1D, adherence to treatment …). Only a few studies have searched for genetic factors influencing HbA1c level, most of which focused on candidate genes using classical genetic statistical methods, with generally limited power and incomplete adjustment for confounding factors and multiple testing. Our review shows the complexity of explaining HbA1c level variations, which involves numerous correlated predictors. Overall, our review underlines the lack of studies investigating jointly genetic and non-genetic factors and their interactions to better understand factors influencing glycaemic control for T1D patients.
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Affiliation(s)
- Emilie Gloaguen
- Inserm UMRS-958, Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
| | | | - Marc Nicolino
- Hôpital Femme-Mère-Enfant, Hospices Civils de Lyon, Bron, France
| | - Cécile Julier
- Inserm UMRS-958, Paris, France
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
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26
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Abstract
PURPOSE OF REVIEW Insulin resistance (IR) is recognized to play an important role in the pathogenesis of dyslipidemia. This review summarizes the complex interplay between IR and dyslipidemia in people with and without diabetes. RECENT FINDINGS IR impacts the metabolism of triglycerides, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and very low-density lipoprotein cholesterol (VLDL-C) by several mechanisms. Trials with insulin sensitizing therapies, including biguanides and thiazolidinediones, have provided inconsistent results on lipid lowering in people with and without diabetes. In this review, we focus on the pathophysiological interplay between IR and dyslipidemia and recapitulate lipid and lipoprotein data from insulin-sensitizing trials. Further research elucidating the reciprocal relationship between IR and dyslipidemia is needed to better target these important risk factors for cardiovascular disease.
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Affiliation(s)
- Petter Bjornstad
- Department of Pediatrics, Division of Endocrinology, University of Colorado School of Medicine, 13123 East 16th Ave, Box B26, Aurora, CO, 80045, USA.
- Department of Medicine, Division of Renal Diseases and Hypertension, University of Colorado School of Medicine, Aurora, CO, USA.
| | - Robert H Eckel
- Department of Medicine, Division of Endocrinology and Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA.
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27
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Cheon CK. Understanding of type 1 diabetes mellitus: what we know and where we go. KOREAN JOURNAL OF PEDIATRICS 2018; 61:307-314. [PMID: 30304895 PMCID: PMC6212709 DOI: 10.3345/kjp.2018.06870] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 09/23/2018] [Accepted: 10/04/2018] [Indexed: 12/12/2022]
Abstract
The incidence of type 1 diabetes mellitus (T1DM) in children and adolescents is increasing worldwide. Combined effects of genetic and environmental factors cause T1DM, which make it difficult to predict whether an individual will inherit the disease. Due to the level of self-care necessary in T1DM maintenance, it is crucial for pediatric settings to support achieving optimal glucose control, especially when adolescents are beginning to take more responsibility for their own health. Innovative insulin delivery systems, such as continuous subcutaneous insulin infusion (CSII), and noninvasive glucose monitoring systems, such as continuous glucose monitoring (CGM), allow patients with T1DM to achieve a normal and flexible lifestyle. However, there are still challenges in achieving optimal glucose control despite advanced technology in T1DM administration. In this article, disease prediction and current management of T1DM are reviewed with special emphasis on biomarkers of pancreatic β-cell stress, CSII, glucose monitoring, and several other adjunctive therapies.
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Affiliation(s)
- Chong Kun Cheon
- Department of Pediatrics, Pusan National University School of Medicine, Yangsan, Korea
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28
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Chiang JL, Maahs DM, Garvey KC, Hood KK, Laffel LM, Weinzimer SA, Wolfsdorf JI, Schatz D. Type 1 Diabetes in Children and Adolescents: A Position Statement by the American Diabetes Association. Diabetes Care 2018; 41:2026-2044. [PMID: 30093549 PMCID: PMC6105320 DOI: 10.2337/dci18-0023] [Citation(s) in RCA: 281] [Impact Index Per Article: 40.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Affiliation(s)
- Jane L Chiang
- McKinsey & Company and Diasome Pharmaceuticals, Inc., Palo Alto, CA
| | - David M Maahs
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Katharine C Garvey
- Division of Endocrinology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Korey K Hood
- Department of Pediatrics, Stanford University School of Medicine, Stanford, CA
| | - Lori M Laffel
- Joslin Diabetes Center, Harvard Medical School, Boston, MA
| | - Stuart A Weinzimer
- Pediatric Endocrinology & Diabetes, Yale School of Medicine, New Haven, CT
| | - Joseph I Wolfsdorf
- Division of Endocrinology, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Desmond Schatz
- Division of Endocrinology, Department of Pediatrics, University of Florida, Gainesville, FL
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29
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Abstract
PURPOSE OF REVIEW Insulin therapy alone fails to achieve target glycemic control in the majority of individuals with type 1 diabetes (T1D), motivating the investigation of additive medications. This review focuses on the recent findings on the use of adjunctive pharmacotherapy in T1D. RECENT FINDINGS Metformin and glucagon-like peptide-1 receptor agonists have been associated with weight reduction and decrease in daily insulin requirements without sustainable improvement in glycemic control. Sodium-glucose cotransporter (SGLT)-2 inhibitors, dual SGLT-1/2 inhibitors, and pramlintide have been shown to reduce hemoglobin A1c, induce weight loss, and lower insulin dose. The benefits of dipeptidyl peptidase-4 inhibitors, thiazolidinediones, and alpha glucosidase inhibitors appear to be more limited. Gastrointestinal symptoms and increased hypoglycemia are adverse effects of certain classes. Although not devoid of side effects, additive pharmacotherapies in T1D can improve glycemic control and lower body weight and insulin requirement. Longer studies are needed before consideration for widespread clinical care.
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Affiliation(s)
- Mustafa Tosur
- Section of Diabetes and Endocrinology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, 6701 Fannin St, Suite 10.20, Houston, TX, 77030, USA.
| | - Maria J Redondo
- Section of Diabetes and Endocrinology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, 6701 Fannin St, Suite 10.20, Houston, TX, 77030, USA
| | - Sarah K Lyons
- Section of Diabetes and Endocrinology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, 6701 Fannin St, Suite 10.20, Houston, TX, 77030, USA
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30
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Meng H, Zhang A, Liang Y, Hao J, Zhang X, Lu J. Effect of metformin on glycaemic control in patients with type 1 diabetes: A meta-analysis of randomized controlled trials. Diabetes Metab Res Rev 2018; 34:e2983. [PMID: 29351716 DOI: 10.1002/dmrr.2983] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Revised: 01/08/2018] [Accepted: 01/09/2018] [Indexed: 11/09/2022]
Abstract
BACKGROUND For type 1 diabetes (T1D) patients, adding metformin to insulin therapies is thought to improve blood glucose levels, but current evidence does not support this clinical benefit. Additional data from large clinical trials are now available; therefore, we conducted a meta-analysis of studies on assessing the efficacy and adverse effects of metformin. METHODS We searched the MEDLINE, EMBASE, and Cochrane Library databases for data from randomized controlled trials. We performed statistical analyses by using Review Manager 5.2. RESULTS Thirteen randomized controlled trials that compared metformin versus placebo met our inclusion criteria and were included in the study. The final meta-analysis included a total of 1183 participants with T1D. Metformin was associated with reductions in BMI (-1.14, 95% CI -2.05 to -0.24, P = .01), insulin requirements (-0.47, 95% CI -0.70 to -0.23, P = .0001), total cholesterol (-0.23, 95% CI -0.34 to -0.12, P < .0001), and low-density lipoprotein cholesterol (-0.20, 95% CI -0.29 to -0.11, P < .0001) in T1D patients. No clear evidence indicated that metformin improved HbA1c, triglyceride, or high-density lipoprotein cholesterol levels. A safety analysis showed that metformin slightly increased the risk of severe hypoglycaemia (1.23, 95% CI 1.00 to 1.52, P = .05) and mainly gastrointestinal adverse events (2.67, 95% CI 2.06 to 3.45, P < .00001). No evidence showed that metformin increased diabetic ketoacidosis events. CONCLUSIONS Compared with placebo, metformin was not associated with glycaemic control in T1D patients. Although it exhibited other benefits, such as lower BMI and reduced insulin requirements, total cholesterol, and low-density lipoprotein cholesterol, negative outcomes, such as gastrointestinal adverse effects and severe hypoglycaemia, should also be considered in the use of metformin for T1D patients.
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Affiliation(s)
- Haiyang Meng
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Ailing Zhang
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Yan Liang
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Jie Hao
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Xiaojian Zhang
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
| | - Jingli Lu
- Department of Pharmacy, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Henan Key Laboratory of Precision Clinical Pharmacy, Zhengzhou University, Zhengzhou, China
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Naciu AM, Pozzilli P. Novel blood glucose lowering therapies for managing type 1 diabetes in paediatric patients. Expert Opin Pharmacother 2018; 19:355-364. [PMID: 29460641 DOI: 10.1080/14656566.2018.1441288] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Therapy for type 1 diabetes (T1D) is mainly restricted to insulin treatment. The management of paediatric patients with T1D should tackle not only glucose control, but also insulin resistance, beta-cell preservation, quality of life and cardiovascular disease risk factors, which are increasingly recognized to occur in adolescents with T1D. AREAS COVERED This review examines the recently published literature from PubMed on non-insulin agents for the management of T1D in paediatric patients. EXPERT OPINION Few paediatric patients with T1D are achieving their metabolic targets. Current data support the need for new strategies and the consideration of additional therapies that not only may help patients, their families and their physicians to meet HbA1c targets, but also may preserve residual islet mass and good quality of life and prevent microvascular and macrovascular complications, thereby, reducing hypoglycaemic episodes. Non-insulin adjunctive therapies may improve not only glucose control, but also insulin sensitivity, in addition to preserving beta-cell function in T1D patients. Thus, more studies are required to define the potential role of these therapies in the management of paediatric patients.
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Affiliation(s)
- Anda Mihaela Naciu
- a Unit of Endocrinology and Diabetes, Department of Medicine , University Campus Bio-Medico , Rome , Italy
| | - Paolo Pozzilli
- a Unit of Endocrinology and Diabetes, Department of Medicine , University Campus Bio-Medico , Rome , Italy.,b Centre of Immunobiology, St Bartholomew's and the London School of Medicine , Queen Mary, University of London , London , UK
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32
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Priya G, Kalra S. A Review of Insulin Resistance in Type 1 Diabetes: Is There a Place for Adjunctive Metformin? Diabetes Ther 2018; 9:349-361. [PMID: 29139080 PMCID: PMC5801219 DOI: 10.1007/s13300-017-0333-9] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Indexed: 12/18/2022] Open
Abstract
There is a rising trend of overweight and obesity among individuals with type 1 diabetes. This is often associated with insulin resistance, increased insulin dose requirements and poor glycemic control. Insulin resistance is also seen during puberty and is strongly related to increased risk of cardiovascular disease. The role of metformin as an adjunct to ongoing intensive insulin therapy in type 1 diabetics has been evaluated in several randomized trials, including the recently concluded T1D Exchange Network trial in adolescents and the REMOVAL trial in adults. Metformin reduces the insulin dose requirement, insulin-induced weight gain, and total and LDL cholesterol, but results in an increased risk of gastrointestinal adverse effects and a minor increase in the risk of hypoglycemia. In addition, metformin has been shown to reduce maximal carotid intima media thickness and therefore may extend cardioprotective benefits in type 1 diabetes. The role of metformin as adjunctive therapy in type 1 diabetes needs to be explored further in outcome trials.
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33
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Harris K, Boland C, Meade L, Battise D. Adjunctive therapy for glucose control in patients with type 1 diabetes. Diabetes Metab Syndr Obes 2018; 11:159-173. [PMID: 29731652 PMCID: PMC5927142 DOI: 10.2147/dmso.s141700] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) is characterized by relative or absolute insulin deficiency. Despite treatment with insulin therapy, glycemic goals are not always met, and insulin therapy is sometimes limited by adverse effects, including hypoglycemia and weight gain. Several adjunctive therapies have been evaluated in combination with insulin in patients with T1DM to improve glycemic control while minimizing adverse effects. Pramlintide, an amylin analog, can improve glycemic control, primarily through lowering postprandial blood glucose levels. Patients may experience weight loss and an increased risk of hypoglycemia and require additional mealtime injections. Metformin provides an inexpensive, oral treatment option and may reduce blood glucose, especially in overweight or obese patients with minimal risk of hypoglycemia. Metformin may be more effective in patients with impaired insulin sensitivity. Glucagon-like peptide-1 receptor agonists reduce primarily postprandial blood glucose and insulin dose and promote weight loss. They are expensive, cause transient nausea, may increase risk of hypoglycemia and require additional injections. Sodium-glucose transport-2 inhibitors improve glycemic control, promote weight loss and have low risk of hypoglycemia with appropriate insulin adjustment; however, these agents may increase the risk of diabetic ketoacidosis in patients with T1DM. Patient-specific characteristics should be considered when selecting adjunctive therapy for patients with T1DM. Close monitoring, insulin dose adjustments and patient education are all important to ensure safe and effective use of these agents.
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Affiliation(s)
- Kira Harris
- Pharmacy Practice Faculty, Wingate University School of Pharmacy, Wingate, NC, USA
- Clinical Pharmacy Specialist – Novant Health Family Medicine Residency Program, Cornelius, NC, USA
- Correspondence: Kira Harris, Wingate University School of Pharmacy, 515 North Main St, Wingate, NC 28174, USA, Tel +1 704 233 8965, Fax +1 704 233 8332, Email
| | - Cassie Boland
- Pharmacy Practice Faculty, Wingate University School of Pharmacy, Wingate, NC, USA
- Clinical Pharmacy Specialist – Novant Health Cotswold Family Medicine – Arboretum, Charlotte, NC, USA
| | - Lisa Meade
- Pharmacy Practice Faculty, Wingate University School of Pharmacy, Wingate, NC, USA
- Clinical Pharmacy Specialist – Piedmont HealthCare Endocrinology, Statesville, NC, USA
| | - Dawn Battise
- Pharmacy Practice Faculty, Wingate University School of Pharmacy, Wingate, NC, USA
- Clinical Pharmacy Specialist – Cabarrus Family Medicine – Harrisburg, Harrisburg, NC, USA
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34
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Anderson JJA, Couper JJ, Giles LC, Leggett CE, Gent R, Coppin B, Peña AS. Effect of Metformin on Vascular Function in Children With Type 1 Diabetes: A 12-Month Randomized Controlled Trial. J Clin Endocrinol Metab 2017; 102:4448-4456. [PMID: 29040598 DOI: 10.1210/jc.2017-00781] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2017] [Accepted: 10/03/2017] [Indexed: 11/19/2022]
Abstract
CONTEXT Children with type 1 diabetes have vascular dysfunction preceding atherosclerosis. Early interventions are needed to reduce cardiovascular disease. OBJECTIVE To evaluate the effect of metformin on vascular function in children with type 1 diabetes. DESIGN Twelve-month double-blind, randomized, placebo-controlled trial. SETTING Tertiary pediatric diabetes clinic. PARTICIPANTS Ninety children (8 to 18 years of age), >50th percentile body mass index (BMI), with type 1 diabetes. INTERVENTION Metformin (up to 1 g twice a day) or placebo. MAIN OUTCOME MEASURE Vascular function measured by brachial artery ultrasound [flow-mediated dilatation/glyceryl trinitrate-mediated dilatation (GTN)]. RESULTS Ninety participants were enrolled [41 boys, 13.6 (2.5) years of age, 45 per group], 10 discontinued intervention, and 1 was lost to follow-up. On metformin, GTN improved, independent of glycosylated hemoglobin (HbA1c), by 3.3 percentage units [95% confidence interval (CI) 0.3, 6.3, P = 0.03] and insulin dose reduced by 0.2 U/kg/d (95% CI 0.1, 0.3, P = 0.001) during 12 months, with effects from 3 months. Metformin had a beneficial effect on HbA1c at 3 months (P = 0.001) and difference in adjusted HbA1c between groups during 12 months was 1.0%; 95% CI 0.4, 1.5 (10.9 mmol/mol; 95% CI 4.4, 16.4), P = 0.001. There were no effects on carotid/aortic intima media thickness, BMI, lipids, blood pressure, or other cardiovascular risk factors. Median (95% CI) adherence, evaluated by electronic monitoring, was 75.5% (65.7, 81.5), without group differences. More gastrointestinal side effects were reported on metformin (incidence rate ratio 1.65, 95% CI 1.08, 2.52, P = 0.02), with no difference in hypoglycemia or diabetic ketoacidosis. CONCLUSIONS Metformin improved vascular smooth muscle function and HbA1c, and lowered insulin dose in type 1 diabetes children. These benefits and good safety profile warrant further consideration of its use.
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Affiliation(s)
- Jemma J A Anderson
- Discipline of Paediatrics, Robinson Research Institute, University of Adelaide, Australia
- Endocrinology and Diabetes Department, Women's and Children's Hospital, Australia
| | - Jennifer J Couper
- Discipline of Paediatrics, Robinson Research Institute, University of Adelaide, Australia
- Endocrinology and Diabetes Department, Women's and Children's Hospital, Australia
| | - Lynne C Giles
- School of Public Health, Faculty of Health and Medical Sciences, University of Adelaide, Australia
| | - Catherine E Leggett
- Discipline of Paediatrics, Robinson Research Institute, University of Adelaide, Australia
- Pharmacy, Women's and Children's Hospital, Australia
| | - Roger Gent
- Medical Imaging, Women's and Children's Hospital, Australia
| | - Brian Coppin
- Flinders Medical Centre, Bedford Park, Australia
| | - Alexia S Peña
- Discipline of Paediatrics, Robinson Research Institute, University of Adelaide, Australia
- Endocrinology and Diabetes Department, Women's and Children's Hospital, Australia
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Barrella N, Eisenberg B, Simpson SN. Hypoglycemia and severe lactic acidosis in a dog following metformin exposure. Clin Case Rep 2017; 5:2097-2104. [PMID: 29225865 PMCID: PMC5715605 DOI: 10.1002/ccr3.1255] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2017] [Revised: 09/01/2017] [Accepted: 10/06/2017] [Indexed: 01/18/2023] Open
Abstract
Hypoglycemia and lactic acidosis are rare complications with metformin use in humans. As metformin is not commonly used in veterinary medicine, severe adverse effects secondary to exposure are not known. Awareness of potentially life-threatening complications with metformin exposure is an important addition to the veterinary literature.
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Affiliation(s)
- Nicole Barrella
- Massachusetts Veterinary Referral HospitalWoburnMassachusetts01801USA
- Present address:
Bulger Veterinary HospitalNorth AndoverMassachusetts01845USA
| | - Beth Eisenberg
- Massachusetts Veterinary Referral HospitalWoburnMassachusetts01801USA
| | - Stephanie Nicole Simpson
- Massachusetts Veterinary Referral HospitalWoburnMassachusetts01801USA
- Present address:
VCA Roberts Animal HospitalHanoverMassachusetts02339USA
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36
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Gourgari E, Dabelea D, Rother K. Modifiable Risk Factors for Cardiovascular Disease in Children with Type 1 Diabetes: Can Early Intervention Prevent Future Cardiovascular Events? Curr Diab Rep 2017; 17:134. [PMID: 29101482 PMCID: PMC5670186 DOI: 10.1007/s11892-017-0968-y] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
PURPOSE OF REVIEW Patients with type 1 diabetes have increased risk for cardiovascular disease. The purpose of this review is to examine the following: i) current evidence for subclinical cardiovascular disease (CVD) in children with type 1 diabetes (T1DM) ii) known modifiable risk factors for CVD and their relationship to subclinical CVD in this population iii) studies that have addressed these risk factors in order to improve CVD outcomes in children with T1DM RECENT FINDINGS: Subclinical CVD presents in children as increased carotid intima-media thickness, increased arterial stiffness, and endothelial and myocardial dysfunction. Modifiable risk factors for CVD include hyperglycemia, hyperlipidemia, obesity, hypertension, depression, and autonomic dysfunction. Very few randomized controlled studies have been done in children with T1DM to examine how modification of these risk factors can affect their CVD. Children with T1DM have subclinical CVD and multiple modifiable risk factors for CVD. More research is needed to define how modification of these factors affects the progression of CVD.
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Affiliation(s)
- Evgenia Gourgari
- Department of Pediatrics, Georgetown University, Washington DC, USA
- Section on Endocrinology and Genetics, Program on Developmental Endocrinology & Genetics (PDEGEN) and Pediatric Endocrinology Inter-Institute Training Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), Bethesda, MD USA
| | - Dana Dabelea
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Denver, Aurora, CO USA
| | - Kristina Rother
- Section on Pediatric Diabetes and Metabolism, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD USA
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37
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Al Khalifah RA, Alnhdi A, Alghar H, Alanazi M, Florez ID. The effect of adding metformin to insulin therapy for type 1 diabetes mellitus children: A systematic review and meta-analysis. Pediatr Diabetes 2017; 18:664-673. [PMID: 28145083 DOI: 10.1111/pedi.12493] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 11/29/2016] [Accepted: 11/29/2016] [Indexed: 12/12/2022] Open
Abstract
We aimed to assess the effectiveness of adding metformin to insulin in type 1 diabetes mellitus (T1DM) children for improving metabolic outcomes. We performed a systematic review and meta-analysis of randomized controlled trials (RCTs) conducted on children age 6 to 19 years who are diagnosed with T1DM, and examined the effect of adding Metformin to standard insulin therapy. We performed literature searches on Ovid Midline, Ovid Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) from the date of inception of the database to February 15, 2016. Two reviewers screened titles and abstracts independently, assessed full text eligibility, and extracted information from eligible trials. The primary outcome is glycated hemoglobin (HbA1c), and the secondary outcomes are health-related quality of life, body mass index (BMI), lipid profile, total insulin daily dose, hypoglycaemia, and diabetes ketoacidosis. We screened 736 studies, and included 6 RCTs with 325 patients. All RCTs were of low risk of bias, and included adolescents (mean age 15 years). The meta-analysis showed that the addition of Metformin resulted in decreased total insulin daily dose (TIDD) (unit/kg/d) (mean difference [MD] = -0.15, 95%CI, -0.24, -0.06), and reduced BMI kg/m2 (MD -1.46, 95%CI -2.54, 0.38), and BMI z-score (MD= - 0.11, 95%CI -0.21, -0.01), and similar HbA1c (%) (MD= - 0.05, 95%CI, -0.19, 0.29). The overall evidence quality was high to moderate. Current evidence does not support use of Metformin in T1DM adolescents to improve HbA1c. However, Metformin may provide modest reduction in TIDD and BMI.
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Affiliation(s)
- Reem A Al Khalifah
- Department of Pediatrics, Division of Pediatric Endocrinology, King Saud University, Riyadh, Saudi Arabia
| | | | - Hassan Alghar
- Department of Pediatrics, King Saud University, Riyadh, Saudi Arabia
| | - Mohammad Alanazi
- Department of Pediatrics, King Saud University, Riyadh, Saudi Arabia
| | - Ivan D Florez
- Department of Pediatrics, Universidad de Antioquia, Medellin, Colombia.,Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Canada
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38
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Livingstone R, Boyle JG, Petrie JR. A new perspective on metformin therapy in type 1 diabetes. Diabetologia 2017; 60:1594-1600. [PMID: 28770327 PMCID: PMC5552844 DOI: 10.1007/s00125-017-4364-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2017] [Accepted: 06/27/2017] [Indexed: 12/14/2022]
Abstract
Metformin is quite frequently used off-label in type 1 diabetes to limit insulin dose requirement. Guidelines recommend that it can improve glucose control in those who are overweight and obese but evidence in support of this is limited. Recently-published findings from the REducing with MetfOrmin Vascular Adverse Lesions (REMOVAL) trial suggest that metformin therapy in type 1 diabetes can reduce atherosclerosis progression, weight and LDL-cholesterol levels. This provides a new perspective on metformin therapy in type 1 diabetes and suggests a potential role for reducing the long-term risk of cardiovascular disease.
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Affiliation(s)
- Rachel Livingstone
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK
| | - James G Boyle
- Glasgow Royal Infirmary, Glasgow, UK
- School of Medicine, University of Glasgow, Glasgow, UK
| | - John R Petrie
- Institute of Cardiovascular and Medical Sciences, BHF Glasgow Cardiovascular Research Centre, University of Glasgow, 126 University Place, Glasgow, G12 8TA, UK.
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Ziaee A, Esmailzadehha N, Honardoost M. Comparison of adjunctive therapy with metformin and acarbose in patients with Type-1 diabetes mellitus. Pak J Med Sci 2017; 33:686-690. [PMID: 28811795 PMCID: PMC5510127 DOI: 10.12669/pjms.333.12669] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Objective: All the aforementioned data have stimulated interest in studying other potential therapies for T1DM including noninsulin pharmacological therapies. The present study attempts to investigate the effect of adjunctive therapy with metformin and acarbose in patients with Type-1 diabetes mellitus. Method: In a single-center, placebo-controlled study (IRCT201102165844N1) we compared the results of two clinical trials conducted in two different time periods on 40 patients with Type-1 diabetes mellitus. In the first section, metformin was given to the subjects. After six months, metformin was replaced with acarbose in the therapeutic regimen. In both studies, subjects were checked for their BMI, FBS, HbA1C, TGs, Cholesterol, LDL, HDL, 2hpp, unit of NPH and regular insulin variations. Results: Placebo-controlled evaluation of selected factors has showna significant decrease in FBS and TG levels in the metformin group during follow up but acarbose group has shown substantial influence on two hour post prandial (2hpp) and regular insulin intake decline. Moreover, Comparison differences after intervention between two test groups has shown that metformin has had superior impact on FBS and HbA1C decline in patients. Nonetheless, acarbose treatment had noteworthy influence on 2hpp, TGs, Cholesterol, LDL, and regular insulin intake control. Conclusion: The results of this experiment demonstrate that the addition of acarbose or metformin to patients with Type-1 diabetes mellitus who are controlled with insulin is commonly well tolerated and help to improve metabolic control in patients.
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Affiliation(s)
- Amir Ziaee
- Amir Ziaee, Professor of Endocrinology, Padiatric Growth and Development Research Center, Institute of Endocrinology and Metabolism, ran University of Medical Sciences, Tehran, Iran
| | - Neda Esmailzadehha
- Neda Esmailzadehha, General Practitioners, Metabolic Diseases Research Center, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Maryam Honardoost
- Maryam Honardoost, Assistant Professor of Molecular Medicine, Endocrine Research Center, Institute of Endocrinology and Metabolism, ran University of Medical Sciences, Tehran, Iran
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40
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Setoodeh A, Didban A, Rabbani A, Sayarifard A, Abbasi F, Sayarifard F, Hoseinzade F. The Effect of Metformin as an Adjunct Therapy in Adolescents with Type 1 Diabetes. J Clin Diagn Res 2017; 11:SC01-SC04. [PMID: 28571222 DOI: 10.7860/jcdr/2017/24901.9725] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2016] [Accepted: 02/14/2017] [Indexed: 11/24/2022]
Abstract
INTRODUCTION The strict control of blood glucose levels in adolescents with Type 1 Diabetes Mellitus (T1DM) is accompanied with a considerable long term decrease in microvasular and macrovascular complications. AIM This study was conducted to investigate the effect of metformin as an adjunct therapy in adolescents with poorly controlled Type 1 diabetes. MATERIALS AND METHODS It was a quasi-experimental (an uncontrolled before and after) study. The study population consisted of the patients aged over 10 years with T1DM. Metformin tablet was added to patient's insulin therapy for 12 months. Haemoglobin A1c protein was measured in the beginning of the study and repeated with three months intervals till the end of it. Insulin dosage, Body Mass Index (BMI), serum lipid, creatinine and lactate level were measured twice; in the beginning of the study and at the end of it (after 12 months). Data was analysed by SPSS (version 18) software. Paired- t-test, Wilcoxon signed ranks test and Repeated Measure ANOVA were used to examine the study's hypothesis. A p-value <0.05 was considered as significant. RESULTS Twenty nine patients were included in the study. HbA1c level and insulin dosage was significantly reduced (p<0.001) after one month of metformin as an adjunct therapy. Serum lipid was decreased (p=0.7). Weight (p<0.001) and BMI (p=0.007) were increased. CONCLUSION Adjunctive metformin therapy reduced HbA1c value and the insulin dosage received in adolescents with T1DM.
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Affiliation(s)
- Aria Setoodeh
- Associate Professor, Department of Paediatrics, Endocrinologist, Growth and Development Research Center, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Abdollah Didban
- Assistant Professor, Department of Paediatrics, Endocrinologist, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Ali Rabbani
- Professor, Department of Paediatrics, Endocrinologist, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Azadeh Sayarifard
- Assistant Professor, Department of Paediatrics, Preventive and Community Medicine Specialist, Growth and Development Research Center, Children's Medical Center, Center for Academic and Health Policy, Tehran University of Medical Sciences, Tehran, Iran
| | - Farzaneh Abbasi
- Assistant Professor, Department of Paediatrics, Endocrinologist, Growth and Developmental Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Sayarifard
- Assistant Professor, Department of Paediatrics, Endocrinologist, Growth and Developmental Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Hoseinzade
- PhD Candidate of Nutrition, Department of Clinical Nutrition, Nutrition and Food Sciences Research Center, School of Nutrition and Food Sciences, Shiraz University of Medical Sciences, Shiraz, Fars, Iran
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41
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Thomas I, Gregg B. Metformin; a review of its history and future: from lilac to longevity. Pediatr Diabetes 2017; 18:10-16. [PMID: 28052534 DOI: 10.1111/pedi.12473] [Citation(s) in RCA: 105] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 10/16/2016] [Accepted: 10/20/2016] [Indexed: 12/25/2022] Open
Abstract
Metformin is a widely prescribed medication that has been used to treat children with type 2 diabetes in the United States for the past 15 years. Metformin now has a variety of clinical applications in pediatrics, and its potential clinical uses continue to expand. In addition to reviewing the current understanding of its mechanisms of action including the newly discovered effects on the gastrointestinal tract, we will also discuss current clinical uses in pediatrics, including in type 1 diabetes. Finally, we examine the existing state of monitoring for metformin efficacy and side effects and discuss prospective future clinical uses.
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Affiliation(s)
- Inas Thomas
- Division of Pediatric Endocrinology, Diabetes and Metabolism, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan
| | - Brigid Gregg
- Division of Pediatric Endocrinology, Diabetes and Metabolism, Department of Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, Michigan
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42
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Bacha F, Klinepeter Bartz S. Insulin resistance, role of metformin and other non-insulin therapies in pediatric type 1 diabetes. Pediatr Diabetes 2016; 17:545-558. [PMID: 26592507 DOI: 10.1111/pedi.12337] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2015] [Revised: 09/17/2015] [Accepted: 10/12/2015] [Indexed: 12/28/2022] Open
Abstract
Type 1 diabetes mellitus (T1DM) in youth is a challenging chronic medical condition. Its management should address not only the glycemic control but also insulin resistance and cardiovascular disease risk factors which are increasingly recognized to be present in youth with TID. Current knowledge on the mechanisms of insulin resistance in T1DM is reviewed. The use of adjunctive therapies that are beneficial to achieve adequate glycemic control while mitigating the effects of insulin resistance are discussed with a focus on metformin therapy and an overview of other new pharmacologic agents.
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Affiliation(s)
- Fida Bacha
- Children's Nutrition Research Center, Texas Children's Hospital, Baylor College of Medicine Houston, Houston, TX, USA. .,Division of Pediatric Endocrinology and Diabetes, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
| | - Sara Klinepeter Bartz
- Children's Nutrition Research Center, Texas Children's Hospital, Baylor College of Medicine Houston, Houston, TX, USA.,Division of Pediatric Endocrinology and Diabetes, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA
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43
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Axon E, Atkinson G, Richter B, Metzendorf M, Baur L, Finer N, Corpeleijn E, O'Malley C, Ells LJ, Cochrane Metabolic and Endocrine Disorders Group. Drug interventions for the treatment of obesity in children and adolescents. Cochrane Database Syst Rev 2016; 11:CD012436. [PMID: 27899001 PMCID: PMC6472619 DOI: 10.1002/14651858.cd012436] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Child and adolescent obesity has increased globally, and can be associated with significant short- and long-term health consequences. OBJECTIVES To assess the efficacy of drug interventions for the treatment of obesity in children and adolescents. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, PubMed (subsets not available on Ovid), LILACS as well as the trial registers ICTRP (WHO) and ClinicalTrials.gov. Searches were undertaken from inception to March 2016. We checked references and applied no language restrictions. SELECTION CRITERIA We selected randomised controlled trials (RCTs) of pharmacological interventions for treating obesity (licensed and unlicensed for this indication) in children and adolescents (mean age under 18 years) with or without support of family members, with a minimum of three months' pharmacological intervention and six months' follow-up from baseline. We excluded interventions that specifically dealt with the treatment of eating disorders or type 2 diabetes, or included participants with a secondary or syndromic cause of obesity. In addition, we excluded trials which included growth hormone therapies and pregnant participants. DATA COLLECTION AND ANALYSIS Two review authors independently assessed trial quality and extracted data following standard Cochrane methodology. Where necessary we contacted authors for additional information. MAIN RESULTS We included 21 trials and identified eight ongoing trials. The included trials evaluated metformin (11 trials), sibutramine (six trials), orlistat (four trials), and one trial arm investigated the combination of metformin and fluoxetine. The ongoing trials evaluated metformin (four trials), topiramate (two trials) and exenatide (two trials). A total of 2484 people participated in the included trials, 1478 participants were randomised to drug intervention and 904 to comparator groups (91 participants took part in two cross-over trials; 11 participants not specified). Eighteen trials used a placebo in the comparator group. Two trials had a cross-over design while the remaining 19 trials were parallel RCTs. The length of the intervention period ranged from 12 weeks to 48 weeks, and the length of follow-up from baseline ranged from six months to 100 weeks.Trials generally had a low risk of bias for random sequence generation, allocation concealment and blinding (participants, personnel and assessors) for subjective and objective outcomes. We judged approximately half of the trials as having a high risk of bias in one or more domain such as selective reporting.The primary outcomes of this review were change in body mass index (BMI), change in weight and adverse events. All 21 trials measured these outcomes. The secondary outcomes were health-related quality of life (only one trial reported results showing no marked differences; very low certainty evidence), body fat distribution (measured in 18 trials), behaviour change (measured in six trials), participants' views of the intervention (not reported), morbidity associated with the intervention (measured in one orlistat trial only reporting more new gallstones following the intervention; very low certainty evidence), all-cause mortality (one suicide in the orlistat intervention group; low certainty evidence) and socioeconomic effects (not reported).Intervention versus comparator for mean difference (MD) in BMI change was -1.3 kg/m2 (95% confidence interval (CI) -1.9 to -0.8; P < 0.00001; 16 trials; 1884 participants; low certainty evidence). When split by drug type, sibutramine, metformin and orlistat all showed reductions in BMI in favour of the intervention.Intervention versus comparator for change in weight showed a MD of -3.9 kg (95% CI -5.9 to -1.9; P < 0.00001; 11 trials; 1180 participants; low certainty evidence). As with BMI, when the trials were split by drug type, sibutramine, metformin and orlistat all showed reductions in weight in favour of the intervention.Five trials reported serious adverse events: 24/878 (2.7%) participants in the intervention groups versus 8/469 (1.7%) participants in the comparator groups (risk ratio (RR) 1.43, 95% CI 0.63 to 3.25; 1347 participants; low certainty evidence). A total 52/1043 (5.0%) participants in the intervention groups versus 17/621 (2.7%) in the comparator groups discontinued the trial because of adverse events (RR 1.45, 95% CI 0.83 to 2.52; 10 trials; 1664 participants; low certainty evidence). The most common adverse events in orlistat and metformin trials were gastrointestinal (such as diarrhoea, mild abdominal pain or discomfort, fatty stools). The most frequent adverse events in sibutramine trials included tachycardia, constipation and hypertension. The single fluoxetine trial reported dry mouth and loose stools. No trial investigated drug treatment for overweight children. AUTHORS' CONCLUSIONS This systematic review is part of a series of associated Cochrane reviews on interventions for obese children and adolescents and has shown that pharmacological interventions (metformin, sibutramine, orlistat and fluoxetine) may have small effects in reduction in BMI and bodyweight in obese children and adolescents. However, many of these drugs are not licensed for the treatment of obesity in children and adolescents, or have been withdrawn. Trials were generally of low quality with many having a short or no post-intervention follow-up period and high dropout rates (overall dropout of 25%). Future research should focus on conducting trials with sufficient power and long-term follow-up, to ensure the long-term effects of any pharmacological intervention are comprehensively assessed. Adverse events should be reported in a more standardised manner specifying amongst other things the number of participants experiencing at least one adverse event. The requirement of regulatory authorities (US Food and Drug Administration and European Medicines Agency) for trials of all new medications to be used in children and adolescents should drive an increase in the number of high quality trials.
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Affiliation(s)
- Emma Axon
- University of NottinghamCochrane Skin GroupNottinghamUKNG7 2NR
| | - Greg Atkinson
- Teesside UniversityHealth and Social Care InstituteMiddlesbroughUKTS1 3BA
| | - Bernd Richter
- Institute of General Practice, Medical Faculty of the Heinrich‐Heine‐University DüsseldorfCochrane Metabolic and Endocrine Disorders GroupPO Box 101007DüsseldorfGermany40001
| | - Maria‐Inti Metzendorf
- Institute of General Practice, Medical Faculty of the Heinrich‐Heine‐University DüsseldorfCochrane Metabolic and Endocrine Disorders GroupPO Box 101007DüsseldorfGermany40001
| | - Louise Baur
- The University of SydneyDepartment of Paediatrics and Child HealthLocked Bag 4001WestmeadAustraliaNSW 2145
| | - Nicholas Finer
- UCL Institute of Cardiovascular ScienceNational Centre for Cardiovascular Prevention and Outcomes170 Tottenham Court RoadLondonUKW1T 7HA
- Novo Nordisk A/SGlobal Medical Affairs ManagementCopenhagenDenmark
| | - Eva Corpeleijn
- University Medical Centre GroningenDepartment of EpidemiologyHanzeplein 1GroningenNetherlands9713 GZ
| | - Claire O'Malley
- Durham UniversityDepartment of Sport and Exercise SciencesDurhamUKDH1 3HN
| | - Louisa J Ells
- Teesside UniversitySchool of Health and Social CareParkside West OfficesMiddlesbroughUKTS1 3BA
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Liu W, Yang XJ. The Effect of Metformin on Adolescents with Type 1 Diabetes: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Int J Endocrinol 2016; 2016:3854071. [PMID: 27478438 PMCID: PMC4960345 DOI: 10.1155/2016/3854071] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 05/21/2016] [Accepted: 06/05/2016] [Indexed: 02/08/2023] Open
Abstract
Background. The effect of metformin in combination with insulin in adolescents with type 1 diabetes (T1DM) is controversial. Methods and Results. The PubMed and EMBASE online databases were searched. Five double-blind randomized controlled trials (RCTs) that included 301 adolescents with T1DM were identified. Metformin plus insulin was associated with reduced hemoglobin A1C levels, total daily insulin dosage, body mass index (BMI), and body weight. However, the subgroup analysis demonstrated that HbA1c levels were not significantly changed in overweight/obese adolescents and were significantly reduced in the general patients. On the contrary, BMI and body weight were significantly reduced in overweight/obese adolescents but not in the general patients. Metformin was associated with higher incidence of adverse events. Conclusions. Among adolescents with T1DM, administering adjunctive metformin therapy in addition to insulin was associated with improved HbA1c levels, total daily insulin dosage, BMI, and body weight. However, there may be differences in the effects of this regimen between overweight/obese and nonobese adolescents. The risk of an adverse event may be increased with metformin treatment. These results provide strong evidence supporting future high-quality, large-sample trials.
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Affiliation(s)
- Wei Liu
- Department of Cardiology, Guizhou Provincial People's Hospital, Guizhou 550002, China
| | - Xiao-Jie Yang
- Department of Endocrinology, Guizhou Provincial People's Hospital, Guizhou 550002, China
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45
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Cree-Green M, Maahs DM, Ferland A, Hokanson JE, Wang H, Pyle L, Kinney GL, King M, Eckel RH, Nadeau KJ. Lipoprotein subfraction cholesterol distribution is more atherogenic in insulin resistant adolescents with type 1 diabetes. Pediatr Diabetes 2016; 17:257-65. [PMID: 26080650 PMCID: PMC4887262 DOI: 10.1111/pedi.12277] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2014] [Revised: 03/15/2015] [Accepted: 03/16/2015] [Indexed: 02/06/2023] Open
Abstract
AIMS/HYPOTHESIS Adolescents with type 1 diabetes (T1D) often have a less atherogenic-appearing fasting lipid profile than controls, despite increased rates of cardiovascular disease (CVD) as adults. We previously reported an atherogenic lipoprotein subfraction cholesterol distribution associated with insulin resistance (IR) in T1D adults. We sought to determine if T1D youth have more atherogenic profile than controls via a cross-sectional study. METHODS Following 3 days of controlled diet and restricted exercise, fasting plasma samples were drawn from 28 T1D youth [50% female, age 15.3 ± 2 yr, body mass index (BMI) 48%ile; diabetes duration 73 ± 52 months, hemoglobin A1c (HbA1c) 8.3 ± 1.4%] and 17 non-diabetic controls (47% female, age: 15.0 ± 2 yr, BMI 49%ile) prior to a hyperinsulinemic euglycemic clamp. Lipoproteins were fractionated by fast protein liquid chromatography (FPLC) and lipoprotein cholesterol distribution determined. Outcome measures were IR assessed by glucose infusion rate (GIR) and FPLC lipoprotein subfraction cholesterol distribution. RESULTS T1D youth were more IR (GIR 9.1 ± 3.6 vs. 14.7 ± 3.9 mg/kg/min, p < 0.0001) and had more cholesterol distributed as small dense low density lipoprotein-cholesterol (LDL-C) and less as large buoyant high density lipoprotein-cholesterol (HDL-C) than controls (p < 0.05), despite no differences in the fasting lipid panel. T1D girls lacked the typical female less-atherogenic profile, whereas control girls tended to have a shift toward less dense LDL-C and HDL-C vs. control boys. Among T1D, IR but not HbA1c was associated with a more atherogenic lipoprotein profile. CONCLUSIONS/INTERPRETATIONS Normal weight T1D youth, especially females, had more atherogenic LDL-C and HDL-C distributions which correlated with lower insulin sensitivity. IR may contribute to the increased CVD burden in T1D.
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Affiliation(s)
- Melanie Cree-Green
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO
- Center for Women’s Health Research, Aurora, CO
| | - David M. Maahs
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Annie Ferland
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - John E. Hokanson
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Hong Wang
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Laura Pyle
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Gregory L. Kinney
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO
- Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Martina King
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Robert H. Eckel
- Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO
| | - Kristen J. Nadeau
- Barbara Davis Center for Childhood Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO
- Department of Pediatrics, Division of Pediatric Endocrinology, University of Colorado Anschutz Medical Campus, Aurora, CO
- Center for Women’s Health Research, Aurora, CO
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Abstract
Managing severe insulin resistance (IR) in patients with type 1 diabetes (T1DM) can be challenging for both clinicians and patients. As average weight for patients with T1DM has increased in recent decades, IR in this population has become more widespread. Currently, almost 50 % of patients with T1DM are overweight or obese. While intensive insulin therapy is associated with reduction in complications, aggressive treatment can lead to weight gain. With increasing weight, insulin can become less effective to control glycemia, resulting in higher insulin doses and hence more weight gain. Novel strategies to break this vicious cycle are needed. This review will investigate current research on insulin formulations, lifestyle modification, adjunct therapies, and surgery that may help better manage patients with T1DM and IR.
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A Randomized, Double-Blind, Placebo-Controlled Trial of Adjunctive Metformin Therapy in Overweight/Obese Youth with Type 1 Diabetes. PLoS One 2015; 10:e0137525. [PMID: 26367281 PMCID: PMC4569440 DOI: 10.1371/journal.pone.0137525] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 08/18/2015] [Indexed: 11/19/2022] Open
Abstract
Context Insulin resistance has been proposed as one of the causes of poor glycemic control in overweight/obese youth with type 1 diabetes (T1D). However, the role of adjunctive metformin, an insulin sensitizer, on glycemic control in these patients is unclear. Objective To compare the effect of metformin vs. placebo on hemoglobin A1c (HbA1c), total daily dose (TDD) of insulin, and other parameters in overweight/obese youth with T1D. Hypothesis Adjunctive metformin therapy will improve glycemic control in overweight/obese youth with T1D. Design, Setting, and Participants A 9-mo randomized, double-blind, placebo controlled trial of metformin and placebo in 28 subjects (13m/15f) of ages 10-20years (y), with HbA1c >8% (64 mmol/mol), BMI >85%, and T1D > 12 months was conducted at a university outpatient facility. The metformin group consisted of 15 subjects (8 m/ 7f), of age 15.0 ± 2.5 y; while the control group was made up of 13 subjects (5m/ 8f), of age 14.5 ± 3.1y. All participants employed a self-directed treat-to-target insulin regimen based on a titration algorithm of (-2)-0-(+2) units to adjust their long-acting insulin dose every 3rd day from -3 mo through +9 mo to maintain fasting plasma glucose (FPG) between 90–120 mg/dL (5.0–6.7 mmol/L). Pubertal maturation was determined by Tanner stage. Results Over the course of the 9 months of observation, the between-treatment differences in HbA1c of 0.4% (9.85% [8.82 to 10.88] for placebo versus 9.46% [8.47 to 10.46] for metformin) was not significant (p = 0.903). There were non-significant reduction in fasting plasma glucose (189.4 mg/dL [133.2 to 245.6] for placebo versus 170.5 mg/dL [114.3 to 226.7] for metformin), (p = 0.927); total daily dose (TDD) of short-acting insulin per kg body weight/day(p = 0.936); and the TDD of long-acting insulin per kg body weight per day (1.15 units/kg/day [0.89 to 1.41] for placebo versus 0.90 units/kg/day [0.64 to 1.16] for metformin) (p = 0.221). There was no difference in the occurrence of hypoglycemia between the groups. Conclusions This 9-month RCT of adjunctive metformin therapy in overweight and obese youth with T1D resulted in a 0.4% lower HbA1c value in the metformin group compared to the placebo group. Trial Registration ClinicalTrial.gov NCT01334125
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Abstract
The incidence of both type 1 and type 2 diabetes (T1DM and T2DM) continues to rise within the pediatric population. However, T1DM remains the most prevalent form diagnosed in children. It is critical that health-care professionals understand the types of diabetes diagnosed in pediatrics, especially the distinguishing features between T1DM and T2DM, to ensure proper treatment. Similar to all individuals with T1DM, lifelong administration of exogenous insulin is necessary for survival. However, children have very distinct needs and challenges compared to those in the adult diabetes population. Accordingly, treatment, goals, and age-appropriate requirements must be individually addressed. The main objectives for the treatment of pediatric T1DM include maintaining glucose levels as close to normal as possible, avoiding acute complications, and preventing long-term complications. In addition, unique to pediatrics, facilitating normal growth and development is important to comprehensive care. To achieve these goals, a careful balance of insulin therapy, medical nutrition therapy, and exercise or activity is necessary. Pharmacological treatment options consist of various insulin products aimed at mimicking prior endogenous insulin secretion while minimizing adverse effects. This review focuses on the management of pediatric T1DM in the outpatient environment, highlighting pharmacotherapy management strategies.
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Affiliation(s)
- Joni K. Beck
- Pediatric Diabetes and Endocrinology, Health Sciences Center and Harold Hamm Diabetes Center, College of Medicine, University of Oklahoma, Oklahoma City, Oklahoma
| | - Fran R. Cogen
- Department of Endocrinology and Diabetes, Children's National Medical Center, Washington, District of Columbia
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49
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Li X, Kover KL, Heruth DP, Watkins DJ, Moore WV, Jackson K, Zang M, Clements MA, Yan Y. New Insight Into Metformin Action: Regulation of ChREBP and FOXO1 Activities in Endothelial Cells. Mol Endocrinol 2015; 29:1184-94. [PMID: 26147751 DOI: 10.1210/me.2015-1090] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Metformin has been considered a potential adjunctive therapy in treating poorly controlled type 1 diabetes with obesity and insulin resistance, owing to its potent effects on improving insulin sensitivity. However, the underlying mechanism of metformin's vascular protective effects remains obscure. Thioredoxin-interacting protein (TXNIP), a key regulator of cellular redox state induced by high-glucose concentration, decreases thioredoxin reductase activity and mediates apoptosis induced by oxidative stress. Here we report that high glucose-induced endothelial dysfunction is associated with induction of TXNIP expression in primary human aortic endothelial cells exposed to high-glucose conditions, whereas the metformin treatment suppresses high-glucose-induced TXNIP expression at mRNA and protein levels. We further show that metformin decreases the high-glucose-stimulated nuclear entry rate of two transcription factors, carbohydrate response element-binding protein (ChREBP) and forkhead box O1 (FOXO1), as well as their recruitment on the TXNIP promoter. An AMP-activated protein kinase inhibitor partially compromised these metformin effects. Our data suggest that endothelial dysfunction resulting from high-glucose concentrations is associated with TXNIP expression. Metformin down-regulates high-glucose-induced TXNIP transcription by inactivating ChREBP and FOXO1 in endothelial cells, partially through AMP-activated protein kinase activation.
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Affiliation(s)
- Xiaoyu Li
- Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481
| | - Karen L Kover
- Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481
| | - Daniel P Heruth
- Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481
| | - Dara J Watkins
- Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481
| | - Wayne V Moore
- Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481
| | - Kathyrin Jackson
- Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481
| | - Mengwei Zang
- Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481
| | - Mark A Clements
- Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481
| | - Yun Yan
- Division of Endocrinology (X.L., K.L.K., D.J.W., W.V.M., K.J., M.A.C., Y.Y.), Department of Pediatrics, and Division of Experimental and Translational Genetics (D.P.H.), Department of Pediatrics, Children's Mercy Hospital and University of Missouri-Kansas City, Kansas City, Missouri 64108; and Department of Medicine (M.Z.), Vascular Biology Section, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, Massachusetts 02481
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50
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Fazeli Farsani S, Souverein PC, Overbeek JA, van der Vorst MMJ, Knibbe CAJ, Herings RMC, de Boer A, Mantel-Teeuwisse AK. Long term trends in oral antidiabetic drug use among children and adolescents in the Netherlands. Br J Clin Pharmacol 2015; 80:294-303. [PMID: 25683632 DOI: 10.1111/bcp.12608] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2014] [Revised: 02/07/2015] [Accepted: 02/10/2015] [Indexed: 12/18/2022] Open
Abstract
AIM The aim of the study was to document long term trends in oral antidiabetic drug (OAD) use among children and adolescents in the Netherlands. METHODS A population-based cohort study was conducted using the Dutch PHARMO Database Network. All patients younger than 20 years old with at least one OAD dispensing were identified. Age-adjusted and age-specific incidence (1999-2011) and prevalence (1998-2011) rates of OAD use were calculated. Trends over time were assessed using joinpoint regression software. A subset of PHARMO Database Network (including community pharmacy dispensing records linked to general practitioner data (OPD-GP database)) was used to assess indications for OADs. RESULTS In 2011, the overall age-adjusted incidence and prevalence rates of OAD use were 20.7/100 000 (95% CI 19.2, 22.1) person-years (PY) and 53.8/100 000 (95% CI 51.5, 56.1) persons, respectively. The average annual percentage change (AAPC) in the overall age-adjusted incidence rates from 1999 to 2011 was 18.9% (95% CI 4.5, 35.2). The incidence and prevalence rates of OAD use were higher among females and older age categories. The increases in rates of OAD use were mainly driven by metformin. For only 50% of the 98 patients in the OPD-GP database, indications for OAD prescriptions were reported with type 1 diabetes (n = 20), type 2 diabetes (n = 16), and overweight/obesity (n = 10). CONCLUSIONS Incidence and prevalence rates of OAD use in children and adolescents substantially increased in the Netherlands, especially among older age categories (10-14 and 15-19 years) and females. The main indications for use of OADs were type 1 and 2 diabetes and overweight/obesity.
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Affiliation(s)
- S Fazeli Farsani
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands
| | - P C Souverein
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands
| | - J A Overbeek
- PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands
| | - M M J van der Vorst
- Department of Paediatrics, St. Antonius Hospital, Nieuwegein, the Netherlands
| | - C A J Knibbe
- Department of Clinical Pharmacy, St. Antonius Hospital, Nieuwegein, the Netherlands.,Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands
| | - R M C Herings
- PHARMO Institute for Drug Outcomes Research, Utrecht, the Netherlands.,Department of Medical Informatics, Erasmus Medical Centre, Rotterdam, the Netherlands
| | - A de Boer
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands
| | - A K Mantel-Teeuwisse
- Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences (UIPS), Utrecht University, Utrecht, the Netherlands
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