An aging population combined with a rapidly increasing prevalence of diabetes foreshadows a global epidemic of cardiovascular and kidney disease that threatens to halt improvements in life and health-span and will have particularly severe consequences in older adults. The management of diabetes has been transformed with the recent development of newer anti-hyperglycemic agents that have demonstrated superior efficacy. However, the utility of these drugs extends beyond glycemic control to benefits for managing obesity, cardiovascular disease (CVD), chronic kidney disease, and heart failure. Numerous cardiovascular and kidney outcomes trials of these drugs have played an instrumental role in shaping current guidelines for the management of diabetes and CVD. Older adults with diabetes are diverse in terms of their comorbidities, diabetic complications, and cognitive and functional status. Therefore, there is an unmet need for personalized management of diabetes and CVD in this population. In this review, we provide an overview of the epidemiological burden and management of diabetes and CVD in older adults. We then focus on randomized cardiovascular and kidney outcome trials with anti-hyperglycemic agents to propose an evidence-based approach to the management of diabetes in older adults with high risk of cardiovascular and kidney disease.

To investigate the safety and efficiency of dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with diabetic kidney disease.

We conducted a comprehensive literature search across multiple databases, including Embase, PubMed, CNKI, and the Cochrane Central Register of Controlled Trials, from inception to January 2024. The search focused on randomized controlled trials (RCTs) that directly compared DPP-4 inhibitors with placebos or other glucose-lowering therapies. A meta-analysis was performed to pool data and quantify the therapeutic effects and safety profile of DPP-4 inhibitors in DKD.

Twenty-three RCTs with 16,378 participants were included. DPP-4 inhibitors significantly reduced urinary albumin-to-creatinine ratio (UACR) and HbA1c levels compared to controls (UACR: SMD -0.23, 95% CI: -0.41, -0.06; p = 0.01; HbA1c: SMD -0.32, 95% CI: -0.51, -0.14; p = 0.0006). A higher proportion of patients in the DPP-4 inhibitor group achieved at least a 30% reduction in UACR (OR = 1.73, 95% CI: 1.10, 2.73; p = 0.02). However, estimated glomerular filtration rate (eGFR) and serum creatinine (SCr) changes were similar between groups (eGFR: p = 1.00; SCr: p = 0.67). No significant differences were found in all-cause mortality (OR = 0.94, 95% CI: 0.83, 1.06; p = 0.31) or hypoglycemia risk (OR = 1.10, 95% CI: 0.80, 1.52; p = 0.54) between the DPP-4 inhibitor and control groups.

DPP-4 inhibitors exhibit renoprotective properties, indicated by significant reductions in UACR and HbA1c levels. They do not appear to increase the risk of hypoglycemia, presenting a favorable safety profile when compared to placebo or alternative antidiabetic agents.

Type 2 diabetes mellitus (T2DM) is increasingly being diagnosed in older adults. Our objective is to assess the advantages and potential drawbacks of different glucose-lowering medications in this specific population.

A network meta-analysis was conducted to identify randomized controlled trials that examined patient-centered outcomes in adults aged ≥65 years with T2DM. We searched PubMed, Cochrane CENTRAL, and Embase up to September 23, 2023. Quality of eligible studies were assessed using the Cochrane RoB 2.0 tool.

A total of 22 trials that involved 41 654 participants were included, incorporating sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 (DPP-4) inhibitors, metformin, sulfonylureas (SU) and acarbose. Our findings reveal that GLP-1RAs reduce the risk of major adverse cardiovascular events (risk ratio [RR], 0.83; 95% confidence interval [CI], 0.71 to 0.97) and body weight (mean difference [MD], -3.87 kg; 95% CI, -5.54 to -2.21). SGLT2 inhibitors prevent hospitalization for heart failure (RR, 0.66; 95% CI, 0.57 to 0.77), renal composite outcome (RR, 0.69; 95% CI, 0.53 to 0.89), and reduce body weights (MD, -1.85 kg; 95% CI, -2.42 to -1.27). SU treatment increases the risk of any hypoglycaemia (RR, 4.19; 95% CI, 3.52 to 4.99) and severe hypoglycaemia (RR, 7.06; 95% CI, 3.03 to 16.43). GLP-1RAs, SGLT2 inhibitors, metformin, SU and DPP-4 inhibitors are effective in reducing glycaemic parameters. Notably, the number of treatments needed decreases in most cases as age increases.

Novel glucose-lowering medications with benefits that outweigh risks should be prioritized for older patients with diabetes.

To demonstrate cardiovascular safety of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and sodium/glucose cotransporter 2 inhibitors (SGLT-2i) across age-groups.

PubMed, Embase and Cochrane were searched for cardiovascular outcome trials (CVOTs) testing newer agents until August 31, 2022 (PROSPERO ID CRD42021260167). Studies with ≥1000 T2D participants enrolled for ≥12 months were included. Random effect models were used to report relative-risk (RR) for three-point major adverse cardiovascular events (3P-MACE) and its components by age subgroups (65 years; 75 years).

For SGLT-2is, five CVOTs (46,969 patients, 45-50 % ≥65 years) were included. SGLT-2is reduced risk of MACE (RR; 0.91 [CI, 0.85-0.98]); cardiovascular death (CV-death) (RR; 0.84 [CI, 0.73-0.96]); and all-cause mortality (ACM) (RR; 0.86 [CI, 0.79-0.93]) with no difference in subgroups <65 or ≥65 years. For GLP-1RAs, nine CVOTs (n = 64,236, 34-75 % ≥65 years) were included. GLP-1RAs reduced risk of MACE (RR; 0.89 [CI, 0.83-0.95]), stroke (RR; 0.86 [CI, 0.76-0.97]) and ACM (RR; 0.90 [CI, 0.83-0.97]) with no significant difference in subgroups <65 or ≥65 years. Additionally, GLP-1RAs reduced risk of MACE (10 %), ACM (12 %) and CV-death (12 %) with no significant difference in subgroups <75 or ≥75 years. Four CVOTs (n = 33,063; 35-58 % ≥65 years) with DPP-4is were included. There were no significant differences in risk for CV outcomes with DPP-4is compared to placebo in any of the age subgroups.

The overall cardiovascular safety profile of newer anti-hyperglycemic agents is consistent in older and younger individuals.

Diabetes is considered a significant risk factor for the development of atrial fibrillation/flutter (AF/AFL). However, there is still insufficient evidence to determine the varying effects of different hypoglycemic drugs (HDs) on the incidence of new-onset AF/AFL in diabetic patients. To address this gap, we conducted a network meta-analysis to investigate whether various HDs have different effects on the risk of new-onset AF/AFL compared with insulin.

We conducted a comprehensive search in PubMed, EMBASE, Cochrane Library, and Web of Science to identify all clinical trials investigating the association between various HDs or insulin and incident AF/AFL up until April 1, 2024. Bayesian random-effects model was used for network meta-analysis, and the results were expressed as relative risk (RR) and 95% confidence interval (CI).

After searching 2070 articles, a total of 12 studies (2,349,683 patients) were included in the network meta-analysis. The treatment regimen comprised insulin and 8 HDs hypoglycemic drugs, which are sodium-dependent glucose transporters 2 inhibitor (SGLT2i), glucagon-like peptide 1 receptor agonist (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4i), metformin (Met), sulfonylureas (SU), non-sulfonylureas (nSU), thiazolidinedione (TZD) and α-glycosidase inhibitors (AGI). The use of SGLT2i [RR 0.23, 95%CI (0.11, 0.49)], GLP-1RA [RR 0.28, 95%CI (0.13, 0.57)], and DPP4i [RR 0.34, 95%CI (0.17, 0.67)] demonstrated significant efficacy in reducing the incidence of new-onset AF/AFL when compared to insulin. When HDs were compared in pairs, SGLT2i is more effective than Met [RR 0.35, 95% CI (0.19, 0.62)], SU (RR 0.27, 95% CI (0.14, 0.51)], nSU [RR 0.28, 95% CI (0.08, 0.95)], TZD [RR 0.34, 95% CI (0.17, 0.7)], GLP-1RA is more effective Met [RR 0.42, 95% CI (0.25, 0.71)], SU (RR 0.33, 95% CI (0.18, 0.6)], TZD [RR 0.41, 95% CI (0.21, 0.82)], while Met[RR 1.98, 95% CI (1.23, 3.23)], SU [RR 2.54, 95% CI (1.46, 4.43)], TZD [RR 2.01, 95% CI (1.05, 3.79)] was not as effective as DPP4i.

SGLT-2i, GLP-1RA, and DPP4i showed a superior efficacy in reducing the risk of new-onset AF/AFL compared to insulin therapy.

Drug-associated bullous pemphigoid has been shown to follow long-term gliptin (dipeptidyl-peptidase 4 inhibitors) intake. This study aimed at identifying risk factors for gliptin-associated bullous pemphigoid among patients with type 2 diabetes. A retrospective study was conducted in a tertiary centre among diabetic patients exposed to gliptins between the years 2008-2021. Data including demographics, comorbidities, medications, and laboratory results were collected using the MDClone platform. Seventy-six patients with type 2 diabetes treated with dipeptidyl-peptidase 4 inhibitors who subsequently developed bullous pemphigoid were compared with a cohort of 8,060 diabetic patients exposed to dipeptidyl-peptidase 4 inhibitors who did not develop bullous pemphigoid. Based on a multivariable analysis adjusted for age and other covariates, Alzheimer's disease and other dementias were significantly more prevalent in patients with bullous pemphigoid (p = 0.0013). Concomitant use of either thiazide or loop diuretics and gliptin therapy was associated with drug-associated bullous pemphigoid (p < 0.0001 for both). While compared with sitagliptin, exposure to linagliptin and vildagliptin were associated with bullous pemphigoid with an odds ratio of 5.68 and 6.61 (p < 0.0001 for both), respectively. These results suggest gliptins should be prescribed with caution to patients with type 2 diabetes with coexisting Alzheimer's and other dementias, or patients receiving long-term use of thiazides and loop diuretics. The use of sitagliptin over linagliptin and vildagliptin should be preferred in these patients.

Aging is a key risk factor for atherosclerosis progression that is associated with increased incidence of ischemic events in supplied organs, including stroke, coronary events, limb ischemia, or renal failure. Cardiovascular disease is the leading cause of death and major disability in adults ≥ 75 years of age. Atherosclerotic occlusive disease affects everyday activity, quality of life, and it is associated with reduced life expectancy. As most multicenter randomized trials exclude elderly and very elderly patients, particularly those with severe comorbidities, physical or cognitive dysfunctions, frailty, or residence in a nursing home, there is insufficient data on the management of older patients presenting with atherosclerotic lesions outside coronary territory. This results in serious critical gaps in knowledge and a lack of guidance on the appropriate medical treatment. In addition, due to a variety of severe comorbidities in the elderly, the average daily number of pills taken by octogenarians exceeds nine. Polypharmacy frequently results in drug therapy problems related to interactions, drug toxicity, falls with injury, delirium, and non-adherence. Therefore, we have attempted to gather data on the medical treatment in patients with extra-cardiac atherosclerotic lesions indicating where there is some evidence of the management in elderly patients and where there are gaps in evidence-based medicine. Public PubMed databases were searched to review existing evidence on the effectiveness of lipid-lowering, antithrombotic, and new glucose-lowering medications in patients with extra-cardiac atherosclerotic occlusive disease.

The global prevalence of diabetes mellitus (DM) has led to widespread multi-system damage, especially in cardiovascular and renal functions, heightening morbidity and mortality. Emerging antidiabetic drugs sodium-glucose cotransporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase-4 inhibitors (DPP-4i) have demonstrated efficacy in preserving cardiac and renal function, both in type 2 diabetic and non-diabetic individuals. To understand the exact impact of these drugs on cardiorenal protection and underlying mechanisms, we conducted a comprehensive review of recent large-scale clinical trials and basic research focusing on SGLT2i, GLP-1RAs, and DPP-4i. Accumulating evidence highlights the diverse mechanisms including glucose-dependent and independent pathways, and revealing their potential cardiorenal protection in diabetic and non-diabetic cardiorenal disease. This review provides critical insights into the cardiorenal protective effects of SGLT2i, GLP-1RAs, and DPP-4i and underscores the importance of these medications in mitigating the progression of cardiovascular and renal complications, and their broader clinical implications beyond glycemic management.

With the deepening of aging in China, the prevalence of diabetes in older people has increased noticeably, and standardized diabetes management is critical for improving clinical outcomes of diabetes in older people. In 2021, the National Center of Gerontology, Chinese Society of Geriatrics, and Diabetes Professional Committee of Chinese Aging Well Association organized experts to write the first guideline for diabetes diagnosis and treatment in older people in China, the Guideline for the Management of Diabetes Mellitus in the Elderly in China (2021 Edition). The guideline emphasizes that older patients with diabetes are a highly heterogeneous group requiring comprehensive assessment and stratified and individualized management strategies. The guideline proposes simple treatments and de-intensified treatment strategies for older patients with diabetes. This edition of the guideline provides clinicians with practical and operable clinical guidance, thus greatly contributing to the comprehensive and full-cycle standardized management of older patients with diabetes in China and promoting the extensive development of clinical and basic research on diabetes in older people and related fields. In the past 3 years, evidence-based medicine for older patients with diabetes and related fields has further advanced, and new treatment concepts, drugs, and technologies have been developed. The guideline editorial committee promptly updated the first edition of the guideline and compiled the Guideline for the Management of Diabetes Mellitus in the Elderly in China (2024 Edition). More precise management paths for older patients with diabetes are proposed, for achieving continued standardization of the management of older Chinese patients with diabetes and improving their clinical outcomes.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Diabetic cardiomyopathy is a chronic cardiovascular complication caused by diabetes that is characterized by changes in myocardial structure and function, ultimately leading to heart failure and even death. Mitochondria serve as the provider of energy to cardiomyocytes, and mitochondrial dysfunction plays a central role in the development of diabetic cardiomyopathy. In response to a series of pathological changes caused by mitochondrial dysfunction, the mitochondrial quality control system is activated. The mitochondrial quality control system (including mitochondrial biogenesis, fusion and fission, and mitophagy) is core to maintaining the normal structure of mitochondria and performing their normal physiological functions. However, mitochondrial quality control is abnormal in diabetic cardiomyopathy, resulting in insufficient mitochondrial fusion and excessive fission within the cardiomyocyte, and fragmented mitochondria are not phagocytosed in a timely manner, accumulating within the cardiomyocyte resulting in cardiomyocyte injury. Currently, there is no specific therapy or prevention for diabetic cardiomyopathy, and glycemic control remains the mainstay. In this review, we first elucidate the pathogenesis of diabetic cardiomyopathy and explore the link between pathological mitochondrial quality control and the development of diabetic cardiomyopathy. Then, we summarize how clinically used hypoglycemic agents (including sodium-glucose cotransport protein 2 inhibitions, glucagon-like peptide-1 receptor agonists, dipeptidyl peptidase-4 inhibitors, thiazolidinediones, metformin, and α-glucosidase inhibitors) exert cardioprotective effects to treat and prevent diabetic cardiomyopathy by targeting the mitochondrial quality control system. In addition, the mechanisms of complementary alternative therapies, such as active ingredients of traditional Chinese medicine, exercise, and lifestyle, targeting mitochondrial quality control for the treatment of diabetic cardiomyopathy are also added, which lays the foundation for the excavation of new diabetic cardioprotective drugs.

Patients with diabetes mellitus (DM) have a higher risk of incident and aggravating frailty over time. Frailty-initiating risk factors have been identified, but modulators of frail severity over time remain poorly defined. We aimed to explore the influences of glucose-lowering drug (GLD) strategy on DM patients' risk of increasing frail severity. We retrospectively identified type 2 DM patients between 2008 and 2016, dividing them into "no GLD", oral GLD (oGLD) monotherapy, oGLD combination, and those receiving insulin without or with oGLD at baseline. Increasing frail severity, defined as ≥1 FRAIL component increase, was the outcome of interest. Cox proportional hazard regression was utilized to analyze the risk of increasing frail severity associated with GLD strategy, accounting for demographic, physical data, comorbidities, medication, and laboratory panel. After screening 82,208 patients with DM, 49,519 (no GLD, 42.7%; monotherapy, 24.0%; combination, 28.5%; and insulin user, 4.8%) were enrolled for analysis. After 4 years, 12,295 (24.8%) had increasing frail severity. After multivariate adjustment, oGLD combination group exhibited a significantly lower risk of increasing frail severity (hazard ratio (HR) 0.90, 95% confidence interval (CI) 0.86 - 0.94), while the risk of insulin users increased (HR 1.11, 95% CI 1.02 - 1.21) than no GLD group. Users receiving more oGLD exhibited a trend of less risk reduction relative to others. In conclusion, we discovered that the strategy of oral glucose lowering drugs combination might reduce the risk of frail severity increase. Accordingly, medication reconciliation in frail diabetic older adults should take into account their GLD regimens.

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P < 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria.

Diabetes is prevalent in older adults and older adults with diabetes are more likely to have multiple comorbidities. It is, therefore, important to personalize diabetes management in this group. Newer glucose-lowering drugs, including dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter 2 inhibitors, and glucagon-like peptide-1 receptor agonists can be safely used in older patients and are preferred choices in many cases due to their safety, efficacy, and low risk of hypoglycemia.

The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Diabetes mellitus (DM) is a serious epidemic around the globe, and cardiovascular diseases account for the majority of deaths in patients with DM. Diabetic cardiomyopathy (DCM) is defined as a cardiac dysfunction derived from DM without the presence of coronary artery diseases and hypertension. Patients with either type 1 or type 2 DM are at high risk of developing DCM and even heart failure. Metabolic disorders of obesity and insulin resistance in type 2 diabetic environments result in dyslipidaemia and subsequent lipid-induced toxicity (lipotoxicity) in organs including the heart. Although various mechanisms have been proposed underlying DCM, it remains incompletely understood how lipotoxicity alters cardiac function and how DM induces clinical heart syndrome. With recent progress, we here summarize the latest discoveries on lipid-induced cardiac toxicity in diabetic hearts and discuss the underlying therapies and controversies in clinical DCM.

The world is suffering from a rapid increase in the number of people with diabetes due to the increased prevalence of obesity and lengthened life span. Since the development of insulin thanks to the efforts of Prof. Banting and Dr. Best in 1922, for which they won the Nobel Prize, remarkable developments in anti-diabetic medications have dramatically lengthened the lifespan of patients with diabetes. However, the control rate of hyperglycemia in patients with diabetes remains unsatisfactory, since glycemic control requires both medication and lifestyle modifications to slow the deterioration of pancreatic beta-cell function and prevent diabetic complications. From the initial "triumvirate" to the "ominous octet," and now the "egregious eleven," the number of organs recognized as being involved in hyperglycemia and diabetes has increased with the development of anti-diabetic medications. Recent unexpected results from outcome trials of anti-diabetic medications have enabled anti-diabetic medications to be indicated for the prevention of chronic kidney disease and heart failure, even in patients without diabetes. In this review, I would like to summarize the extra-glycemic effects of anti-diabetic medications.

In recent years, important changes have occurred in the field of diabetes treatment. The focus of the treatment of diabetic patients has shifted from the control of blood glucose itself to the overall management of risk factors, while adjusting blood glucose goals according to individualization. In addition, regulators need to approve new antidiabetic drugs which have been tested for cardiovascular safety. Thus, the newest class of drugs has been shown to reduce major adverse cardiovascular events, including sodium-glucose transporter 2 (SGLT2) and some glucagon like peptide 1 receptor (GLP1) analog. As such, they have a prominent place in the hyperglycemia treatment algorithms. In recent years, the role of DPP4 inhibitors (DPP4i) has been modified. DPP4i have a favorable safety profile and anti-inflammatory profile, do not cause hypoglycemia or weight gain, and do not require dose escalation. In addition, it can also be applied to some types of chronic kidney disease patients and elderly patients with diabetes. Overall, DPP4i, as a class of safe oral hypoglycemic agents, have a role in the management of diabetic patients, and there is extensive experience in their use.

The purpose of this review is to highlight the evidence behind landmark trials involving these two novel drug classes in conjunction with a review of long-standing therapies used to improve cardiovascular (CV) outcomes among patients with peripheral artery disease (PAD) patients and type 2 diabetes mellitus (T2DM).

Recently, societal guideline recommendations have expanded the management of T2DM to incorporate therapies with CV risk factor modification. This is due to CV outcome trials (CVOT) uncovering advantageous cardioprotective effects of several novel therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Providers who manage high-risk patients with T2DM, such as those with concomitant PAD, are expected to incorporate these novel medical therapies into routine patient care. The body of evidence surrounding GLP-1 RA demonstrates a strong benefit in mitigating the innate heightened CV risk among patients with T2DM. Furthermore, SGLT2i not only have a favorable CV profile but also reduce the risk of HF hospitalizations and progression of renal disease. Patients with T2DM and PAD are known to be at a heightened risk for major adverse cardiac and lower extremity events, heart failure, and chronic kidney disease. As such, the use of novel therapies such as GLP-RA and SGLT2i should be strongly considered to minimize morbidity and mortality in this vulnerable population.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc22-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc22-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Heart failure (HF) and type 2 diabetes mellitus (T2DM) represent two important public health problems, and despite improvements in the management of both diseases, they are responsible for high rates of hospitalizations and mortality. T2DM accelerates physiological cardiac aging through hyperglycemia and hyperinsulinemia. Thus, HF and T2DM are chronic diseases widely represented in elderly people who often are affected by numerous comorbidities with important functional limitations making it difficult to apply the current guidelines. Several antidiabetic drugs should be used with caution in elderly individuals with T2DM. For instance, sulfonylureas should be avoided due to the risk of hypoglycemia associated with its use. Insulin should be used with caution because it is associated with higher risk of hypoglycemia, and may determine fluid retention which can lead to worsening of HF. Thiazolindinediones should be avoided due to the increased risk of fluid retention and HF. Biguanides may lead to a slightly increased risk of lactic acidosis in particular in elderly individuals with impaired renal function. Dipeptidyl peptidase 4 (DPP-4) inhibitors are safe having few side effects, minimal risk of hypoglycemia, and a neutral effect on cardiovascular (CV) outcome, even if it has been reported that saxagliptin treatment is associated with increased risk of hospitalizations for HF (hHF). Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown a CV protection without a significant reduction in hHF. On the other hand, sodium-glucose cotransporter 2 (SGLT2) inhibitors have shown a significant improvement in CV outcome, with a strong reduction of hHF and a positive impact on renal damage progression. However, it is necessary to consider the possible some side effects related to their use in elderly individuals including hypotension, bone fractures, and ketoacidosis.It is important to remark that elderly patients, in particular the very elderly, are not sufficiently represented in the trials; thus, the management and treatment of elderly diabetic patients with HF should be mainly based on the integration of scientific evidence with clinical judgment and patients' condition, with respect to the dignity and quality of life.

Dipeptidyl peptidase-4 inhibitors (DPP-4is) and sodium-glucose cotransporter type 2 inhibitors (SGLT2is) offer new options for the oral management of type 2 diabetes mellitus (T2DM), with the advantage in the elderly population to be devoid of a high risk of hypoglycaemia. SGLT2is have also shown benefits regarding cardiovascular (heart failure) and renal protection, including in patients with T2DM aged ≥ 65 years while DPP-4is have only proved cardiovascular and renal safety without superiority compared with placebo. The glucose-lowering efficacy of the two pharmacological classes is almost similar including in older patients with T2DM. However, the tolerance and safety profile may be highly different and overall more favourable with DPP-4is than with SGLT2is. Some adverse events have been reported with SGLT2is which may be more prevalent or severe in older patients than in younger patients. The present comprehensive review focuses on the benefit/risk balance in the elderly population with T2DM by comparing the profile of DPP-4is and SGLT2is regarding the following potential issues: metabolic disorders (hypoglycaemia and diabetic ketoacidosis); cardiac and vascular issues (atheromatous cardiovascular disease, heart failure, volume reduction hypotension, and lower limb amputations); renal endpoints including acute renal injury; risk of infections; digestive disorders; bone and skin adverse events; and cancer risk. Both DPP-4is and SGLT2is have their own advantages and disadvantages. Personalised treatment is recommended based upon the efficacy/safety profile of each drug class and individual patient characteristics that may be markedly different among the heterogeneous population of older individuals with T2DM.

The past 50 years have seen a growing ageing population with an increasing prevalence of type 2 diabetes mellitus (T2DM); now, nearly half of all individuals with diabetes mellitus are older adults (aged ≥65 years). Older adults with T2DM present particularly difficult challenges. For example, the accentuated heterogeneity of these patients, the potential presence of multiple comorbidities, the increased susceptibility to hypoglycaemia, the increased dependence on care and the effect of frailty all add to the complexity of managing diabetes mellitus in this age group. In this Review, we offer an update on the key pathophysiological mechanisms associated with T2DM in older people. We then evaluate new evidence relating particularly to the effects of frailty and sarcopenia, the clinical difficulties of age-associated comorbidities, and the implications for existing guidelines and therapeutic options. Our conclusions will focus on the effect of T2DM on an ageing society.

Type 2 diabetes mellitus (T2DM) is highly prevalent and associated with a 2-fold increased mortality, mostly explained by cardiovascular diseases. Trial evidence on older glucose-lowering agents such as metformin and sulfonylureas is limited in terms of cardiovascular efficacy. Since 2008, after rosiglitazone was observed to increase the risk of myocardial infarction and heart failure (HF), cardiovascular outcome trials (CVOT) have been required by regulators for licensing new glucose-lowering agents. In the following CVOTs, dipeptidyl peptidase 4 inhibitors (DPP4i) have been shown to be safe but not to improve morbidity/mortality, except for saxagliptin which increased the risk of HF. Several glucagon-like peptide-1 receptor agonists (GLP1-Ra) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been demonstrated to reduce the risk of cardiovascular morbidity and mortality. SGLT2i have shown a class effect for the reduction in risk of HF events in patients with T2DM, leading to trials testing their efficacy/safety in HF regardless of T2DM. In the DAPA-HF and the EMPEROR-Reduced trials dapagliflozin and empagliflozin, respectively, improved cardiovascular mortality/morbidity in patients with HF and reduced ejection fraction (HFrEF), with and without T2DM. Therefore, these drugs are now key part of HFrEF pharmacotherapy. In the SOLOIST-WHF, sotagliflozin reduced cardiovascular mortality/morbidity in patients with T2DM and a recent acute episode of HF regardless of EF. The DELIVER and the EMPEROR-Preserved are testing dapagliflozin and empagliflozin, respectively, in patients with HF with mildly reduced and preserved EF. A strong renal protective role of SGLT2i has also emerged in trials enrolling patients with and without T2DM.

An increasing number of older patients has type 2 diabetes treated with different oral antidiabetic agents whose safety may raise concern considering some particularities of a heterogeneous elderly population.

This article discusses some characteristics of older patients that could increase the risk of adverse events, with a focus on hypoglycemia. It describes the most frequent and/or severe complications reported in the elderly in both randomized controlled trials and observational studies with metformin, sulfonylureas, meglitinides, alpha-glucosidase inhibitors, thiazolidinediones, dipeptidyl peptidase-4 inhibitors (gliptins) and sodium-glucose cotransporter type 2 inhibitors (gliflozins).

Old patients may present comorbidities (renal impairment, vascular disease, heart failure, risk of dehydration, osteoporosis, cognitive dysfunction) that could increase the risk of severe adverse events. Sulfonylureas (and meglitinides) induce hypoglycemia, which may be associated with falls/fractures and cardiovascular events. Medications lacking hypoglycemia should be preferred. Gliptins appear to have the best tolerance/safety profile whereas gliflozins exert a cardiorenal protection. However, data are lacking in very old or frailty old patients so that caution and appropriate supervision of such patients are required. Taking advantage of a large choice of pharmacotherapies, personalized treatment is recommended based upon both drug safety profiles and old patient individual characteristics.

To compare the cardiovascular (CV) safety of linagliptin with glimepiride in older and younger participants in the CAROLINA trial in both prespecified and post hoc analyses.

People aged 40 to 85 years with relatively early type 2 diabetes, inadequate glycaemic control and elevated CV risk were randomly assigned to linagliptin 5 mg or glimepiride 1 to 4 mg. The primary endpoint was time to first occurrence of three-point major adverse CV events (MACE: CV death, non-fatal myocardial infarction, or non-fatal stroke). We evaluated clinical and safety outcomes across age groups.

Of 6033 participants, 50.7% were aged <65 years, 35.3% were aged 65 to 74 years, and 14.0% were aged ≥75 years. During the 6.3-year median follow-up, CV/mortality outcomes did not differ between linagliptin and glimepiride overall (hazard ratio [HR] for three-point MACE 0.98, 95.47% confidence interval [CI] 0.84, 1.14) or across age groups (interaction P >0.05). Between treatment groups, reductions in glycated haemoglobin were comparable across age groups but moderate-to-severe hypoglycaemia was markedly reduced with linagliptin (HR 0.18, 95% CI 0.15, 0.21) with no differences among age groups (P = 0.23). Mean weight was -1.54 kg (95% CI -1.80, -1.28) lower for linagliptin versus glimepiride. Adverse events increased with age, but were generally balanced between treatment groups. Significantly fewer falls or fractures occurred with linagliptin.

Linagliptin and glimepiride were comparable for CV/mortality outcomes across age groups. Linagliptin had significantly lower risk of hypoglycaemia and falls or fractures than glimepiride, including in "older-old" individuals for whom these are particularly important treatment considerations.

Results regarding the cardiovascular (CV) effects of dipeptidyl peptidase-4 (DPP-4) inhibitors are inconsistent. This study aimed to assess the effects of teneligliptin, a DPP-4 inhibitor, on the risk of major CV outcomes in type 2 diabetes mellitus (T2DM) patients compared to sulfonylurea.

From January 1, 2015 to December 31, 2017, we conducted a retrospective cohort study using the Korean National Health Insurance Service database. A total of 6,682 T2DM patients who were newly prescribed DPP-4 inhibitors or sulfonylurea were selected and matched in a 1:1 ratio by propensity score. The hazard ratios (HRs) for all-cause mortality, hospitalization for heart failure (HHF), all-cause mortality or HHF, myocardial infarction (MI), stroke, and hypoglycemia were assessed.

During 641 days of follow-up, the use of teneligliptin was not associated with an increased risk of all-cause mortality (HR, 1.00; 95% confidence interval [CI], 0.85 to 1.19), HHF (HR, 0.99; 95% CI, 0.86 to 1.14), all-cause mortality or HHF (HR, 1.02; 95% CI, 0.90 to 1.14), MI (HR, 0.90; 95% CI, 0.68 to 1.20), and stroke (HR, 1.00; 95% CI, 0.86 to 1.17) compared to the use of sulfonylurea. However, it was associated with a significantly lower risk of hypoglycemia (HR, 0.68; 95% CI, 0.49 to 0.94) compared to sulfonylurea therapy.

Among T2DM patients, teneligliptin therapy was not associated with an increased risk of CV events including HHF, but was associated with a lower risk of hypoglycemia compared to sulfonylurea therapy.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc21-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc21-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

Diabetes mellitus (DM) and peripheral artery disease (PAD) are two clinical entities closely associated. They share many pathophysiological pathways such as inflammation, endothelial dysfunction, oxidative stress and pro-coagulative unbalance. Emerging data focusing on agents targeting these pathways may be promising. Moreover, due to the increased cardiovascular risk, there is a growing interest in cardiovascular and "pleiotropic" effects of novel glucose lowering drugs. This review summarizes the main clinical features of PAD in patients, the diagnostic process and current medical/interventional approaches, ranging from "classical treatment" to novel agents.

Dipeptidyl peptidase 4 inhibitors (DPP4i) have been available for treating type 2 diabetes mellitus since 2006. Although they are a diverse group, DPP4i are all small, orally available molecules that interact with the catalytic site of DPP4 without disturbing any of its other known functions, including its effects on the immune system. DPP4i have no intrinsic glucose-lowering activity, so their efficacy as anti-diabetic agents is related directly to their ability to inhibit DPP4 activity and is mediated through the effects of the substrates they protect. Of these, the incretin hormone, glucagon-like peptide 1, is probably the most important. As the effects of glucagon-like peptide 1 are glucose-dependent, the risk of hypoglycaemia with DPP4i is low. Class effects, which are directly related to the mechanism of action, are common to all DPP4i; these include their overall good safety profile and tolerability, as well as their efficacy in improving glycaemic control, but also, potentially, a small increased risk of acute pancreatitis. Compound-specific effects are those related to their differing chemistries and/or pharmacokinetic profiles. These compound-specific effects could affect the way in which individual DPP4i are used therapeutically and potentially explain off-target adverse effects, such as hospitalization for heart failure, which is seen only with one DPP4i. Overall, DPP4i have a favourable therapeutic profile and are safe and effective in the majority of patients with type 2 diabetes mellitus.

Older people (those aged 65 years or more) with diabetes comprise a heterogenous group of patients with special needs and features; this is particularly true for those aged 75 years or more. It is important that individualized glycemic targets be adopted in this population, after considering life expectancy, presence of diabetic complications and other comorbidities. In general, less rigorous targets and avoidance of overtreatment seems to be a reasonable strategy in daily clinical settings. There is a paucity of data regarding the efficacy and safety of various hypoglycemic agents, especially for those aged over 75. The evidence suggests that sulfonylureas and insulin regimens should be used with caution due to a high risk of hypoglycemia. Dipeptidyl peptidase-4 inhibitors are a good choice for the management of diabetes in older age groups, although a warning against the use of specific agents in people with heart failure is valid. There are insufficient data to decide whether the cardiorenal protective properties of sodium-glucose co-transporter 2 inhibitors outweigh the risks associated with these drugs. The use of glucagon-like peptide-1 receptor agonists by older patients is supported not only by their good safety and efficacy profiles, but also by their potential to improve glucose-independent outcomes, through their pleiotropic actions. The aim of this narrative review is to summarize the evidence on glycemic targets and optimal therapeutic approaches for older patients with type 2 diabetes and discuss the risk-benefit balance of various therapeutic approaches in this group.

Dipeptidyl peptidase 4 (DPP4) inhibitors (DPP4is) are oral anti-diabetic drugs (OADs) for the treatment of type 2 diabetes mellitus (T2DM) through inhibiting the degradation of incretin peptides. Numerous investigations have been focused on the effects of DPP4is on glucose homeostasis. However, there are limited evidences demonstrating their Potential modulatory functions in the immune system. DPP4, originally known as the lymphocyte cell surface protein CD26, is widely expressed in many types of immune cells including CD4(+) and CD8(+) T cells, B cells, NK cells, dendritic cells, and macrophages; and regulate the functions of these cells. In addition, DPP4 is capable of modulating plenty of cytokines, chemokines and peptide hormones. Accordingly, DPP4/CD26 is speculated to be involved in various immune/inflammatory diseases and DPP4is may become a new drug class applied in these diseases. This review focuses on the regulatory effects of DPP4is on immune functions and their possible underlying mechanisms. Further clinical studies will be necessitated to fully evaluate the administration of DPP4is in diabetic patients with or without immune diseases.

Data regarding the effects of sodium-glucose cotransporter 2 inhibitors in the elderly (age ≥65 years) and very elderly (age ≥75 years) are limited.

The Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 assessed cardiac and renal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. Efficacy and safety outcomes were studied within age subgroups for treatment effect and age-based treatment interaction.

Of the 17,160 patients, 9,253 were <65 years of age, 6,811 ≥65 to <75 years, and 1,096 ≥75 years. Dapagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure consistently, with a hazard ratio (HR) of 0.88 (95% CI 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 (0.65, 1.36) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.5277). Overall, dapagliflozin did not significantly decrease the rates of major adverse cardiovascular events, with HR 0.93 (95% CI 0.81, 1.08), 0.97 (0.83, 1.13), and 0.84 (0.61, 1.15) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.7352). The relative risk reduction for the secondary prespecified cardiorenal composite outcome ranged from 18% to 28% in the different age-groups with no heterogeneity. Major hypoglycemia was less frequent with dapagliflozin versus placebo, with HR 0.97 (95% CI 0.58, 1.64), 0.50 (0.29, 0.84), and 0.68 (0.29, 1.57) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.2107). Safety outcomes, including fractures, volume depletion, cancer, urinary tract infections, and amputations were balanced with dapagliflozin versus placebo, and acute kidney injury was reduced, all regardless of age. Genital infections that were serious or led to discontinuation of the study drug and diabetic ketoacidosis were uncommon, yet more frequent with dapagliflozin versus placebo, without heterogeneity (interaction P values 0.1058 and 0.8433, respectively).

The overall efficacy and safety of dapagliflozin are consistent regardless of age.

Concerns of elevated cardiovascular risk with some anti-diabetic medications warranted trials on the cardiovascular outcome to demonstrate cardiovascular safety of newly marketed anti-diabetic drugs. Although these trials were initially designed to evaluate safety, some of these demonstrated significant cardiovascular benefits.

We reviewed the cardiovascular and safety outcomes of novel antidiabetic agents in patients with type 2 diabetes and established cardiovascular disease or at high risk of it. We included the outcomes of safety trials, randomized controlled trials, meta-analysis, large cohort studies, and real-world data, which highlighted the cardiovascular profile of DPP-4is, GLP-1RAs and SGLT-2is.

Although DPP-4is demonstrated non-inferiority to placebo, gaining cardiovascular safety, as well market authorization, SGLT-2is and most of the GLP-1RAs have shown impressive cardiovascular benefits in patients with T2D and established CVD or at high risk of it. These favorable effects of novel antidiabetic agents on cardiovascular parameters provide novel therapeutic approaches in medical management, risk stratification and prevention.

Dipeptidyl peptidase-4 inhibitors are a relatively new class of oral anti-hyperglycaemic drugs to treat type 2 diabetes through prevention of degradation of incretins by the dipeptidyl peptidase-4 enzyme. The large trials evaluating the dipeptidyl peptidase-4 inhibitors sitagliptin, alogliptin and saxagliptin demonstrated safety for cardiovascular disease. Post hoc analyses on renal endpoints yielded similar findings. Linagliptin is the latest dipeptidyl peptidase-4 inhibitor evaluated in the CARMELINA trial. CARMELINA included individuals with type 2 diabetes and high cardiovascular and renal risk. Even in this setting, linagliptin displayed cardiovascular safety. CARMELINA also removed initial concerns for heart failure as a class-specific side-effect of dipeptidyl peptidase-4 inhibitors, as no signal for heart failure was found. Although numerically low, CARMELINA did confirm increased rates of pancreatitis in the linagliptin group, suggesting that pancreatitis is a class-specific side-effect of dipeptidyl peptidase-4 inhibitors. Linagliptin reduced progression of albuminuria, but had no effect on other hard renal endpoints. Overall, dipeptidyl peptidase-4 inhibitors are safe but do not confer significant reductions in complications observed for some of the other new glucose-lowering drugs. However, linagliptin is a safe alternative in renal impairment, without dose adjustment. Furthermore, dipeptidyl peptidase-4 inhibitors may hold value as alternatives to sulfonyl-urea derivatives or as an add-on therapy to delay insulin prescription given their favourable safety profile.

Treatment of older adults with type 2 diabetes (T2D) is complex because they represent a heterogeneous group with a broad range of comorbidities, functional abilities, socioeconomic status, and life expectancy. Older adults with T2D are at high risk of recurring hypoglycemia, a condition associated with marked morbidity and mortality, because their counter-regulatory mechanism to hypoglycemia is attenuated, and recurring hypoglycemic episodes can lead to hypoglycemia unawareness. In addition, polypharmacy, a result of multiple chronic comorbidities (including heart disease, stroke, and chronic kidney disease), can increase the risk of severe hypoglycemia, especially when patients are taking sulfonylureas or insulin. Often the signs of hypoglycemia are nonspecific (sweating, dizziness, confusion, visual disturbances) and are mistaken for neurological symptoms or dementia. Consequences of hypoglycemia include acute and long-term cognitive changes, cardiac arrhythmia and myocardial infarction, serious falls, frailty, and death, often resulting in hospitalization, which come at a high economic cost. The American Diabetes Association has recently added three new recommendations regarding hypoglycemia in the elderly, highlighting individualized pharmacotherapy with glucose-lowering agents with a low risk of hypoglycemia and proven cardiovascular safety, avoidance of overtreatment, and simplifying treatment regimens while maintaining HbA1c targets. Thus, glycemic goals can be relaxed in the older population as part of individualized care, and physicians must make treatment decisions that best serve their patients' circumstances. This article highlights the issues faced by older people with T2D, the risk factors for hypoglycemia in this population, and the challenges faced by health care providers regarding glycemic management in this patient group.

To investigate the risk of hypoglycaemia in people aged ≥65 years with type 2 diabetes mellitus (T2DM) treated with linagliptin, in the largest pooled analysis performed to date.

One thousand four hundred and eighty-nine patients aged ≥65 years with T2DM were pooled from 11 randomised, double-blind, parallel group, placebo-controlled trials evaluating linagliptin 5 mg alone, or in addition to various background therapies. The primary safety endpoint was the incidence of investigator-defined hypoglycaemia.

There was no significant difference in the risk of hypoglycaemia between linagliptin and placebo in the all-patient population at 24 weeks (hazard ratio [HR] 1.07; 95% confidence interval [CI]: 0.84, 1.36; P = 0.5943)-despite significant (P < 0.0001) improvements in glycaemic control-and 1 year (HR 1.02; 95% CI: 0.81, 1.27; P = 0.8803). Similar findings were observed for linagliptin vs placebo in subgroup analyses by background medication (eg, sulphonylureas (SUs) and/or insulin vs no such drugs), age, baseline glycated haemoglobin (HbA1c), ethnicity, and baseline estimated glomerular filtration rate. Patients with a baseline HbA1c ≥7.5% had significantly higher odds of achieving HbA1c <7.5% without hypoglycaemia in the linagliptin group compared with placebo at 24 weeks (34.1% vs 13.7%; 95% CI: 2.04, 4.12; P < 0.0001).

This pooled analysis indicates that linagliptin was effective in treating older people with T2DM towards their HbA1c targets with a favourable safety and tolerability profile and low risk of hypoglycaemia. The safety profile was maintained even on background therapies with known risk of hypoglycaemia, such as insulin and SU.

The current approach to diabetes in the elderly incorporates components from the comprehensive geriatric approach. The most updated guidelines from the American Diabetes Association reflect influence from the consensus made in 2012 with the American Geriatrics Society. Notably, the framework included the evaluation for geriatric syndromes (falls and urinary incontinence), functional and cognitive abilities. The goal for this review is to provide an updated summary of treatment strategies for community-dwelling older adults. We identified the need to expand our approach by addressing innovative approaches and scientific concepts from telemedicine, functional medicine, and geriatrics.

Findings on cardiovascular protection with sodium-glucose co-transporter 2 inhibitors (SGLT-2i) and some glucagon-like peptide 1 receptor agonists (GLP-1RA) support their use for older patients with diabetes. However, careful consideration for agent selection must incorporate the presence of geriatric issues, such as geriatric syndromes, or functional and cognitive decline, as they could increase the risk and impact adverse reactions. Telemedicine interventions can improve communication and connection between older patients and their providers, and improve glycemic control. Functional medicine concepts can offer additional adjuvant strategies to support the therapeutic interventions and management of diabetes in the elderly. A systematic review confirmed the efficacy and safety of metformin as first-line therapy of type 2 diabetes in the older adult, but multiple reports highlighted the risk for vitamin B12 deficiency. Randomized controlled trials showed the efficacy and safety of antihyperglycemic agents in the elderly, including some with longer duration and lesser risk for hypoglycemia. Randomized clinical trials showed cardiovascular protection with SGLT-2i (empagliflozin, canagliflozin) and GLP-1RA (liraglutide, semaglutide). The most current guidelines recommend addressing for geriatric syndromes, physical and cognitive function in the elderly, in order to individualize targets and therapeutic strategies. Clinicians managing diabetes in the elderly can play a major role for the early detection and evaluation of geriatric issues in their patients. Telemedicine interventions improve glycemic control, and certain functional medicine strategies could be adjuvant interventions to reduce inflammation and stress, but more studies focused on the elderly population are needed.

The U.S. Food and Drug Administration issued a guidance for pharmaceutical industry defining preapproval and postapproval requirements for the demonstration of cardiovascular (CV) safety for all new medications developed for glycemic management in type 2 diabetes. However, results published from the studies of dipeptidyl peptidase-4 (DPP-4) inhibitors are conflicting with regard to different CV endpoints. Upcoming CV outcome studies perhaps will be able to provide additional insights related to diabetes management and help to provide the answers to some of these concerns. This article provides a brief overview regarding how various CV safety evidence of DPP-4 inhibitor evolved over time that highlights possible implication in clinical practice and translates them into effective diabetes management.

To show long-term cardiovascular safety of the GLP-1 receptor agonists for diabetes patients with cardiovascular risk.

For cardiovascular outcomes, the association between treatment and outcomes was estimated using the odds ratio and 95% confidence interval. I² test was adopted to assess the magnitude of heterogeneity between studies, with values more than 25%, 50%, and 75% defined as low, moderate, or high heterogeneity.

We combined data from four cardiovascular outcomes trials and prospectively blinded endpoint adjudication. 4105 cardiovascular events including cardiovascular death, acute MI or stroke experienced during the trials. And the odds ratios of the cardiovascular outcomes were 0.90 (95% CI 0.81, 1.00) for the cardiovascular outcome, 0.93 (95% CI 0.85, 1.02) for nonfatal myocardial infarction, 0.88 (95% CI 0.76, 1.03) for nonfatal stroke, 0.94 (95% CI 0.84, 1.05) for heart failure hospitalization, 0.89 (95% CI 0.63, 1.27) for pancreatitis, 0.98 (95% CI 0.92, 1.05) for any hypoglycemic events, 0.92 (95% CI 0.83, 1.01) for the severe hypoglycemic events, 0.96 (95% CI 0.83, 1.01) for serious adverse events. Significant differences showed in mortality parameters: 0.88 (95% CI 0.81, 0.95) for all-cause mortality, 0.87 (95% CI 0.79, 0.97) for cardiovascular mortality. CV benefits were obtained in the male, black, Asian patients and patients with BMI ≥ 30 kg/m².

Additional GLP-1 receptor agonists treatment did not increase cardiovascular outcomes in diabetes patients with high cardiovascular risk or established cardiovascular disease.

Cardiovascular disease (CVD) is a major challenge in the management of type 2 diabetes mellitus. Glucose-lowering agents that reduce the risk of major cardiovascular events would be considered a major advance, as recently reported with liraglutide and semaglutide, 2 glucagon-like peptide-1 receptor agonists, and with empagliflozin and canagliflozin, 2 SGLT-2 (sodium-glucose cotransporter type 2) inhibitors, but not with DPP-4 (dipeptidyl peptidase-4) inhibitors. The present review is devoted to CV effects of new oral glucose-lowering agents. DPP-4 inhibitors (gliptins) showed some positive cardiac and vascular effects in preliminary studies, and initial data from phase 2 to 3 clinical trials suggested a reduction in major cardiovascular events. However, subsequent CV outcome trials with alogliptin, saxagliptin, and sitagliptin showed noninferiority but failed to demonstrate any superiority compared with placebo in patients with type 2 diabetes mellitus and high CV risk. An unexpected higher risk of hospitalization for heart failure was reported with saxagliptin. SGLT-2 inhibitors (gliflozins) promote glucosuria, thus reducing glucose toxicity and body weight, and enhance natriuresis, thus lowering blood pressure. Two CV outcome trials in type 2 diabetes mellitus patients mainly in secondary prevention showed remarkable positive results. Empagliflozin in EMPA-REG-OUTCOME (EMPAgliflozin Cardiovascular OUTCOME Events in Type 2 Diabetes Mellitus Patients) reduced major cardiovascular events, CV mortality, all-cause mortality, and hospitalization for heart failure. In CANVAS (Canagliflozin Cardiovascular Assessment Study), the reduction in CV mortality with canagliflozin failed to reach statistical significance despite a similar reduction in major cardiovascular events. The underlying protective mechanisms of SGLT-2 inhibitors remain unknown and both hemodynamic and metabolic explanations have been proposed. CVD-REAL studies (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors; with the limitation of an observational approach) suggested that these favorable results may be considered as a class effect shared by all SGLT-2 inhibitors (including dapagliflozin) and be extrapolated to a larger population of patients with type 2 diabetes mellitus in primary prevention. Ongoing CV outcome trials with other DPP-4 (linagliptin) and SGLT-2 (dapagliflozin, ertugliflozin) inhibitors should provide additional information about CV effects of both pharmacological classes.

Dipeptidyl peptidase-4 inhibitors (DPP-4is) are generally considered as glucose-lowering agents with a safe profile in type 2 diabetes.

An updated review of recent safety data from randomised controlled trials, observational studies, meta-analyses, pharmacovigilance reports regarding alogliptin, linagliptin, saxagliptin, sitagliptin, and vildagliptin, with a special focus on risks of hypoglycemia, pancreatitis and pancreatic cancer, major cardiovascular events, hospitalisation for heart failure and other new safety issues, such as bone fractures and arthralgia. The safety of DPP-4i use in special populations, elderly patients, patients with renal impairment, liver disease or heart failure, will also be discussed.

The good tolerance/safety profile of DPP-4is has been largely confirmed, including in more fragile populations, with no gastrointestinal adverse effects and a minimal risk of hypoglycemia. DPP-4is appear to be associated with a small increased incidence of acute pancreatitis in placebo-controlled trials, although most observational studies are reassuring. Most recent studies with DPP-4is do not confirm the increased risk of hospitalisation for heart failure reported with saxagliptin in SAVOR-TIMI 53, but further post-marketing surveillance is still recommended. New adverse events have been reported such as arthralgia, yet a causal relationship remains unclear.

The first clinical study to investigate effects of dipeptidyl peptidase-4 (DPP-4) inhibition was published in 2002, and since then, numerous randomized controlled trials (RCTs) have shown that DPP-4 inhibitors are efficacious, safe and well-tolerated. This review will focus upon RCTs which have investigated DPP-4 inhibitors in patient groups which are often under-represented or excluded from typical phase 3 clinical trials. Large cardiovascular (CV) safety outcome trials in patients with established CV disease have confirmed that DPP-4 inhibitors are not associated with any additional CV risk in these already-at-high-risk individuals, while raising awareness of any uncommon adverse events, such as heart failure hospitalization seen in one of the trials. Studies in patients with kidney disease have shown DPP-4 inhibitors to be efficacious without increasing the risk of hypoglycaemia, irrespective of the degree of renal impairment, while data from the large CV trials as well as smaller RCTs have even pointed towards potential renoprotective effects such individuals. The use of DPP-4 inhibitors with insulin when therapy requires intensification may be beneficial without affecting the incidence or severity of hypoglycaemia, with these effects also being replicated in patients with chronic kidney disease, for whom other agents may not be suitable. Attention is now turning towards exploring the potential utility of DPP-4 inhibitors in other circumstances, including for in-hospital management of hyperglycaemia and in other metabolic disorders. Together, these RCTs raise the possibility that in the future, DPP-4 inhibitors may have a broader use which may extend beyond glycaemic control in the typical type 2 diabetes mellitus (T2DM) patient seen in general practice and may encompass conditions other than T2DM.

Saxagliptin (a dipeptidyl peptidase-4 inhibitor, DPP-4i) and dapagliflozin (a sodium-glucose cotransporter type 2 inhibitor, SGLT2i) improve glucose control in type 2 diabetes (T2D) through different potentially complementary mechanisms, thus offering the opportunity for a combined therapy. Area covered: The characteristics of the saxagliptin/dapagliflozin combination are analysed, focusing on: 1) pharmacokinetic and pharmacodynamic properties; 2) efficacy and safety in phase III trials with concurrent and sequential add-on therapy; and 3) potential use in clinical practice, including in special populations (cardiovascular disease, heart failure, chronic kidney disease, elderly). Expert commentary: Conclusions drawn from clinical trials investigating combination with the separate drugs are considered to apply to the fixed-dose combination (FDC) that demonstrates bioequivalence. Dual saxagliptin/dapagliflozin therapy is more potent than either monotherapy and can be used as an initial combination or a stepwise sequential approach. Dual therapy is generally well tolerated and may be used in special populations, with some limitations because of the presence of dapagliflozin. However, the latter may offer some advantages because of multiple effects attributed to SGLT2i. The best place of this dual combination for the management of T2D and the profile of patients who will make the most of this combined therapy remains to be defined.