Effect of glycemic control on markers of subclinical atherosclerosis in patients with type 2 diabetes mellitus: A review

Table 1 Interventional and observational studies on glycemic control in type 2 diabetes mellitus patients and carotid intima media thickness outcomes

Ref.	Year	HbA1c (%), mean ± SD	Type of study	Intervention	Sample size	Main findings
Nambi et al[10]	2010	Glucose levels 105 ± 30.7 mg/dL	Population-based cohort	Risk prediction model: Whether cIMT and plaque improves CHD risk prediction when added to traditional risk factors	13145	0.07 mm greater cIMT in the presence of DM
Kawasumi et al[15]	2006	5.8-6.4	Cohort	Insulin, sulfonylureas, nateglinide, metformin, pioglitazone, α-GI for 3 yr	100	HbA1c improvement > 0.2% prevents cIMT increase
Di Pino et al[14]	2014	5.7-6.4 or > 6.5	Cohort	Subjects without a previous history of diabetes were stratified into three groups according to HbA1c levels	274	Impaired cIMT even in pre-diabetes
Sharma and Pandita[16]	2017	> 7 or < 7	Cohort	T2DM duration > 1 yr or newly diagnosed, age 10-25 yr	45	HbA1c and longer diabetes duration affect cIMT
Di Flaviani et al[17]	2011	6.7 ± 1.3	Cohort	Continuous glucose monitoring; Diet and/or metformin	26	No association was observed between cIMT any glucose variability or overall glycemic load
Langenfeld et al[19]	2005	7.5 ± 0.9	RCT	Pioglitazone 45 mg/d vs glimepiride 2.7 ± 1.6 mg/d for 12-24 wk	173	Pioglitazone reduces cIMT independently of improvement in glycemic control
Oyama et al[20]	2016	6.2 < HbA1c < 9.4%	Multicenter PROBE	Sitagliptin 25 to 100 mg/d vs conventional treatment over 2 yr	442	Sitagliptin had no additional effect on cIMT progression
Rizzo et al[23]	2014	8.4 ± 0.8	Prospective pilot	Liraglutide added on metformin over 8 mo	64	Beneficial role in plaque formation and inflammation

α-GI: Alpha-glucosidase inhibitors; CHD: Coronary heart disease; cIMT: Carotid intima media thickness; CVD: Cardiovascular disease; DM: Diabetes mellitus; LDL: Low-density lipoprotein; RCT: Randomized controlled trial; SD: Standard deviation; T2DM: Type 2 diabetes mellitus.

Table 2 Interventional and observational studies on glycemic control in type 2 diabetes mellitus patients and coronary artery calcification outcomes

Ref.	Year	HbA1c (%), mean ± SD	Type of study	Intervention	Sample size	Main findings
Razavi et al[43]	2021	Fasting glucose > 126 mg/dL	Multiethnic cohort	Two CAC scans with a 10-yr interval	574	More than 40% of adults with MetS or T2DM and baseline CAC = 0 had long-term absence of CAC
Schindler et al[34]	2009	9.8 ± 2.7	Prospective	Glyburide 10-20 mg/d ± metformin 500-1000 mg/d; Observation for 14 ± 2 mo	39	Lower progression of cIMT and CAC with glucose-lowering treatment
Won et al[38]	2018	7.5 ± 1.2 and 6.4 ± 0.9	Retrospective, single-ethnicity, multicenter observational	Data on the impact of optimal glycemic control on CAC progression	1637	Attenuation of CAC progression, especially if CAC > 400
Funck et al[41]	2017	6.5 ± 0.7	Prospective cohort	Observational, 5-yr follow-up	106	CAC progression in DM compared to healthy. Independently associated with PWV
Malik et al[42]	2017	HbA1c measurements were not available at baseline	Prospective cohort	Observational	6814	Baseline CAC values most important progression determinant

CAC: Coronary artery calcification; cIMT: Carotid intima media thickness; DM: Diabetes mellitus; MetS: Metabolic syndrome; PWV: Pulse wave velocity; SD: Standard deviation; T2DM: Type 2 diabetes mellitus.

Table 3 Interventional and observational studies on glycemic control in type 2 diabetes mellitus patients and flow-mediated dilatation outcomes

Ref.	Year	HbA1c (%), mean ± SD	Type of study	Intervention	Sample size	Main findings
Watanabe et al[48]	2000	Fasting glucose 4.9 ± 0.3 mmol/L	Prospective cohort	Troglitazone 400 mg/d for 4 wk in non-DM	13	Improvement on fasting glucose, insulin and FMD
Caballero et al[49]	2003	7.5 ± 1.2 to 7.9 ± 1.5	Prospective randomized double-blinded	Troglitazone 600 mg/d for 12 wk	87	Improvement of FMD in newly diagnosed without CAD
Martens et al[50]	2005	7.1 ± 0.3	Prospective, randomized, crossover, placebo-controlled, double-blinded	Pioglitazone 30 mg/d for 4 wk	20	Improvement of FMD and adiponectin levels
Asnani et al[52]	2006	10 ± 2.3	Prospective randomized double-blinded	Pioglitazone 30 mg/d for 16 wk	20	Improvement of FMD
Chen et al[56]	2011	7.4 ± 1.3	Prospective controlled	Gliclazide 30-90 mg/d for 12 wk	58	Improvement of FMD, ECs and insulin resistance
Naka et al[59]	2012	7.8 ± 0.9 and 8.1 ± 1.3	Open-label randomized	Pioglitazone 30 mg/d or metformin 850 mg/d added to sulfonylureas for 6 mo	36	Improvement of FMD and insulin resistance
Sawada et al[60]	2014	6.9 ± 0.7 vs 7.0 ± 0.4	Randomized prospective	Miglitol 150 mg/d or nateglinide 270 mg/d for 16 wk	104	Improvement of FMD, insulin resistance index and markers of atherogenic dyslipidemia in the α-GI miglitol group
Irace et al[64]	2013	8.9 ± 1.2 and 8.2 ± 1.2	Observational	Exenatide 10-20 μg/d plus metformin vs glimepiride 2-4 mg/d plus metformin for 16 wk	20	Improvement of FMD; Better control on glycemic variability
Nomoto et al[66]	2015	8.6 ± 0.8 and 8.7 ± 0.8	Multicenter, prospective randomized parallel-group comparison	Liraglutide 0.3-0.9 mg/d vs glargine added on metformin and/or sulfonylurea for 14 wk	31	Similar FMD changes and β-cell function protection
Amira et al[68]	2017	Median (range): 8.7 (8.03 – 9.15)	Prospective controlled	Sitagliptin 100 mg/d for 24 wk	80	Improvement of FMD, insulin sensitivity blood pressure and hyperlipidemia
Kubota et al[69]	2012	7.3 ± 0.8	Open-labeled prospective observational single-arm	Sitagliptin 50 mg/d for 12 wk	40	Improvement of FMD and plasma adiponectin increase
Lambadiari et al[70]	2019	8.9 ± 1.8	Prospective cohort	Incretin-based treatment	100	Improvement of FMD and subclinical atherosclerosis after optimal glycemic control
Baltzis et al[71]	2016	7.1 ± 0.8	Randomized, double-blind, placebo-controlled	Linagliptin 5 mg/d vs placebo for 12 wk	40	No improvement in large vessel endothelial function
Takase et al[73]	2018	9.2 ± 1.4	Retrospective preliminary cross-sectional single-center pilot	Canagliflozin 100 mg/d for 4 wk	11	FMD improvement
Shigiyama et al[74]	2017	6.8 ± 0.5 and 6.9 ± 0.5	Prospective, randomized, open-label, blinded end-point, parallel-group, comparative	Dapagliflozin 5 mg/d added on metformin 1500 mg/d for 16 wk	80	Improvement of FMD in newly diagnosed T2DM
Zainordin et al[75]	2020	9.7 ± 1.9	Prospective, randomized, crossover, placebo-controlled, double-blind	Dapagliflozin 10 mg/d vs placebo added on metformin and insulin over 12 wk	81	No difference in FMD between the two groups observed; Significant reduction in surrogate marker of the endothelial function ICAM-1

α-GI: Alpha-glucosidase inhibitor; CAD: Coronary artery disease; DM: Diabetes mellitus; EC: Endothelial cell; FMD: flow-mediated dilatation; SD: Standard deviation; T2DM: Type 2 diabetes mellitus; IL: Interleukin.

Table 4 Interventional and observational studies on glycemic control in type 2 diabetes mellitus patients and pulse wave velocity outcomes

Ref.	Year	HbA1c (%), mean ± SD	Type of study	Intervention	Sample size	Main findings
Koshiba et al[90]	2006	7.8 ± 2.0 and 7.7 ± 1.9	Prospective, randomized	Glibenclamide followed by glimepiride for 28 wk vs continuous administration of glibenclamide vs insulin therapy	34	Improvement of PWV, AIx, IR in the glimepiride group
de Oliveira et al[85]	2015	5.6 ± 0.7 and 6.3 ± 1.1	Prospective cohort	Observational	1675	Higher HbA1c levels are associated with higher PWV
Yu et al[91]	2007	6.5 ± 0.2	Prospective, randomized	Rosiglitazone 4 mg/d for 12 wk in diabetic patients with CAD	123	Decrease in PWV
Sofer et al[93]	2011	Fasting glucose: 132 ± 51 mg/dL	Prospective, randomized, placebo-controlled, double-blind	Metformin in patients with NAFLD with or without T2DM/IFG for 4 mo	63	Decrease in PWV and AIx
Shah et al[94]	2018	7.7± 2.0	Subanalysis of an RCT	Obese patients with metformin vs metformin plus intensive lifestyle intervention vs metformin plus rosiglitazone for 7.6 yr post-randomization	453	PWV increased; Attenuation possible
Scalzo et al[97]	2017	7.3 ± 1.1	Prospective, randomized, placebo-controlled, double-blind	Exenatide 20 μg/d subcutaneously, 30-60 min prior to meals, for 3 mo	23	Decrease in PWV
Koren et al[98]	2012	Fasting glucose: 169 ± 12 mg/dL	Prospective, controlled, open labeled, crossover	Sitagliptin 100 mg/d or glibenclamide 5 mg/d for 3 mo, cross-over switch for an additional 3 mo	34	No PWV benefits; Beneficial BMI effects of sitagliptin
Zografou et al[99]	2015	8.1 ± 0.8	Prospective randomized open-label	Vildagliptin 100 mg/d plus metformin 1700 mg/d vs metformin monotherapy 1700 mg/d	64	No effect on arterial stiffness in drug-naive patients with T2DM
Duvnjak and Blaslov[100]	2016	6.9 ± 1.1	Prospective, uncontrolled, open label, parallel-arm, randomized	Sitagliptin 100 mg/d or vildagliptin 100 mg/d for 3 mo	51	Decrease in PWV and Aix; No HbA1c reduction
De Boer et al[101]	2017	6.3 ± 0.4	Prospective, randomized, placebo-controlled, double-blind	Linagliptin 5 mg/d vs placebo for 26 wk	45	PWV improvement disappears after 4-wk washout period in newly diagnosed T2DM
Chen et al[103]	2009	6.9 ± 1.3	Prospective cohort	Observational	1000	PWV correlates with HbA1c and diabetes duration in patients with T2DM and hypertension
Chang et al[104]	2018	11.7 ± 1.9	Prospective cohort	Insulin or oral hypoglycemic agents (metformin, sulfonylurea, α-GI, DDP-4i) or combined insulin and oral agents for 12 wk	64	No PWV improvement
Ferreira et al[105]	2015	7.6 ± 1.4	Prospective cohort	Metformin, sulfonylureas or insulin for 4.2 yr	417	Attenuation of PWV progression

α-GI: Alpha-glucosidase inhibitor; AIx: Augmentation Index; BMI: Body mass index; CAD: Coronary artery disease; cIMT: Carotid intima media thickness; DDP-4i: dipeptidyl peptidase-4 inhibitor; HCT: Hydrochlorothiazide; IFG: Impaired fasting glucose; IR: Insulin resistance; NAFLD: Nonalcoholic fatty liver disease; PWV: Pulse wave velocity; RCT: Randomized controlled trial; SD: Standard deviation; T2DM: Type 2 diabetes mellitus.