Glycemia Reduction in Type 2 Diabetes - Microvascular and Cardiovascular Outcomes

Abstract

Background: Data are lacking on the comparative effectiveness of commonly used glucose-lowering medications, when added to metformin, with respect to microvascular and cardiovascular disease outcomes in persons with type 2 diabetes.

Methods: We assessed the comparative effectiveness of four commonly used glucose-lowering medications, added to metformin, in achieving and maintaining a glycated hemoglobin level of less than 7.0% in participants with type 2 diabetes. The randomly assigned therapies were insulin glargine U-100 (hereafter, glargine), glimepiride, liraglutide, and sitagliptin. Prespecified secondary outcomes with respect to microvascular and cardiovascular disease included hypertension and dyslipidemia, confirmed moderately or severely increased albuminuria or an estimated glomerular filtration rate of less than 60 ml per minute per 1.73 m² of body-surface area, diabetic peripheral neuropathy assessed with the Michigan Neuropathy Screening Instrument, cardiovascular events (major adverse cardiovascular events [MACE], hospitalization for heart failure, or an aggregate outcome of any cardiovascular event), and death. Hazard ratios are presented with 95% confidence limits that are not adjusted for multiple comparisons.

Results: During a mean 5.0 years of follow-up in 5047 participants, there were no material differences among the interventions with respect to the development of hypertension or dyslipidemia or with respect to microvascular outcomes; the mean overall rate (i.e., events per 100 participant-years) of moderately increased albuminuria levels was 2.6, of severely increased albuminuria levels 1.1, of renal impairment 2.9, and of diabetic peripheral neuropathy 16.7. The treatment groups did not differ with respect to MACE (overall rate, 1.0), hospitalization for heart failure (0.4), death from cardiovascular causes (0.3), or all deaths (0.6). There were small differences with respect to rates of any cardiovascular disease, with 1.9, 1.9, 1.4, and 2.0 in the glargine, glimepiride, liraglutide, and sitagliptin groups, respectively. When one treatment was compared with the combined results of the other three treatments, the hazard ratios for any cardiovascular disease were 1.1 (95% confidence interval [CI], 0.9 to 1.3) in the glargine group, 1.1 (95% CI, 0.9 to 1.4) in the glimepiride group, 0.7 (95% CI, 0.6 to 0.9) in the liraglutide group, and 1.2 (95% CI, 1.0 to 1.5) in the sitagliptin group.

Conclusions: In participants with type 2 diabetes, the incidences of microvascular complications and death were not materially different among the four treatment groups. The findings indicated possible differences among the groups in the incidence of any cardiovascular disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.).

Figure 1.. Cumulative Incidences of Hypertension and Dyslipidemia in the Intention-to-Treat Analyses.

Shown are the cumulative incidences of hypertension (Panel A) and dyslipidemia (Panel B) over 6.5 years of follow-up among participants who did not have each condition at baseline. The numbers plotted below the x axis of each panel are the numbers of participants at risk for the outcome at each follow-up time point (i.e., the number of participants in whom a specified outcome event had not developed by that time). Participants who had the condition at baseline were excluded, leaving 1168 of 5047 participants (23%) in the analysis of hypertension and 195 of 5047 participants (4%) in the analysis of dyslipidemia. There was no substantial difference among the groups with respect to the cumulative incidences of hypertension or dyslipidemia.

Figure 2.. Cumulative Incidences of Microvascular Outcomes in the Intention-to-Treat Analyses.

Shown are the cumulative incidences of the following conditions over 6.5 years of follow-up among participants who did not have one of these conditions at baseline: confirmed moderately increased albuminuria level (≥30 mg of albumin per gram of creatinine) or dialysis, transplantation, or death due to end-stage kidney disease (Panel A); severely increased albuminuria level (≥300 mg of albumin per gram of creatinine) or dialysis, transplantation, or death due to end-stage kidney disease (Panel B); renal impairment (estimated glomerular filtration rate of <60 ml per minute per 1.73 m² of body-surface area) (Panel C); and diabetic peripheral neuropathy (Panel D). The numbers plotted below the x axis of each panel are the participants at risk for the outcome at each follow-up time point (i.e., the number of participants in whom a specified outcome event had not developed by that time). The insets show the same data on an enlarged y axis.

Figure 3. Cumulative Incidences of Cardiovascular Outcomes and Mortality in the Intention-to-Treat Analyses.

Shown are the cumulative incidences of any cardiovascular disease (Panel A), a major adverse cardiovascular event (MACE) (Panel B), hospitalization for heart failure (Panel C), death from cardiovascular causes (Panel D), and death from any cause (Panel E) over 6.5 years of follow-up. The numbers plotted below the x axis of each panel are the participants at risk for the outcome at each follow-up time point (i.e., the number of participants in whom a specified outcome event had not developed by that time).