Glycemia Reduction in Type 2 Diabetes - Glycemic Outcomes

Abstract

Background: The comparative effectiveness of glucose-lowering medications for use with metformin to maintain target glycated hemoglobin levels in persons with type 2 diabetes is uncertain.

Methods: In this trial involving participants with type 2 diabetes of less than 10 years' duration who were receiving metformin and had glycated hemoglobin levels of 6.8 to 8.5%, we compared the effectiveness of four commonly used glucose-lowering medications. We randomly assigned participants to receive insulin glargine U-100 (hereafter, glargine), the sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or sitagliptin, a dipeptidyl peptidase 4 inhibitor. The primary metabolic outcome was a glycated hemoglobin level, measured quarterly, of 7.0% or higher that was subsequently confirmed, and the secondary metabolic outcome was a confirmed glycated hemoglobin level greater than 7.5%.

Results: A total of 5047 participants (19.8% Black and 18.6% Hispanic or Latinx) who had received metformin for type 2 diabetes were followed for a mean of 5.0 years. The cumulative incidence of a glycated hemoglobin level of 7.0% or higher (the primary metabolic outcome) differed significantly among the four groups (P<0.001 for a global test of differences across groups); the rates with glargine (26.5 per 100 participant-years) and liraglutide (26.1) were similar and lower than those with glimepiride (30.4) and sitagliptin (38.1). The differences among the groups with respect to a glycated hemoglobin level greater than 7.5% (the secondary outcome) paralleled those of the primary outcome. There were no material differences with respect to the primary outcome across prespecified subgroups defined according to sex, age, or race or ethnic group; however, among participants with higher baseline glycated hemoglobin levels there appeared to be an even greater benefit with glargine, liraglutide, and glimepiride than with sitagliptin. Severe hypoglycemia was rare but significantly more frequent with glimepiride (in 2.2% of the participants) than with glargine (1.3%), liraglutide (1.0%), or sitagliptin (0.7%). Participants who received liraglutide reported more frequent gastrointestinal side effects and lost more weight than those in the other treatment groups.

Conclusions: All four medications, when added to metformin, decreased glycated hemoglobin levels. However, glargine and liraglutide were significantly, albeit modestly, more effective in achieving and maintaining target glycated hemoglobin levels. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; GRADE ClinicalTrials.gov number, NCT01794143.).

Figure 1.. Kaplan–Meier Analysis of Outcome Events and Mean Glycated Hemoglobin Levels.

Shown are the cumulative incidences of a glycated hemoglobin level of 7.0% or higher (the primary metabolic outcome) (Panel A), a glycated hemoglobin level of greater than 7.5% (the secondary metabolic outcome) (Panel B), and a confirmed glycated hemoglobin level greater than 7.5% after the secondary outcome (the tertiary metabolic outcome) (Panel C), as well as the mean glycated hemoglobin levels (Panel D). In Panels A through C, the shaded bars along the x axis indicate the number of participants with data available for the analyses over time (i.e., the number of participants in whom a specified outcome event had not developed by that time). The vertical dashed lines indicate the results at 4 years, when 85.8% of the participants were undergoing follow-up. To convert values for glycated hemoglobin to millimoles per mole, multiply by 10.93 and then subtract 23.5.

Figure 2.. Analyses of the Primary Outcome According to Baseline Glycated Hemoglobin Levels.

The risk reductions, calculated from the hazard ratios, with glargine, glimepiride, and liraglutide, as compared with sitagliptin, are shown with unadjusted 95% confidence intervals. To convert values for glycated hemoglobin to millimoles per mole, multiply by 10.93 and then subtract 23.5.

Figure 3.. Overall Incidence of Adverse Events.

Event rates were calculated as the number of events per 100 participant-years. Simple P values (not corrected for multiple tests among event types or treatment groups) were obtained from a Poisson regression model of the rates. The diagram denotes the range of the P values for the six pairwise group comparisons of each adverse event. The following were adjudicated events: serious adverse events or any targeted events, including severe hypoglycemia, lactic acidosis, pancreatitis, diabetic ketoacidosis or hyperosmolar hyperglycemic syndrome, revascularization (coronary, peripheral, or cerebral), congestive heart failure, or cancer. The first occurrence of weight gain of 10% or more was compared with the baseline weight. Gastrointestinal symptoms included any one of the following symptoms that occurred at least once per week in the 30 days before the quarterly visit and were reported by the participant: nausea, vomiting, bloating or stomach pain, or diarrhea.