Longitudinal effects of glucose-lowering medications on β-cell responses and insulin sensitivity in type 2 diabetes: The GRADE randomized clinical trial

Objective: To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, sitagliptin) when added to metformin on insulin sensitivity and β-cell function.

Research Design and Methods: In the GRADE cohort with type 2 diabetes (n=4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting β-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. OGTT β-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 minutes]) were evaluated at the same timepoints. These responses adjusted for HOMA2-%S in regression analysis provided estimates of β-cell function.

Results: HOMA2-%S increased from baseline to year 1 with glargine and remained stable thereafter, while it did not change from baseline in the other treatment groups. HOMA2-%B and C-peptide responses increased to variable degrees at year 1 in all groups, but then declined progressively over time. At year 5, CPI was similar between liraglutide and sitagliptin, both higher than glargine and glimepiride (0.80, 0.87, 0.74, 0.64 (nmol/L)/(mg/dL)*100, respectively, p<0.001), while the total C-peptide response was greatest with liraglutide followed in descending order by sitagliptin, glargine and glimepiride (1.54, 1.25, 1.02, 0.87 (nmol/L)/(mg/dL)*100, respectively, p<0.001). After adjusting for HOMA2-%S to obtain an estimate of β-cell function, the nature of the change in β-cell responses reflected those in β-cell function.

Conclusion: The differential long-term effects on insulin sensitivity and β-cell function of four different glucose-lowering medications when added to metformin highlight the importance of the loss of β-cell function in the progression of type 2 diabetes.