Longitudinal Effects of Glucose-Lowering Medications on β-Cell Responses and Insulin Sensitivity in Type 2 Diabetes: The GRADE Randomized Clinical Trial

Abstract

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

Research design and methods: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (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. Oral glucose tolerance test β-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 min]) were evaluated at the same time points. 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 were 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, and higher for both than for glargine and glimepiride [0.80, 0.87, 0.74, and 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, and 0.87 (nmol/L)/(mg/dL) * 100, respectively, P < 0.001]. After adjustment 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.

Conclusions: 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.

Graphical abstract

Figure 1

Effects of four different glucose-lowering medications on levels of HbA_1c (A), fasting glucose (B), and fasting C-peptide (C). The square diagrams in the lower part of the panels denote the range of the P values for the six pairwise group comparisons of treatment groups. Bold line represents P < 0.05. G and Glim, glimepiride; I and Ins, insulin glargine; L and Lira, liraglutide; and S and Sita, sitagliptin. Rand. represents randomization, or baseline.

Figure 2

Effects of four different glucose-lowering medications on glucose (left) and C-peptide (right) profiles during the OGTT at baseline (A and B), at year 1 (C and D), at year 3 (E and F), and at year 5 (G and H).

Figure 3

Effects of four different glucose-lowering medications on insulin sensitivity, β-cell responses, and β-cell function at baseline and years 1, 3, and 5 on treatment. HOMA2-%S based on C-peptide (A), HOMA2-%B based on C-peptide (B), CPI (C), total C-peptide response [calculated as 100 × (C-peptide incAUC_0–120/(glucose incAUC_0–120)] (D), CPI adjusted for HOMA2-%S (E), and total C-peptide response adjusted for HOMA2-%S (F). The square diagrams in the lower parts of the panels denote the range of the P values for the six pairwise group comparisons of treatment groups. Bold line represents P < 0.05. G and Glim, glimepiride; I and Ins, insulin glargine; L and Lira, liraglutide; S and Sita, sitagliptin. Rand. represents randomization, or baseline.