Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, University of Colorado School of Medicine, and VA Eastern Colorado Health Care System, Aurora, CO.
The Biostatistics Center, Department of Biostatistics and Bioinformatics, Milken Institute School of Public Health, The George Washington University, Rockville, MD.
Diabetes Care. 2024 Apr 1;47(4):580-588. doi: 10.2337/dc23-1070.
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.
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.
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.
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.
比较在二甲双胍的基础上加用不同的降糖药物（甘精胰岛素 U-100、格列美脲、利拉鲁肽和西他列汀）对胰岛素敏感性和β细胞功能的长期影响。
在糖尿病血糖控制：疗效比较研究（GRADE）队列中，纳入 4801 例 2 型糖尿病患者，在基线及治疗 1、3 和 5 年时采用 HOMA2 估计胰岛素敏感性（HOMA2-%S）和空腹β细胞功能（HOMA2-%B）。同时在相同时间点评估口服葡萄糖耐量试验的β细胞反应（C 肽指数[CPI]和总 C 肽反应[120 分钟内 C 肽的增量/葡萄糖的增量]）。在回归分析中对 HOMA2-%S 进行校正后，提供β细胞功能的估计值。
甘精胰岛素治疗后 HOMA2-%S 从基线增加到第 1 年，并在此后保持稳定，而其他治疗组从基线开始没有变化。所有组在第 1 年均不同程度地增加了 HOMA2-%B 和 C 肽反应，但随着时间的推移逐渐下降。在第 5 年时，利拉鲁肽和西他列汀的 CPI 相似，且均高于甘精胰岛素和格列美脲[分别为 0.80、0.87、0.74 和 0.64（nmol/L）/（mg/dL）*100；P<0.001]，而利拉鲁肽的总 C 肽反应最大，其次是西他列汀、甘精胰岛素和格列美脲[分别为 1.54、1.25、1.02 和 0.87（nmol/L）/（mg/dL）*100；P<0.001]。在对 HOMA2-%S 进行校正以获得对β细胞功能的估计后，β细胞反应的变化性质反映了β细胞功能的变化。
四种不同降糖药物在加用至二甲双胍治疗时对胰岛素敏感性和β细胞功能的长期影响不同，突出了 2 型糖尿病进展中β细胞功能丧失的重要性。
