Aims/hypothesis The aim of this study was to investigate the incremental and proportional effect of a sulfonylurea on insulin secretion rates at low, elevated and high blood glucose, using parallel groups with ascending or descending glucose steps to minimise potential biases of a single stepped clamp order. Methods Following 14 days on placebo or glibenclamide (2.5 mg) tablets twice daily, separated by 14 days washout, 19 type 2 diabetic patients had ascending or descending threestep hyperinsulinaemic glucose clamps at 4, 8 and 12 mmol/l. C-peptide secretion was estimated by two-compartment C-peptide deconvolution. Results Patients in the ascending glucose steps group (n=10) had mean (SD) age of 60.3 (6.5) years, BMI of 29.8 (4.9)kg/m 2 and fasting glucose on diet alone of 10.6 (2.9) mmol/l; while those in the descending glucose steps group (n=9) had mean age of 58.2 (8.0) years, BMI of 30.5 (5.4)kg/m 2 and fasting glucose on diet alone of 9.8 (2.2) mmol/l. The geometric means (95% CI) of C-peptide secretion rates on placebo for glucose at 4.0, 8.0 and 12.0 mmol/l were 63 (46, 86), 143 (105, 195) and 205 (149, 281)pmol/min, respectively. On glibenclamide, this increased by 140 (99, 181), 126 (85, 167) and 158 (117, 199) pmol/min, respectively ( p<0.001 vs placebo). The absolute increment was significant ( p<0.001) and independent of clamp glucose concentration ( p=0.54). The proportional increase was greater at 4 mmol/l: 2.8-fold (2.4, 3.2), compared with 1.8-fold (1.5, 2.0) and 1.7-fold (1.4, 1.9) at 8 and 12 mmol/l, respectively ( p<0.001). Conclusions/interpretation At low-normal glucose, glibenclamide exerted a disproportionate effect on insulin secretion. This study highlights the risks of hypoglycaemia when aiming for tight glucose control on this agent.

Background Early use of combination therapy in diabetes patients may lead to sustained glycemic control and thereby reduce the progression of diabetic complications. Given the limitation of the traditional stepwise intensification strategy, early combination therapy can be an effective approach. Therefore, this study aims to assess the real-world efficacy of a combination of metformin and vildagliptin in comparison to metformin alone in type 2 diabetes mellitus (T2DM) patients in India. Methods This was an observational, retrospective, non-interventional study based on electronic medical records (EMRs) of 2740 T2DM patients, retrieved from 2010 onwards from 22 diabetes centres across India. Adult drug naïve patients with a 5-year history of T2DM treated with either metformin or a combination of metformin and vildagliptin for at least 3 months were considered for this study. Efficacy assessment was done to evaluate the post-treatment HbA1c levels and patients requiring additional oral antidiabetic drugs (OADs) at the time of follow-up visit. Patients were also analyzed for the occurrence of adverse events. Results Out of the total, 2452 patients were in metformin only arm, and 288 patients were in metformin plus vildagliptin treatment arm. A more significant reduction in HbA1c level was observed in metformin plus vildagliptin arm than metformin only arm (median: −0.5% vs 0%, respectively; p <0.001). Patients requiring additional OAD at follow-up were significantly lesser in the metformin plus vildagliptin arm than the metformin only arm (15.6% vs 35.2%, respectively; p <0.001). The adverse events were comparable across the two arms, and commonly reported adverse events were giddiness, fatigue and gastric discomfort. Conclusion The findings of this EMR-based real-world study emphasizes the need for early initiation of combination therapy (metformin plus vildagliptin) over metformin monotherapy for achieving better glycemic control.

Diabetes mellitus is a global health concern associated with significant morbidity and mortality. Inadequate control of diabetes leads to chronic complications and higher mortality rates, which emphasizes the importance of achieving glycemic targets. Although glycated hemoglobin (HbA 1c ) is the gold standard for measuring glycemic control, it has several limitations. Therefore, in recent years, along with the emergence of continuous glucose monitoring (CGM) technology, glycemic control modalities have moved beyond HbA 1c . They encompass modern glucometrics, such as glycemic variability (GV) and time-in-range (TIR). The key advantage of these newer metrics over HbA 1c is that they allow personalized diabetes management with person-centric glycemic control. Basal insulin analogues, especially second-generation basal insulins with properties such as longer duration of action and low risk of hypoglycemia, have demonstrated clinical benefits by reducing GV and improving TIR. Therefore, for more effective and accurate diabetes management, the development of an integrated approach with second-generation basal insulin and glucometrics involving GV and TIR is the need of the hour. With this objective, a multinational group of endocrinologists and diabetologists reviewed the existing recommendations on TIR, provided their clinical insights into the individualization of TIR targets, and elucidated on the role of the second-generation basal insulin analogues in addressing TIR.