Double‐blind, randomized clinical trial assessing the efficacy and safety of early initiation of sitagliptin during metformin uptitration in the treatment of patients with type 2 diabetes: The CompoSIT‐M study

Abstract

Aims To characterize the glycaemic efficacy and safety of initiation of the dipeptidyl peptidase‐4 inhibitor sitagliptin during metformin dose escalation in people with type 2 diabetes (T2D) not at glycated haemoglobin (HbA1c) goal on a sub‐maximal dose of metformin. Materials and methods Study participants with HbA1c ≥58 mmol/mol and ≤97 mmol/mol (≥7.5% and ≤11.0%) while on 1000 mg/d metformin were randomized to sitagliptin 100 mg once daily or placebo. All were to uptitrate metformin to 2000 mg/d. A longitudinal data analysis model was used to test the primary hypothesis that sitagliptin is superior to placebo when initiated during uptitration of metformin in reducing HbA1c at week 20. [ ClinicalTrials.gov Identifier: NCT02791490, EudraCT: 2015‐004224‐59] Results A total of 458 participants (mean HbA1c 71.1 mmol/mol [8.7%], T2D duration 6.3 years) were treated. After 20 weeks, the least squares (LS) mean changes from baseline in HbA1c were −12.1 mmol/mol (−14.0, −10.1) (−1.10% [−1.28, −0.93]) and −7.6 mmol/mol (−9.6, −5.6) (−0.69% [−0.88, −0.51]) with sitagliptin and placebo, respectively; the between‐group difference in LS mean changes from baseline HbA1c was −4.5 mmol/mol (−6.5, −2.5) (−0.41% [−0.59, −0.23]); P < 0.001. The likelihood of having HbA1c <53 mmol/mol (<7.0%) at week 20 was higher in the sitagliptin group than in the placebo group in the overall population (relative risk 1.7, P = 0.002) and in those with a baseline HbA1c ≥69 mmol/mol (≥8.5%) (relative risk 2.4, P = 0.026). There were no notable differences between groups with regard to adverse events overall, hypoglycaemia events, changes in body weight or other safety variables. Conclusion In participants not at HbA1c goal on a sub‐maximal dose of metformin, addition of sitagliptin at the time of metformin dose uptitration improved glycaemic response and HbA1c goal attainment, with similar safety and tolerability, compared to metformin uptitration alone.

Optimization of Metformin in the GRADE Cohort: Effect on Glycemia and Body Weight

“…Three smaller studies compared increments in metformin dosing from 1,000 to 2,000 mg/day to continuation of metformin 1,000 mg/day with additions of sitagliptin (20), vildagliptin (21), or rosiglitazone (22). Respectively, for participants whose metformin dose was increased, these studies showed changes in HbA 1c of 20.80% (28.7 mmol/mol) from a baseline mean of 8.7% (72 mmol/mol), 20.37% (24.0 mmol/mol) from a baseline mean of 7.3% (56 mmol/mol), and 20.71% (27.8 mmol/mol) from a baseline mean of 8.0% (64 mmol/mol).…”

Drug-Drug Interactions at Organic Cation Transporter 1

“…There are additional reports on DDIs between metformin and clinical used drugs. Frias et al reported that in subjects who did not reach the maximal goal of HbA1c with a sub-maximal dose of metformin, the addition of sitagliptin improved the glycemic response and glycated hemoglobin goals, while the safety and tolerability were similar with metformin treatment alone ( Frias et al, 2019 ). A possible mechanism is that the inhibition of OCT1 by sitagliptin could reduce the phosphorylation of AMPK, the first step in metformin's action ( Choi et al, 2010 ).…”

A systematic review on metformin rational pharmacotherapeutics

“…Metformin, as its pharmacological cotherapeutic actions, also stabilises the HbA1c levels, along with reduction in weight, among these patients affected with diabetes associated obesity. [3][4][5][6][7][8][9][10][11][12][13][14][15] Several systematic reviews had been conducted on various oral hypoglycaemic drugs, including metformin. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] To further supplement these systematic reviews, with the main objective to understand and illuminate on the perspectives of metformin rational pharmacotherapeutics, this systematic review was conducted.…”

“…[3][4][5][6][7][8][9][10][11][12][13][14][15] Several systematic reviews had been conducted on various oral hypoglycaemic drugs, including metformin. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15] To further supplement these systematic reviews, with the main objective to understand and illuminate on the perspectives of metformin rational pharmacotherapeutics, this systematic review was conducted. This systematic review of the different and wide-ranged studies on metformin rational pharmacotherapeutics was performed, for a better, clear and complete comprehension of multi-centre maintenance of rational pharmacotherapeutic aspects in regular anti-diabetic treatments prescribed to the new type II diabetic patients.…”