DPP-4 inhibitors (DPP-4is) are often discontinued with initiation of insulin therapy but the impact of this discontinuation on efficacy and hypoglycemia has not been studied. In this double-blind trial the safety and efficacy of initiating insulin while continuing sitagliptin (SITA) was evaluated. Eligible patients had inadequately controlled T2DM on metformin (MET, ≥ 1500 mg/day) in dual or triple combination therapy with a DPP-4i and/or sulfonylurea. Those on MET + SITA (100 mg/day) directly entered the trial; all others were switched to MET + SITA and stabilized during a run-in period. Subjects were randomized to continuing SITA or discontinuing SITA and switching to matching placebo, with both groups initiating insulin (LANTUS®), which was titrated based on fasting glucose.
746 subjects (mean A1C 8.8%, disease duration 10.6 years) were randomized. After 30 weeks, continuing SITA was superior to discontinuing SITA in reducing A1C (p<0.001). Patients who continued SITA had a lower event rate of documented symptomatic hypoglycemia (blood glucose ≤70 mg/dL) and daily insulin dose compared to patients who discontinued SITA. Summary adverse event measures and change in body weight (week 30) were similar in the 2 treatment groups.
In summary, with the initiation of insulin therapy, continuation of SITA resulted in superior glycemic efficacy and less documented symptomatic hypoglycemia.
| Change from Baseline in A1C (%) a | ||
| Treatment | LS Mean (95% CI) | Difference in LS Means (95% CI) |
| SITA, n= 373 | -1.88 (-1.98, -1.78) | -0.46 (-0.58, -0.34) |
| PBO, n= 370 | -1.42 (-1.52, -1.32) | |
| Event Rate of Documented Symptomatic Hypoglycemia (Blood Glucose ≤70 mg/dL) b, c | ||
| Treatment | Event Rate (95% CI) | Event Rate Ratio (95% CI) |
| SITA, n= 371 | 1.55 (1.22, 1.96) | 0.73 (0.54, 0.98) |
| PBO, n= 370 | 2.12 (1.70, 2.66) | |
| Total Daily Insulin Dose (Units) a, d | ||
| Treatment | LS Mean (95% CI) | Difference in LS Means (95% CI) |
| SITA, n= 365 | 53.2 (48.5, 58.0) | -8.0 (-14.6, -1.5) |
| PBO, n= 367 | 61.3 (56.5, 66.0) | |
| Change from Baseline in A1C (%) a | ||
| Treatment | LS Mean (95% CI) | Difference in LS Means (95% CI) |
| SITA, n= 373 | -1.88 (-1.98, -1.78) | -0.46 (-0.58, -0.34) |
| PBO, n= 370 | -1.42 (-1.52, -1.32) | |
| Event Rate of Documented Symptomatic Hypoglycemia (Blood Glucose ≤70 mg/dL) b, c | ||
| Treatment | Event Rate (95% CI) | Event Rate Ratio (95% CI) |
| SITA, n= 371 | 1.55 (1.22, 1.96) | 0.73 (0.54, 0.98) |
| PBO, n= 370 | 2.12 (1.70, 2.66) | |
| Total Daily Insulin Dose (Units) a, d | ||
| Treatment | LS Mean (95% CI) | Difference in LS Means (95% CI) |
| SITA, n= 365 | 53.2 (48.5, 58.0) | -8.0 (-14.6, -1.5) |
| PBO, n= 367 | 61.3 (56.5, 66.0) | |
a Analyzed using a longitudinal data analysis model
b Analyzed using a negative binominal regression model
c Two subjects (both in the sitagliptin group) were not included in the analysis due to a missing value of a model covariate (race)
d 11 subjects did not have post baseline insulin dose data
R. Roussel: Advisory Panel; Self; AbbVie Inc., Abbott, Eli Lilly and Company, Sanofi, Novo Nordisk A/S, AstraZeneca. Speaker's Bureau; Self; Servier. Consultant; Self; Bayer AG. Advisory Panel; Self; Merck Sharp & Dohme Corp.. Research Support; Self; Amgen Inc., Sanofi, Novo Nordisk A/S, Danone Research. Stock/Shareholder; Self; Iriade. Advisory Panel; Self; Physiogenex S.A.S.. S. Duran-Garcia: None. Y. Zhang: None. S. Shah: Employee; Self; Merck & Co., Inc. C. Darmiento: Employee; Self; Merck & Co., Inc. R. Shankar: Employee; Self; Merck & Co., Inc.. Employee; Spouse/Partner; NGM Biopharmaceuticals. E.A. O'Neill: Employee; Self; Merck & Co., Inc. G.T. Golm: Employee; Self; Merck & Co., Inc. R.L. Lam: Employee; Self; Merck & Co., Inc. I. Gantz: Employee; Self; Merck Sharp & Dohme Corp. K.D. Kaufman: Employee; Self; Merck & Co., Inc. S.S. Engel: Employee; Self; Merck & Co., Inc.. Stock/Shareholder; Self; Merck & Co., Inc..
