Double-blind, randomized clinical trial comparing the efficacy and safety of continuing or discontinuing the dipeptidyl peptidase-4 inhibitor sitagliptin when initiating insulin glargine therapy in patients with type 2 diabetes: The CompoSIT-I Study

Abstract

Aims: To compare the effects of continuing versus discontinuing sitagliptin when initiating and intensively titrating insulin glargine.

Materials and methods: Eligible patients had inadequately controlled type 2 diabetes on metformin (≥1500 mg/d) in combination with a dipeptidyl peptidase-4 (DPP-4) inhibitor and/or a sulphonylurea. Those on metformin + sitagliptin were directly randomized; all others were switched to metformin + sitagliptin (discontinuing other DPP-4 inhibitors and sulphonylureas) and stabilized during a run-in period. At randomization, patients were allocated to continuing sitagliptin or discontinuing sitagliptin, with both groups initiating insulin glargine and titrating to a target fasting glucose of 4.0 to 5.6 mmol/L.

Results: A total of 743 participants (mean glycated haemoglobin [HbA1c] 72.6 mmol/mol [8.8%], disease duration 10.8 years), were treated. After 30 weeks, the mean HbA1c and least squares (LS) mean change from baseline in HbA1c were 51.4 mmol/mol (6.85%) and -20.5 mmol/mol (-1.88%) in the sitagliptin group and 56.4 mmol/mol (7.31%) and -15.5 mmol/mol (-1.42%) in the placebo group; the difference in LS mean changes from baseline HbA1c was -5.0 mmol/mol (-0.46%; P < 0.001). The percentage of participants with HbA1c <53 mmol/mol (<7.0%) was higher (54% vs. 35%) and the mean daily insulin dose was lower (53 vs. 61 units) in the sitagliptin group. Despite lower HbA1c, event rates and incidences of hypoglycaemia were not higher in the sitagliptin group. Adverse events overall and changes from baseline in body weight were similar between the two treatment groups.

Conclusion: When initiating insulin glargine therapy, continuation of sitagliptin, compared with discontinuation, resulted in a clinically meaningful greater reduction in HbA1c without an increase in hypoglycaemia. ClinicalTrials.gov Identifier: NCT02738879.

Keywords: clinical trial; insulin therapy; sitagliptin; type 2 diabetes.

Conflict of interest statement

Author contributions

R.R., S.D.G., Y.Z., S.S., C.D., R.R.S., G.T.G., R.L.H.L., E.A.O.N., I.G., K.D.K. and S.S.E. are responsible for the work described in this paper. S.D.G., Y.Z., C.D., R.R.S., G.T.G. and S.S.E. conceived, designed and/or planned the study. S.D.G., S.S. and C.D. acquired the data. S.D.G., Y.Z., S.S., G.T.G. and I.G. analysed the data. R.R., S.D.G., Y.Z., G.T.G., R.L.H.L., E.A.O.N., I.G., K.D.K. and S.S.E. interpreted the results. G.T.G., E.A.O.N. and I.G. drafted the manuscript. R.R., S.D.G., Y.Z., S.S., C.D., R.R.S., G.T.G., R.L.H.L., I.G., K.D.K. and S.S.E. critically reviewed and/or revised the manuscript for important intellectual content.

All authors provided final approval of the version to be published and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Data availability

Merck & Co., Inc.'s data sharing policy, including restrictions, is available at http://engagezone.merck.com/ds_documentation.php. Requests for access to the study data can be submitted through the EngageZone site or via email to dataaccess@merck.com.

© 2018 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

Figure 1

Participant disposition. Abbreviation: eGFR, estimated glomerular filtration rate

Figure 2

Least squares (LS) mean ± SE change from baseline in A, glycated haemoglobin (HbA1c), % B, fasting plasma glucose (FPG), mmol/L and C, daily insulin dose, units (U) up to week 30. Black circles, sitagliptin; open circles, placebo. §Least squares (LS) mean (95% confidence interval) change from baseline. *Between‐group difference and P value are model‐based