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. http://ClinicalTrials.gov Identifier: NCT02738879.

Factors associated with the discontinuation of dipeptidyl peptidase-4 inhibitors (DPP-4is) after initiation of insulin

“…In a study of patients with T2D and in which a DPP-4i was added therapy was intensified for DPP-4i compared with placebo. In another randomized control trial, continuation of a DPP-4i when initiating basal insulin was shown to be associated with better glycemic control (mean HbA1c and least squares (LS) mean change from baseline in HbA1c were 6.85 and À1.88% in the treatment group and 7.31 and À1.42% in the placebo group), a lower daily insulin dose (53 vs. 61 units), and no difference in the incidence of hypoglycemia after 30 weeks 5 . The cost of DPP-4i in addition to insulin was also reported as a potential reason for discontinuation which would be less of an issue outside the US where, for example in the UK, patients do not contribute to the costs of their anti-diabetes medication.…”

“…In a study of patients with T2D and inadequate control on insulin (with or without metformin) in which a DPP-4i was added and insulin therapy was intensified, a lower event rate (1.7 vs. 3.6 events/participant-year) and incidence of symptomatic hypoglycemia (25.2 vs. 36.8%; p ¼ .001) was observed for DPP-4i compared with placebo 9,10 . In another randomized control trial, continuation of a DPP-4i when initiating basal insulin was shown to be associated with better glycemic control (mean HbA1c and least squares (LS) mean change from baseline in HbA1c were 6.85% and À1.88% in the treatment group and 7.31 and À1.42 in the placebo group), a lower daily insulin dose (53 vs. 61 units), and no difference in the incidence of hypoglycemia after 30 weeks 5 . In a study of patients with T2D and in which a DPP-4i was added therapy was intensified for DPP-4i compared with placebo.…”

“…In the case of DDP-4i, continuation of this therapy after insulin initiation has been shown to have advantages. Recent randomized clinical trials demonstrated that among patients initiating insulin therapy, continuing DPP-4i, sitagliptin, resulted in a clinically meaningful greater reduction in HbA1c without an increase in hypoglycemia compared to sitagliptin discontinuation 5,6 . Nevertheless, discontinuation of oral drugs such as DPP-4i upon insulin initiation is common and characteristics associated with this discontinuation are not well understood.…”

Budget Impact of Oral Semaglutide Intensification versus Sitagliptin among US Patients with Type 2 Diabetes Mellitus Uncontrolled with Metformin

“…In addition, a scenario analysis tests the point estimates of the hazard ratios for cardiovascular events relative to placebo for the initial step in therapy from the CVOT studies. MET + SIT 100 mg [22] Weighted oral SEM a [22,23] MET + oral SEM 14 mg + IG [30,31] MET + SIT 100 mg + IG [30,31] MET + IG a [30,31] MET + IG + bolus insulin a [32,33] HbA1c, % −…”

Effect of adding vildagliptin to insulin in haemodialysed patients with type 2 diabetes: The VILDDIAL study, a randomized, multicentre, prospective study

“…Inhibitors of dipeptidyl peptidase‐4 (DPP‐4) are commonly employed as dual‐ or triple‐combination therapy in type 2 diabetes. Recent studies have shown the benefit of continuing these molecules when initiating insulin, allowing for a greater reduction in HbA1c of −5.0 mmol/mol and a decrease in insulin daily doses of −8.0 IU/day versus placebo, without increasing the number of hypoglycaemic episodes. DPP‐4 inhibitors are eliminated by up to 75% by the kidneys and, therefore, require dose adjustment in patients with chronic renal disease, except for linagliptin, which is not currently available in France.…”