Metformin and sitagliptin in patients with impaired glucose tolerance and a recent TIA or minor ischemic stroke: A multicenter, randomized, open-label phase II trial.

Rationale:

Impaired glucose tolerance (defined as a 2-hour post load glucose level 7.8-11.0 mmol/L) is present in one third of the patients with a TIA or ischemic stroke, and is associated with a two-fold risk of recurrent stroke. Intensive glucose control with oral antidiabetic drugs have been shown to reduce the rate of progression to diabetes type II in patients with impaired glucose tolerance. Our recent study suggests that the widely used oral glucose-lowering drug metformin is safe and improves glucose tolerance in patients with TIA or minor ischemic stroke and impaired glucose tolerance, but often leads to gastro-intestinal side effects resulting in permanent discontinuation. The novel antidiabetic drug sitagliptin seems equally effective with fewer side effects in patients with impaired glucose tolerance.



Objective:

We aim to compare the effectiveness, feasibility and safety of both metformin and sitagliptin in patients with TIA or minor ischemic stroke and impaired glucose tolerance. We will assess whether a slow increase in dose of metformin and better support and information on this treatment will reduce the incidence of side effects in these patients, and whether it will improve treatment compliance.



Study design:

Phase 2, multicenter, randomized, controlled, open-label trial with blinded outcome assessment.



Study population:

Patients 18 years or older with recent (<6 months) TIA or minor ischemic stroke (mRS≤3) and impaired glucose tolerance.



Intervention:

Patients will be randomized to receive either open-label metformin or sitagliptin or “no metformin” in a 1:1:2 ratio for 6 months. Patients allocated to metformin will start with 500 mg twice daily, which will be slowly increased in 6-weeks time to a daily dose of two times 1000 mg. Patients allocated to sitagliptin will be treated with a daily dose of 100 mg.



Main study parameters/endpoints:

Primary outcome measures were baseline adjusted differences of 2-hour post-load glucose; secondary outcome measures fasting glucose, glycosylated hemoglobin 1c (HbA1c) levels, tolerability and safety of metformin and sitagliptin at 6 months.

We aim to compare the effectiveness, feasibility and safety of both metformin and sitagliptin in patients with TIA or minor ischemic stroke and impaired glucose tolerance. We will assess whether a slow increase in dose of metformin and better support and information on this treatment will reduce the incidence of side effects in these patients, and whether it will improve treatment compliance.

At 2 weeks, 6 weeks and 3 months to record possible adverse events and to support continuation of treatment.
At 6 months to assess the primary and secondary outcome measures.

Patients will be randomized to receive either open-label metformin or sitagliptin or “no metformin” in a 1:1:2 ratio for 6 months. Patients allocated to metformin will start with 500 mg twice daily, which will be slowly increased in 6-weeks time to a daily dose of two times 1000 mg. Patients allocated to sitagliptin will be treated with a daily dose of 100 mg.