Combination Therapy for Patients with Type 2 Diabetes: Repaglinide in Combination with Metformin

Robert G Moses

Disclosures

Expert Rev Endocrinol Metab. 2010;5(3):331-342. 

In This Article

Pharmacodynamics

Additive Effect

Preclinical and clinical studies have demonstrated that combination of repaglinide and metformin exerts a greater-than-additive effect.[58–61]

Rudovich et al. demonstrated that, in a group of 11 patients with T2DM, combination therapy of repaglinide plus metformin dramatically increased early and late phases of insulin secretion when compared with placebo (443.6 ± 138.5 vs 263.3 ± 133.1 pmol/l/10 min, p = 0.08; 18750.9 ± 5936.4 vs 34508.65 ± 9234.0 pmol/l/25–180 min, p = 0.08).[60] This study also demonstrated that repaglinide combined with metformin improved tissue sensitivity to insulin by 35% when compared with metformin alone. It is thought that improved glycemic control by combination therapy could have led to a reduction in hyperglycemia-induced insulin resistance. In keeping with these results, Hollingdal et al. have demonstrated that repaglinide significantly augmented first-phase insulin secretion as well as high-frequency insulin secretory burst mass and amplitude during glucose entrainment in patients with T2DM.[59]

Glycemic Control

Setter et al. reported the results of a meta-analysis of randomized controlled trials evaluating the efficacy of metformin in achieving glycemic control and body weight control.[62] Metformin monotherapy reduced FPG levels by 2 mmol/l compared with placebo (95% CI: -2.4 to -1.7) and HbA1c values by 0.9 percentage points (95% CI: -1.1 to -0.7). Metformin therapy was associated with a significant mean decrease in body weight compared with SU (-1.2 vs +1.7 kg, respectively; weighted mean difference -2.9 kg; 95% CI: -4.4 to -1.1). In a recent review, Black et al. highlighted efficacy data from four clinical studies comparing repaglinide to placebo as monotherapy and reported that repaglinide led to significant reductions in HbA1C (0.5–2.1%).[29]

Combination therapy with repaglinide plus metformin is well tolerated and has been shown to reduce HbA1c and FPG to levels below those achieved with monotherapy.[60,63–67]

Moses et al. randomized 83 patients with inadequately controlled T2DM (HbA1c > 7.1%) to one of three groups: metformin monotherapy, repaglinide monotherapy, or combination repaglinide and metformin.[63] The group receiving combination repaglinide and metformin had superior glycemic control to either monotherapy alone, with reductions in HbA1c of 1.4 ± 0.2%, from 8.3 to 6.9% (p = 0.0016), and FPG of 2.2 mmol/l (p = 0.0003). By the end of the study period, almost 60% of the patients in the combination therapy group had adequate glycemic control compared with approximately 20% in the metformin monotherapy group. Compared to metformin monotherapy, the combination of repaglinide and metformin was associated with a mean reduction in HbA1c of 1.1% and FPG of 1.9 mmol/l. Additionally, repaglinide in combination with metformin lead to an increase in fasting levels of insulin between baseline and end of trial of 4.23 ± 1.5 mU/l.

Shapiro et al. confirmed that when used in a real-life setting, repaglinide provided effective glycemic control in a heterogeneous population either when used as monotherapy or when used in combination.[66] Reboussin et al. demonstrated that combination therapy with repaglinide plus metformin led to greater reductions in HbA1c levels compared with repaglinide alone (1.7 vs 1%, respectively; p = 0.01).[67] 71% of patients receiving combination therapy achieved a target of HbA1c less than 7.1%, compared with 48% in the monotherapy group. Fasting plasma glucose was reduced in both groups, but the reductions were greater in the combination group (4.7 mmol/l vs 3.7 mmol/l; p = 0.012). In this study, the primary outcome was the change in brachial artery endothelial cell function. Postocclusion brachial artery vasodilation, as measured by ultrasonography, was 3.74% at baseline and 3.82% following 16 weeks of therapy (p = 0.77). The treatment effect was 0.08% (95% CI: -0.48–0.64%) and no difference was seen between treatment groups (repaglinide alone vs combination of repaglinide plus metformin; p = 0.69).

Combination therapy with repaglinide plus metformin has been directly compared with other agents combined with metformin, including nateglinide, glyburide and rosiglitazone.[64,68,69] In a 16-week study involving 192 patients with inadequately controlled T2DM, Raskin et al. demonstrated significantly greater mean reductions in HbA1c (1.3 vs 0.7%; p < 0.001) and FPG values (-39 vs -21 mg/dl [-2.2 vs -1.2 mmol/l]; p = 0.002) for the repaglinide plus metformin treatment group when compared with the nateglinide plus metformin treatment group.[64] Almost 59% of patients in the repaglinide plus metformin combination group achieved a glycemic target when compared with 47% in the nateglinide plus metformin group.

In a 26-week, open-label, parallel-group trial, Raskin et al. demonstrated that FDC repaglinide plus metformin administered twice daily was noninferior to FDC rosiglitazone plus metformin administered twice daily in clinical use.[69] In this study, FDC repaglinide plus metformin was associated with a more rapid reduction of HbA1c values. The authors concluded that FDC repaglinide plus metformin twice daily is a clinically feasible alternative. Although thiazolidinediones (rosiglitazone and pioglitazone) in combination with metformin are well tolerated, adverse events, such as edema, congestive heart failure and weight gain, have been reported. Based on these observations, the FDA ordered a revision to the full prescribing information for rosiglitazone maleate and pioglitazone HCl to include a black box warning to emphasize increased risk of congestive heart failure in specific populations.[104,105]

The dosing schedule for the FDC of repaglinide plus metformin is to start with 1 mg repaglinide/500 mg metformin twice daily unless the patient is already taking higher coadministered doses of repaglinide and metformin HCl.[103] The FDC tablet is administered at mealtime similar to the separate formulations of repaglinide and metformin. The current recommendation is for the FDC to be administered two- to three-times daily up to a maximum daily dose of 10 mg repaglinide/2500 mg metformin HCl. The maximum one-time dose that can be administered during a meal is 4 mg repaglinide/1000 mg metformin HCl.[103]

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