Efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy over 12 weeks in patients with type 2 diabetes

Abstract

The aim of this study was to assess the efficacy and tolerability of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes who have inadequate glycaemic control on diet and exercise. In a randomised, double-blind, placebo- and active-controlled study, 743 patients with type 2 diabetes and a mean baseline HbA(1c) of 7.9% were randomised to receive one of six treatments for 12 weeks: placebo, sitagliptin 5, 12.5, 25 or 50 mg b.i.d., or glipizide 5 mg/day (electively titrated up to 20 mg/day). At week 12, treatment with sitagliptin at all doses tested led to a significant (p < 0.001) reduction in HbA(1c) relative to placebo, with the largest reductions occurring in the 50-mg b.i.d. group. The placebo-subtracted differences in HbA(1c) for the sitagliptin dose groups ranged from -0.38% to -0.77% in a dose-dependent manner, and -1.00% in the glipizide group. Sitagliptin also produced significant reductions in fasting plasma glucose and mean daily glucose across the dose range studied. Sitagliptin treatment was well tolerated and resulted in no significant weight change relative to placebo. There was a modest weight gain observed with glipizide treatment relative to placebo. Hypoglycaemia adverse experiences were reported with the highest incidence in the glipizide group (17%) compared with the placebo (2%) or sitagliptin groups (0-4%, not dose-dependent). In summary, in this study sitagliptin improved glycaemic control, with 50 mg b.i.d. being the most effective dose, and was generally well-tolerated in patients with type 2 diabetes.

Sitagliptin reduces plaque macrophage content and stabilises arteriosclerotic lesions in Apoe −/− mice

“…However, clinical studies are needed to show whether this increase in collagen content in mice translates into a plaque-stabilising effect in humans. In our mouse model, the dose of sitagliptin employed was effective in inhibiting DPP-IV activity, leading to an improvement in the metabolic profile, comparable to what has previously been reported in patients [11]. Despite the improvement in glucose tolerance in sitagliptin-treated mice, the extent of atherosclerotic lesions did not differ compared with controls.…”

“…In addition, clinical data suggest that DPP-IV inhibitors influence various cardiovascular risk factors associated with diabetes. For example, sitagliptin monotherapy significantly decreases triacylglycerol as well as NEFA levels and increases HDLcholesterol in patients with type 2 diabetes [11]. Furthermore, a significant decrease in systolic blood pressure could be shown with sitagliptin in non-diabetic patients with mild to moderate hypertension [12].…”

Incretin mimetics and dipeptidyl peptidase-4 inhibitors: innovative treatment therapies for type 2 diabetes

“…Most trials were designed as short term studies (12 to 24 weeks) with similar characteristics, including diet and exercise counseling for patients and wash-out periods of oral anti-diabetic therapy and dose stabilization periods ranging from 6 to 19 weeks. In the monotherapy trials, sitagliptin therapy compared to placebo resulted in statistically significant improvements in A1C and fasting glucose (52,(60)(61)(62). Similar reductions from baseline in 2-hour PPG values were observed in these trials (-41.4mg/dL to -48.6 mg/dL) (61,62).…”

“…Limited to modest baseline to endpoint improvements in fasting lipids (Table 3) were reported in patients treated with sitagliptin alone, or in combination with metformin or pioglitazone (52)(53)(54). Sitagliptin therapy has been shown to be weight neutral in all clinical trials except in one study in which sitagliptin given with metformin resulted in weight reduction of 1.5kg after 52 weeks of treatment (63).…”

Acute and chronic administration of SHR117887, a novel and specific dipeptidyl peptidase-4 inhibitor, improves metabolic control in diabetic rodent models

“…In contrast, small molecule inhibitors of DPP-4 were discovered to leverage the antidiabetic effects of endogenous GLP-1 and could be administered orally. Several orally available specific inhibitors of DPP-4 have been described and have been reported to improve glucose metabolism in various animal models of type 2 diabetes [16][17][18][19][20][21] and more recently in diabetic patients [22][23][24] . As one of earliest reported DPP-4 inhibitors, vildagliptin (formerly known as LAF237) was shown to be a selective and orally effective DPP-4 inhibitor, which was able to augment insulin release and reduce glucose excursions during an oral glucose tolerance test (OGTT) in Zucker fatty (fa/fa) rats and fat-fed normal rats after single and multiple oral administrations [25,26] .…”