STOCKHOLM, SWEDEN, September 20, 2010 – Results from a 30-week multinational study show that the addition of sitagliptin, a DPP-4 inhibitor, to ongoing metformin therapy provided similar blood sugar reductions as the addition of glimepiride, a commonly used sulphonylurea, in type 2 diabetes patients. The study, presented as a poster at the European Association for the Study of Diabetes (EASD) annual meeting, also showed that treatment with sitagliptin and metformin was associated with significantly fewer hypoglycaemic events and no weight gain, compared with glimepiride + metformin.
“Reducing the risk of hypoglycaemia and weight gain are important considerations when physicians choose among type 2 diabetes medicines for patients, so it is important to have data with different treatment regimens,” said Barry J. Goldstein, M.D., Ph.D., vice president of Clinical Research, Merck Research Laboratories and lead author of the study. “In this study of metformin-treated patients, the addition of sitagliptin lowered blood sugar levels to a similar extent as the addition of a sulphonylurea, and was associated with less hypoglycaemia and no weight gain compared with the sulphonylurea.”
The study aimed to evaluate the safety and efficacy of adding sitagliptin to ongoing metformin therapy in patients with type 2 diabetes compared with adding glimepiride. In a population with a mean baseline A1C[1] of 7.5 percent, similar blood sugar reductions were seen with sitagliptin and glimepiride (mean change from baseline -0.47 percent and -0.54 percent respectively, mean difference - not significant). Twenty-two percent of patients treated with glimepiride reported hypoglycaemia, compared with 7 percent of those treated with sitagliptin.
Hypoglycaemia, or low blood sugar, occurs when the level of glucose in the blood drops too low for the body’s needs.[ii] Hypoglycaemia can occur in patients with type 2 diabetes, sometimes in association with certain medications. Symptoms of hypoglycaemia can range from mild to severe, and may include headache, drowsiness, weakness, dizziness, confusion, irritability, hunger, fast heart beat, sweating and feeling jittery.
As a DPP-4 inhibitor, sitagliptin works in a glucose-dependent manner (i.e., when blood sugar is elevated) to stimulate pancreatic beta cells to release insulin and decrease the overproduction of glucose by the liver. Sulphonylureas such as glimepiride work in a glucose-independent manner (i.e., regardless of blood sugar levels) to stimulate the pancreas to secrete more insulin,[iii],[iv] a mechanism that has been associated with an increased risk of hypoglycaemia.[v]
Sitagliptin is a highly selective, once-daily DPP-4 inhibitor that enhances a natural body system called the incretin system to help regulate blood sugar by increasing levels of active GLP-1 and GIP hormones. Sitagliptin 100 mg once daily inhibits DPP-4 over the full 24-hour dosing interval. It was the first approved compound in the DPP-4 inhibitor class of oral treatments. The product has been approved in more than 90 countries, and to date, more than 24 million prescriptions have been dispensed for sitagliptin in the U.S. alone, and many more globally.[vi]
Study Design
This randomised, double-blind study was conducted in patients with type 2 diabetes mellitus who had inadequate glycaemic control (A1C of 6.5 to 9.0 percent) while on a stable dose of metformin (=1500 mg/day) for more than 12 weeks. After a 2-week placebo run-in period, 1,035 patients were randomised to the addition of either sitagliptin 100 mg once daily (n=516) or glimepiride 1 mg/day (uptitrated to a potential maximum 6 mg/day based upon pre-specified criteria) (n=519) to ongoing metformin therapy for 30 weeks. The primary analysis evaluated whether sitagliptin was non-inferior to glimepiride in reducing A1C from baseline at week 30 in the per protocol study population.
The mean dose of glimepiride after 18 weeks was 2.1 mg/day. After 30 weeks, the addition of sitagliptin (n=443) provided similar A1C reductions from a mean baseline A1C of 7.5 percent compared with the addition of glimepiride (n=436) (mean change from baseline of -0.47 percent with sitagliptin, -0.54 percent with glimepiride; between-group difference of 0.07 percent [95% CI: -0.03, 0.16]).
A greater proportion of patients treated with glimepiride than sitagliptin achieved an A1C of less than 7.0 percent at week 30 (59.6 percent and 52.4 percent respectively [odds ratio of 0.65; 95% CI: 0.47, 0.90]). There was no significant difference in mean changes from baseline in fasting plasma glucose for sitagliptin and glimepiride (-0.8 mmol/L and -0.9 mmol/L, respectively).
Glimepiride was Associated with a Significantly Higher Number of Hypoglycaemic Episodes Compared with Treatment with Sitagliptin Hypoglycaemia was reported for a significantly higher proportion of patients taking glimepiride (22.0 percent) compared with patients taking sitagliptin (7.0 percent) (p<0.001).
During the 30 weeks of treatment, 460 episodes of hypoglycaemia were reported among 114 patients treated with glimepiride compared with 73 episodes among 36 patients treated with sitagliptin. Patients treated with sitagliptin experienced a mean weight loss of 0.8 kg, whilst patients taking glimepiride experienced a mean weight gain of 1.2 kg, a significant between-group difference of -2.0 kg (p<0.001) (95% CI, -2.3, -1.6).
Important Information About Sitagliptin: For patients with type 2 diabetes mellitus, sitagliptin is indicated to improve glycaemic control as monotherapy in patients inadequately controlled by diet and exercise alone and for whom metformin is inappropriate due to contraindications or intolerance; as dual oral therapy in combination with metformin when diet and exercise plus metformin alone do not provide adequate glycaemic control; in combination with a sulphonylurea when diet and exercise plus maximal tolerated dose of a sulphonylurea alone do not provide adequate glycaemic control and when metformin is inappropriate due to contraindications or intolerance; in combination with a PPAR? agonist (ie, a thiazolidinedione) when use of a PPAR? agonist is appropriate and when diet and exercise plus the PPAR? agonist alone do not provide adequate glycaemic control; as triple oral therapy in combination with a sulphonylurea and metformin when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control; and in combination with a PPAR? agonist and metformin when use of a PPAR? agonist is appropriate and when diet and exercise plus dual therapy with these agents do not provide adequate glycaemic control. It is also indicated as add-on to insulin (with or without metformin) when diet and exercise plus stable dosage of insulin do not provide adequate glycaemic control.
Sitagliptin is contraindicated in patients who are hypersensitive to any component of this product. It should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. When sitagliptin was added to a sulphonylurea or to insulin, the incidence of hypoglycaemia was increased over that of placebo. To reduce the risk of hypoglycaemia, a lower dose of sulphonylurea or insulin may be considered. As the experience is limited, patients with moderate to severe renal insufficiency should not be treated with sitagliptin. Neither is it recommended for use in children below 18 years of age due to a lack of data on its safety and efficacy. Sitagliptin should not be used during pregnancy or during breast-feeding.
Selected Safety Information About Sitagliptin:
Postmarketing reports of serious hypersensitivity reactions in patients treated with sitagliptin have been reported, including anaphylaxis, angioedema, and exfoliative skin conditions including Stevens-Johnson syndrome. Onset of these reactions occurred within the first 3 months after initiation of treatment with sitagliptin, with some reports occurring after the first dose. If a hypersensitivity reaction is suspected, discontinue the product and assess for other potential causes for the event, and institute alternative treatment for diabetes.
In clinical studies as monotherapy and in combination with other agents, drug-related adverse reactions reported in excess (>0.2% and difference >1 patient) of placebo in double-blind studies included decreased blood glucose, headache, somnolence, diarrhoea, dry mouth, nausea, flatulence, constipation, upper abdominal pain, vomiting, hypoglycaemia, influenza, peripheral oedema, and dizziness. Adverse events (reported regardless of causal relationship to medicinal product) occurring in at least 5% and more commonly in patients treated with sitagliptin included upper respiratory tract infection and nasopharyngitis. Additional adverse experiences occurring more frequently (not reaching the 5% level but occurring >0.5%) with sitagliptin than in the control group included osteoarthritis and pain in extremity. For additional adverse experience information, see the Summary of Product Characteristics.
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