Practice point www.nature.com/clinicalpractice/endmet Does addition of vildagliptin to monotherapy improve glycemic control in patients with mellitus?

Original article Bosi E et al. (2007) Effects of vildagliptin on OUTCOME MEASURES glucose control over 24 weeks in patients with type 2 diabetes The primary outcome measure was the change inadequately controlled with metformin. Diabetes Care 30: 890–895 in HbA1c level from baseline to study end. Secondary outcome measures included FPG SYNOPSIS levels, lipid profiles, β-cell function, and the Keywords dipeptidyl peptidase 4 inhibitor, incidence and severity of adverse events. glycemic control, HbA1c, type 2 diabetes mellitus, vildagliptin RESULTS BACKGROUND The 50 mg vildagliptin, 100 mg vildagliptin Metformin is frequently prescribed as the and placebo groups comprised 177, 185, and first-line treatment for type 2 diabetes mellitus 182 patients, respectively. Participants were (T2DM); however, additional antidiabetic agents predominantly white and obese, with a mean might be required when glycemic control is age of 54 years. The mean duration of T2DM poor. was 6.2 years, the mean duration of metformin monotherapy was 17 months, and the mean OBJECTIVE metformin dose was 2,100 mg daily. The study To assess the efficacy and safety of the dipeptidyl was completed by >83% of patients in each peptidase 4 (DPP4) inhibitor vildagliptin as group. The mean baseline HbA1c level was 8.4% an add-on to metformin monotherapy. and the mean baseline FPG level was 9.9 mmol/l. Treatment with vildagliptin improved both of DESIGN AND INTERVENTION these parameters. The between-treatment This was a 24-week, multicenter, double- difference (vildagliptin minus placebo) in HbA1c blind, placebo-controlled, randomized study at study end was –0.7% and –1.1% with 50 mg of patients with T2DM inadequately controlled and 100 mg vildagliptin, respectively (P <0.001 with metformin monotherapy. Inclusion criteria for both comparisons). The between-treatment included age 18–78 years, HbA1c level 7.7– difference in FPG at study end was –0.8 mmol/l 11.0%, fasting plasma glucose (FPG) level and –1.7 mmol/l with 50 mg and 100 mg vilda­ <15 mmol/l, and BMI 22–45 kg/m2. Patients gliptin, respectively (P = 0.003 and P <0.001, with type 1 diabetes mellitus, acute metabolic respectively). Treatment with vildagliptin was complications, liver disease, renal disease, or also associated with improved β-cell function history of congestive heart failure, myocardial and postprandial glucose levels. Lipid para­ infarction, unstable angina, or coronary artery meters did not differ between groups with the bypass surgery were excluded. Eligible partici- exception of triglycerides, the levels of which pants had been treated with metformin mono- were increased in patients who received vilda­ therapy for ≥3 months and received a stable gliptin. The incidence of adverse events was dose of ≥1,500 mg daily for ≥4 weeks before similar in all treatment groups, and there were enrollment. Patients were randomly allocated to no episodes of severe hypoglycemia. one of three treatment groups: 50 mg vildagliptin daily, 100 mg vildagliptin daily, or placebo. CONCLUSION All patients continued their usual metformin Glycemic control was markedly improved when regimen. Study visits were at screening, and at vildagliptin was added to metformin monotherapy, weeks 4, 12, 16, and 24 of treatment. and no major safety concerns were identified.

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Commentary either metformin or , DPP4 Acknowledgments inhibitors have yielded reductions in the mean The synopsis was written by Vicky Heath, Ravi Retnakaran HbA1c level of ~0.6–1.0%, with the degree of Associate Editor, Nature Clinical Practice. glucose-lowering related to baseline HbA1c 4 R Retnakaran thanks Dr The natural history of T2DM is characterized by level. Furthermore, these agents have also been Daniel Drucker for helpful increased hyperglycemia and progressive deterio- associated with improvement in measures of discussion and guidance. ration of pancreatic β-cell function over time. As β-cell function. the antidiabetic agents currently available gener- The safety and tolerability of vildagliptin in Competing interests The author has declared ally do not modify the natural history of T2DM, a the study by Bosi et al. is also concordant with a relationship with the need exists for new therapies that target different other reports. DPP4 inhibitors have not been following company: Merck Frosst. See the article aspects of the underlying pathophysiology of this associated with appreciable hypoglycemia (in online for full details of the disorder. One such novel therapeutic target is the keeping with their stimulation of glucose- relationship. incretin system.1 dependent secretion) or weight gain.4 Nutrient ingestion causes secretion of the Moreover, no characteristic pattern of adverse Correspondence Leadership Sinai Centre for gut-derived incretin hormones glucagon-like events has yet been observed in humans treated Diabetes peptide-1 (GLP-1) and glucose-dependent with these agents.1 60 Murray Street Suite L5-039, Mailbox 21 insulinotropic polypeptide, which act upon the The study of Bosi et al. is consistent with the Toronto pancreatic β cells to stimulate glucose-dependent growing body of preliminary clinical data that ON M5T 3L9 Canada insulin secretion. GLP-1 also suppresses glucagon suggests that vildagliptin and are [email protected] secretion, enhances glucose disposal, and slows well-tolerated and efficacious antidiabetic medi- gastric emptying. Furthermore, both GLP-1 and cations. Indeed, a clinical role for these agents Received 21 March 2007 glucose-dependent insulinotropic polypeptide could emerge in early combination therapy with Accepted 20 April 2007 Published online have been shown in animal studies to expand metformin or thiazolidinediones. We should 5 June 2007 β-cell mass (via promotion of islet-cell growth recognize, however, that clinical data about www.nature.com/clinicalpractice and inhibition of apoptosis), an effect that could the long-term safety, efficacy, and durability of doi:10.1038/ncpendmet0552 potentially alter the natural history of T2DM. As DPP4 inhibitors are not yet available.5 Moreover, both hormones are rapidly degraded by DPP4, it is not known whether any meaningful differ- selective inhibition of this enzyme has emerged ences will emerge amongst the different chem- as an antidiabetic strategy. Orally adminis- ical classes of DPP4 inhibitors. In conclusion, tered DPP4 inhibitors such as sitagliptin and although the performance of DPP4 inhibitors vildagliptin, therefore, represent a new class of in clinical studies has been promising, their ulti- medication for the treatment of T2DM. mate role in the management of T2DM remains The study by Bosi et al. demonstrates that to be determined. vildagliptin can improve glycemic control References when used as an add-on therapy in patients 1 Drucker DJ and Nauck MA (2006) The incretin system: with T2DM poorly managed with metformin glucagon-like peptide-1 receptor agonists and monotherapy. Compared with placebo, the dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 368: 1696–1705 adjusted mean ± SE change in HbA1c levels over 2 Ahren B et al. (2004) Twelve- and 52-week efficacy the 24-week study period was –0.7 ± 0.1% with of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. 50 mg vildagliptin and –1.1 ± 0.1% with 100 mg Diabetes Care 27: 2874–2880 vildagliptin. This degree of reduction in HbA1c 3 Charbonnel B et al. (2006) Efficacy and safety of the levels is comparable to that observed in other dipeptidyl peptidase-4 inhibitor sitagliptin added to PRACTICE POINT clinical trials of combination therapy with DPP4 ongoing metformin therapy in patients with type 2 Dipeptidyl peptidase 4 diabetes inadequately controlled with metformin inhibitors, such inhibitors. In a 12-week study of similar design, alone. Diabetes Care 29: 2638–2643 as vildagliptin and vildagliptin in combination with metformin 4 Ahren B (2007) DPP-4 inhibitors—clinical data and sitagliptin, are clinical implications. Diabetes Care [doi: 10.2337/ well-tolerated and treatment reduced HbA1c levels by 0.7% more dc07-0233] efficacious glucose- than metformin alone, a difference that was 5 Nathan DM (2007) Finding new treatments for lowering agents; maintained over 52 weeks during an open-label diabetes—how many, how fast… How good? N Engl however, their 2 J Med 356: 437–440 definitive role in the extension. Similarly, the addition of sitagliptin R Retnakaran is an Assistant Professor in management of type 2 to ongoing metformin reduced HbA1c levels by the Department of Medicine and Division of diabetes mellitus a further 0.65% when compared with placebo.3 remains to Endocrinology and Metabolism, University be determined Overall, in studies of combination therapy with of Toronto, ON, Canada.

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