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Therapeutics

Vildagliptin was effective as add-on therapy in type 2 diabetes inadequately controlled with metformin monotherapy

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ACP J Club. 2008 Sep-Oct;147:47. doi:10.7326/ACPJC-2007-147-2-047


Clinical Impact Ratings

GIM/FP/GP: 5 stars

Endocrinology: 6 stars


Source Citation

Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care. 2007;30:890-5. [PubMed ID: 17277036]


Abstract

Question

In patients with type 2 diabetes inadequately controlled with metformin monotherapy, is vildagliptin (VDGP) effective as add-on therapy for 24 weeks?

Methods

Design: Randomized placebo-controlled trial.

Allocation: Unclear allocation concealment.*

Blinding: Blinded (clinicians and patients).*

Follow-up period: 24 weeks.

Setting: 79 centers in the United States, 8 in France, 6 in Italy, and 16 in Sweden.

Patients: 544 patients 18 to 78 years of age with a body mass index 22 to 45 kg/m2 and fasting plasma glucose (FPG) level < 15 mmol/L, who had type 2 diabetes with inadequate glycemic control (hemoglobin A1c [HbA1c] 7.5% to 11%) with metformin monotherapy for ≥ 3 months. Patients had to be receiving a stable dose of metformin ≥ 1500 mg/d for ≥ 4 weeks before the first screening visit; those not taking the maximum-tolerated dose agreed to increase the dose to 2000 mg/d. Exclusion criteria were type 1 or secondary forms of diabetes, complications of acute metabolic diabetes in the past 6 months, congestive heart failure requiring pharmacologic treatment, myocardial infarction, unstable angina, coronary artery bypass surgery in the past 6 months, liver disease, or renal disease or dysfunction.

Intervention: VDGP, 50 mg/d (n = 177) or 100 mg/d (n = 185), or placebo (n = 182) for 24 weeks.

Outcomes: Mean change from baseline in HbA1c level. Secondary outcomes were mean change from baseline in FPG, fasting lipids (triglycerides and low-, high-, non-high-, and very-low-density lipoprotein cholesterol), and body weight.

Patient follow-up: 85% completed the study; 416 patients (mean age 54 y, 57% men) were included in the primary intention-to-treat analysis.

Main results

At 24 weeks, both doses of VDGP led to greater decreases from baseline in HbA1c and FPG levels than did placebo (Table). VDGP 50 mg/d led to a smaller increase in fasting triglyceride level than did placebo, but VDGP 100 mg/d and placebo did not differ (Table). Groups did not differ for change in any other fasting lipid level. VDGP 100 mg/d led to a greater increase in body weight than did placebo, but VDGP 50 mg/d and placebo did not differ (Table).

Conclusion

Vildagliptin was effective as add-on therapy for 24 weeks in patients with type 2 diabetes inadequately controlled with metformin monotherapy.

*See Glossary.

Source of funding: Novartis Pharmaceuticals Corporation.

For correspondence: Dr. A.J. Garber, Baylor College of Medicine, Houston, TX, USA. E-mail agarber@bcm.tmc.edu.


Table. Vildagliptin (VDGP), 50 mg/d or 100 mg/d, vs placebo (PLAC) as add-on therapy in type 2 diabetes inadequately controlled with metformin monotherapy at 24 weeks†

Outcomes Adjusted mean change from baseline‡ Difference in change between groups P value
VDGP, 50 mg/d VDGP, 100 mg/d PLAC
Hemoglobin A1c level (%) −0.5 0.2 −0.7 < 0.001
−0.9 0.2 −1.1 < 0.001
FPG (mmol/L) −0.1 0.7 −0.8 0.003
−1.0 0.7 −1.7 < 0.001
Fasting triglycerides (%) 1 19 −18 0.014
5 19 −14 NS
Body weight (kg) −0.4 −1 0.6 NS
0.2 −1 1.2 < 0.05

†Results based on primary intention-to-treat analysis (n = 416). Similar results were found for the intention-to-treat analysis (n = 520) (data not reported in article). FPG = fasting plasma glucose; NS = not significant.
‡Adjusted using Hochberg's multiple testing step-up procedure to maintain an overall 2-sided significance level of 0.05.


Commentary

The multicenter study by Bosi and colleagues is one of several recently published clinical trials (1) showing efficacy of dipeptidyl peptidase (DPP)-4 inhibitors in improving glycemic control in type 2 diabetes. These studies have examined effects of DPP-4 inhibitors independently and in combination with metformin, sulphonylurea, or pioglitazone and have shown up to a 1% decline in HbA1c levels. However, hard clinical endpoints, such as changes in incidence of diabetic microvascular and macrovascular complications, are clearly lacking, and further long-term randomized trials are needed.

The physiologic basis for use of DPP-4 inhibitors appears sound. Doubling the levels of native glucagon-like peptide (GLP)-1 postprandially enhances glucose-mediated insulin secretion and inhibits glucagon secretion. This leads to a favorable insulin–glucagon ratio and improved postprandial glucose and FPG. Furthermore, animal studies with DPP-4 inhibitors suggest preservation of β-cell mass by preventing apoptosis and stimulating proliferation. The achieved level of endogenous GLP-1 is insufficient to slow gastric motility, thus preventing the nausea and vomiting that occasionally occur with GLP-1 analogues. Although GLP-1 analogue therapy—unlike DPP-4 inhibition—leads to weight loss, the oral route of administration of the latter provides an advantage (2).

As a word of caution: The DPP-IV system (or CD26) has an immunomodulatory role on T-cell activation. Whether longer-term DPP-IV inhibition perturbs biological activities of T-lymphocytes or various peptides remains unknown. It is also important that DPP-IV inhibitors be highly specific for DPP-4 with minimal or no effect on DPP-8 or 9 because inhibition of DPP-8 or 9 has led to multiorgan toxicities in animal studies (3).

Ananda Basu, MD
Mayo Clinic College of Medicine
Rochester, Minnesota, USA


References

1. Herman GA, Stein PP, Thornberry NA, Wagner JA. Dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes: focus on sitagliptin. Clin Pharmacol Ther. 2007;81:761-7. [PubMed ID: 17392725]

2. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet. 2006;368:1696-705. [PubMed ID: 17098089]

3. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3:153-65. [PubMed ID: 16517403]