Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research - NAVIGATOR

Mar 14, 2010
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
Novartis Pharma
Date Presented:
01/01/2010
Date Published:
01/01/2010
Date Updated:
03/14/2010
Original Posted Date:
03/14/2010
References

Description:

The goal of the trial was to evaluate treatment with nateglinide (a short-acting insulin secretagogue), valsartan, or both among patients with impaired glucose tolerance.

Hypothesis:

Nateglinide and valsartan would be more effective in preventing type 2 diabetes and cardiovascular events.

Study Design

  • Stratified

Patients Screened: 43,502
Patients Enrolled: 9,306
Mean Follow Up: 5 years
Mean Patient Age: 64 years
Female: 50

Patient Populations:

  • Patients with impaired glucose tolerance, fasting glucose level between 95 and 125 mg/dl
  • At least 50 years of age with known cardiovascular disease,
  • Or at least 55 years of age with at least one risk factor for cardiovascular disease

Exclusions:

  • Any laboratory abnormality or condition that could interfere with the assessment of drug efficacy and safety
  • Use of an angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker for hypertension
  • Use of an antidiabetic medication within the last 5 years

Primary Endpoints:

  • Onset of type 2 diabetes
  • Extended cardiovascular outcome: composite of cardiovascular death, nonfatal myocardial infarction, stroke, revascularization, and hospitalization for heart failure or unstable angina
  • Core cardiovascular outcome: composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure

Drug/Procedures Used:

Patients with impaired glucose tolerance were randomized in a factorial manner to nateglinide (n = 4,645) versus placebo (n = 4,661) and to valsartan (n = 4,631) versus placebo (n = 4,675).

Valsartan was started at 80 mg daily and increased to 160 mg daily after 2 weeks. Nateglinide was started at 30 mg three times daily and increased to 60 mg three times daily after 2 weeks.

All patients underwent clinic and telephone-based lifestyle intervention aimed at reducing weight, limiting saturated fats, and increasing physical activity.

Concomitant Medications:

At baseline, the use of any antihypertensive drug was 73%, lipid-lowering drug was 39%, and aspirin or another antiplatelet drug was 37%.

Principal Findings:

Overall, 9,306 patients were randomized. There was no difference in baseline characteristics between the groups. In the valsartan group, the mean age was 64 years, mean weight was 84 kg, mean systolic blood pressure was 139 mm Hg, history of heart disease was present in 25% of patients, mean low-density lipoprotein (LDL) cholesterol was 177 mg/dl, and mean high-density lipoprotein (HDL) cholesterol was 50 mg/dl.

Considering the effect of valsartan: At a mean follow-up of 5 years, incident diabetes occurred in 33% of the valsartan group versus 37% of the placebo group (p < 0.001). The extended cardiovascular outcome occurred in 15% versus 15% (p = NS) and the core cardiovascular outcome occurred in 8.1% versus 8.1% (p = NS), respectively, for valsartan versus placebo. Hypotension-related adverse events occurred in 42% versus 36% (p < 0.001) and study drug discontinuation occurred in 12% versus 11% (p = NS), respectively.

Considering the effect of nateglinide: At a mean follow-up of 5 years, incident diabetes occurred in 36% of the nateglinide group versus 34% of the placebo group (p = 0.05). The extended cardiovascular outcome occurred in 14% versus 15% (p = NS) and the core cardiovascular outcome occurred in 7.9% versus 8.3% (p = NS), respectively, for nateglinide versus placebo. Hypoglycemia occurred in 20% versus 11% (p < 0.001) and study drug discontinuation occurred in 11% versus 10% (p = 0.23), respectively.

Interpretation:

Among patients with impaired glucose tolerance and cardiovascular disease or cardiovascular risk factors, valsartan was effective at reducing incident diabetes. Despite this benefit, valsartan did not reduce long-term adverse cardiovascular events. Nateglinide reduced neither incident diabetes, nor adverse cardiovascular events. In fact, diabetes was marginally increased in the nateglinide group.

It is unknown why these agents were unable to reduce adverse cardiovascular events; however, patients also underwent lifestyle modification, which may have diminished any treatment effect. Also, blood pressure was fairly well-controlled, and the use of other risk-reducing therapies was good. Valsartan may have implications for the treatment of hypertension since thiazide agents and beta-blockers have been associated with the development of diabetes.

References:

The NAVIGATOR Study Group. Effect of valsartan on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;Mar 14:[Epub ahead of print].

The NAVIGATOR Study Group. Effect of nateglinide on the incidence of diabetes and cardiovascular events. N Engl J Med 2010;Mar 14:[Epub ahead of print].

Presented by Dr. Robert Califf at the ACC.10/i2 Summit, Atlanta, GA, March 2010.

Keywords: Life Style, Follow-Up Studies, Pyridinolcarbamate, Cholesterol, LDL, Insulin, Short-Acting, Diabetes Mellitus, Type 2, Telephone, Hypotension, Cyclohexanes, Risk Factors, Valine, Tetrazoles, Hypoglycemia, Thiazides, Glucose, Angiotensin II Type 1 Receptor Blockers, Motor Activity, Hypoglycemic Agents, Phenylalanine, Cholesterol, HDL, Hypertension, Fasting


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