Clinical Health Updates

Intensive control of glucose does not improve T2DM outcomes (VADT)

Clinical Question:
Does intensive control of glucose improve outcomes in patients with type 2 diabetes?

Bottom Line:
Like the ACCORD and ADVANCE studies, this trial provides additional evidence that intensive glucose control does not improve outcomes in patients with type 2 diabetes mellitus. It is important to note that these patients had well-controlled hypertension (mean blood pressure = 126/68) and well-controlled hyperlipidemia (mean low-density lipoprotein = 80 mg/dL). (LOE = 1b)

Reference:
Duckworth W, Abraira C, Moritz T, et al, for the VADT Investigators. Glucose control and vascular complications in veterans with Type 2 diabetes. N Engl J Med 2009(2);360:129-139.

Study Design:
Randomized controlled trial (single-blinded)

Funding:
Industry + govt

Setting:
Outpatient (any)

Allocation:
Concealed

Summary:
The effects of intensive glucose control on cardiovascular events in patients with long-standing type 2 diabetes mellitus remain uncertain. The recent ACCORD (N Engl J Med 2008;358:2545) and ADVANCE (N Engl J Med 2008;358:2560) trials found that tight glucose control does not reduce the risk of macrovascular complications and may actually increase all-cause mortality in patients with type 2 diabetes mellitus. The authors randomly assigned 1791 military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or standard glucose control. Other cardiovascular risk factors were treated uniformly. The mean number of years since the diagnosis of diabetes was 11.5, and 40% of the patients had already had a cardiovascular event. The goal in the intensive-therapy group was an absolute reduction of 1.5 percentage points in the glycated hemoglobin level, as compared with the standard-therapy group. The primary outcome was the time from randomization to the first occurrence of a major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene. The median follow-up was 5.6 years. Median glycated hemoglobin levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. The primary outcome occurred in 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group (hazard ratio in the intensive-therapy group, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P=0.14). There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause (hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P=0.62). No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard-therapy group and 24.1% in the intensive-therapy group.

Small but prolonged weight loss maintenance with orlistat (Xenical)

Clinical Question:
After patients have lost weight, can long-term orlistat help them keep it off?

Bottom Line:
In obese patient who lost at least 5% of their body weight on a very-low-calorie diet, continuous orlistat (Xenical) treatment for 3 years allowed them to keep off more weight than those treated with placebo. The numbers were not striking; treated patients regained an average 2.2 kg less than placebo-treated patients after 3 years. There was also less incidence of new diabetes diagnoses in the treated patients, which echoes results found in other studies.

Reference:
Richelsen B, Tonstad S, Rossner S, et al. Effect of orlistat on weight regain and cardiovascular risk factors following a very-low-energy diet in abdominally obese patients. Diabetes Care 2007;30:27-32.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
The authors investigated the efficacy of orlistat on the maintenance of weight loss over 3 years following a major weight loss induced by very-low-energy diet (VLED) in obese patients with metabolic risk factors such as dyslipidemia, impaired fasting glucose, and diet-treated type 2 diabetes. Initially, weight loss was induced by an 8-week VLED (600-800 kcal/day) in 383 patients with a mean BMI of 37.5 kg/m(2) (range 30.0-45.2). Those who lost > or = 5% of their body weight (309 of 383 patients) were then randomized to receive lifestyle counseling for 3 years together with either orlistat 120 mg t.i.d. or matching placebo capsules. Primary end points were the maintenance of > or = 5% weight loss after 3 years. Additionally, differences in the development of type 2 diabetes between orlistat and placebo were analyzed. The VLED induced a mean weight loss of 14.4 +/- 2.0 kg among the subsequently randomized patients. The mean weight gain after 3 years was lower with orlistat than with placebo (4.6 +/- 8.6 vs. 7.0 +/- 7.1 kg; P <> or =5% weight loss also favored orlistat (67 vs. 56%; P = 0.037). Waist circumference was significantly more reduced in the orlistat group (P < 0.05), but no other differences in the risk factors were observed between the two groups. The incidences of new cases of type 2 diabetes were significantly reduced in the orlistat group (8 cases out of 153 subjects) versus placebo (17 cases out of 156 subjects) (P = 0.041).

Rosiglitazone (Avandia) more likely to succeed as monotherapy but POEMs lacking

Clinical Question:
Which oral diabetes drug is most likely to help patients avoid the need for a second drug?

Bottom Line:
Patients taking rosiglitazone (Avandia) are a bit less likely than those taking metformin to require a second drug after 5 years. However, there is much better evidence to support the benefit of metformin with regard to cardiovascular events. The results of this study should not change the current practice of beginning treatment with metformin whenever possible in patients with type 2 diabetes.

Reference:
Kahn SE, Haffner SM, Heise MA, et al, for the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin or glyburide monotherapy. N Engl J Med 2006;355:2427-2443.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
The efficacy of thiazolidinediones, as compared with other oral glucose-lowering medications, in maintaining long-term glycemic control in type 2 diabetes is not known. The authors evaluated rosiglitazone, metformin, and glyburide as initial treatment for recently diagnosed type 2 diabetes in a double-blind, randomized, controlled clinical trial involving 4360 patients. The patients were treated for a median of 4.0 years. The primary outcome was the time to monotherapy failure, which was defined as a confirmed level of fasting plasma glucose of more than 180 mg per deciliter (10.0 mmol per liter), for rosiglitazone, as compared with metformin or glyburide. Prespecified secondary outcomes were levels of fasting plasma glucose and glycated hemoglobin, insulin sensitivity, and beta-cell function. Kaplan-Meier analysis showed a cumulative incidence of monotherapy failure at 5 years of 15% with rosiglitazone, 21% with metformin, and 34% with glyburide. This represents a risk reduction of 32% for rosiglitazone, as compared with metformin, and 63%, as compared with glyburide (P<0.001 for both comparisons). The difference in the durability of the treatment effect was greater between rosiglitazone and glyburide than between rosiglitazone and metformin. Glyburide was associated with a lower risk of cardiovascular events (including congestive heart failure) than was rosiglitazone (P<0.05), and the risk associated with metformin was similar to that with rosiglitazone. Rosiglitazone was associated with more weight gain and edema than either metformin or glyburide but with fewer gastrointestinal events than metformin and with less hypoglycemia than glyburide (P<0.001 for all comparisons).

Gout and the risk of acute myocardial infarction

Clinical Question:
Are hyperuricemia and gouty arthritis independent risk factors for acute myocardial infarction (MI)?

Bottom Line:
The independent risk relationship between hyperuricemia and acute MI is confirmed. Gouty arthritis is associated with an excess risk of acute MI, and this is not explained by its well-known links with renal function, metabolic syndrome, diuretic use, and traditional cardiovascular risk factors.

Reference:
Gout and the risk of acute myocardial infarction.Krishnan E, Baker JF, Furst DE, Schumacher HR.Arthritis Rheum. 2006 Aug;54(8):2688-96

Study Design:
Randomized Controlled Trial

Synopsis:
To determine if hyperuricemia and gouty arthritis are independent risk factors for acute myocardial infarction (MI) and, if so, whether they are independent of renal function, diuretic use, metabolic syndrome, and other established risk factors. The authors performed multivariable logistic and instrumental variable probit regressions on data from the Multiple Risk Factor Intervention Trial (MRFIT). Overall, there were 12,866 men in the MRFIT who were followed up for a mean of 6.5 years. There were 118 events of acute MI in the group with gout (10.5%) and 990 events in the group without gout (8.43%; P = 0.018). Hyperuricemia was an independent risk factor for acute MI in the multivariable regression models, with an odds ratio (OR) of 1.11 (95% confidence interval [95% CI] 1.08-1.15, P < 0.001). In multivariable regressions in which the above risk factors were used as covariates, gout was found to be associated with a higher risk of acute MI (OR 1.26 [95% CI 1.14-1.40], P < 0.001). Subgroup analyses showed that a relationship between gout and the risk of acute MI was present among nonusers of alcohol, diuretics, or aspirin and among those who did not have metabolic syndrome, diabetes mellitus, or obesity. In separate analyses, a relationship between gout and the risk of acute MI was evident among those with and without those hyperuricemia.