News from the 67th Scientific Sessions of the American Diabetes Association, Chicago, June 22-26, 2007

Cardiology Review® Online, August 2007, Volume 24, Issue 8

Two lipid-lowering classes reduce risk of peripheral neuropathy

Statins and fibrates lower the risk of peripheral neuropathy in patients with type 2 diabetes, probably by different mechanisms and independent of their effect on lipids, found Timothy Davis, MD, PhD, in an observational study (the Fremantle Diabetes Study).

The finding contradicts early case reports that statins may produce neuropathy, but is consistent with epidemiologic evidence that lipid-lowering therapy might benefit diabetic neuropathy, which dates back to 1968, said Dr Davis. Furthermore, his data support those from the Fenofibrate and Event-Lowering in Diabetes (FIELD) study, in which allocation to fenofibrate was associated with about a 30% improvement in laser-treated retinopathy and a significant reduction in the incidence of microalbuminuria compared with placebo.

The Fremantle Diabetes Study was an observational study with 2 components: a cross-sectional component and a longitudinal 5-year component of the larger study. The longitudinal subset of 531 patients with type 2 diabetes formed the population for Dr Davis's present analysis. Of these 531 patients, 395 who were free of neuropathy at baseline were entered into the study.

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Patients were assessed for neuropathy using the clinical portion of the Michigan Neuropathy Screening Instrument. A multiple regression analysis and a Cox proportional hazards model were performed. Because of increased use of statins and fibrates during follow-up, both therapies were considered for entry into the Cox model as time-dependent covariates. Statins were being used by 7.6% at baseline, which increased to 34.9% by the end of the study, while fibrate use increased from 6.1% to 8.9%. Time-dependent statin use was associated with a 35% relative reduction in the risk of developing peripheral neuropathy ( =.019) and time-dependent fibrate use was associated with a 48% relative risk reduction ( =.042).

"Statins and fibrates were independently predictive of neuropathy," said Dr Davis, professor of medicine, University of Western Australia. The data suggest that they work to prevent neuropathy through different mechanisms.

vasa nervorum

Fibrates reduce aldose reductase activity and, through reduced serum very-low-density lipoprotein concentration, increase myoinostol influx. In vitro, statins promote angiogenesis and restore the function of the , independently of lipoprotein effects. Statins may have additional beneficial effects on Schwann cells through restoration of nitric oxide synthase expression.

Therefore, he hypothesizes, the combination of both drugs may produce greater benefit than either alone.

"Because we didn't find any association between lipid parameters and neuropathy at baseline, we postulate that the benefit of lipid-lowering therapy is independent of lipid parameters measured biochemically," he said.

The effect on reducing the development of peripheral neuropathy is probably a class effect of statins and fibrates, he believes. At the beginning of the study in 1993, the statins in use were atorvastatin, simvastatin, and pravastatin, and those taking fibrates were using gemfibrozil. At the end of the longitudinal study, gemfibrozil continued to be the primary fibrate used, although some of the fibrate recipients were treated with fenofibrate, whereas atorvastatin was the predominant statin being used, with simvastatin and pravastatin also used.

"This is an observational study so we need to be a little bit cautious about the interpretation, but this sort of relative risk reduction is the same as or similar to statins when used for preventing heart attacks," he said.

Pioglitazone improves cardiovascular outcomes in high-risk patients with type 2 diabetes

A new analysis of PROactive (Prospective Pioglitazone Clinical Trial in Macrovascular Events) finds that chronic kidney disease is an independent risk factor for major cardiovascular events in patients with type 2 diabetes and evidence of macrovascular disease, and that pioglitazone appears to reduce the risk of such events in this population.

PROactive was a study that included 5238 patients with type 2 diabetes and evidence of macrovascular disease. They were randomized to pioglitazone, 45 mg/day, or placebo in addition to other glucose-lowering and cardiovascular medications, and followed for a mean of 34.5 months.

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In the overall study cohort, pioglitazone was associated with a nonsignificant 10% reduction ( = .095) in the incidence of the primary end point, a composite of 7 macrovascular events— all-cause mortality, nonfatal myocardial infarction [MI], stroke, major leg amputation above the ankle, acute coronary syndrome, cardiac intervention including coronary artery bypass graft surgery or percutaneous coronary intervention, or leg revascularization.

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However, randomization to pioglitazone did result in a significant 16% reduction (= .027) in the combined secondary end point of death, MI, and stroke. The current analysis focused on the 597 patients in PROactive who had renal dysfunction defined as a glomerular filtration rate of less than 60 mL/min/1.73 m2. In this subset, the risk of all-cause mortality, MI, and stroke was 65% greater than in the group without renal dysfunction, said lead investigator Erland Erdmann, MD.

"The impact of chronic kidney disease on recurrent cardiovascular events among patients with diabetes and established macrovascular disease has not been previously studied, and there are a paucity of data on the impact of medical treatments on major outcomes," according to Dr Erdmann, University of Cologne, Germany.

In the patients with renal dysfunction, the incidence of the primary end point was 23.7% in the pioglitazone group compared with 30.7% in placebo group, a 25% reduction in risk that did not quite reach statistical significance (95% confidence interval [CI], 0.55-1.03).

The incidence of the main secondary end point (death, MI, and stroke) was 14.6% in the pioglitazone group and 21.4% in the placebo group, a relative risk reduction of 34% that achieved statistical significance (95% CI, 0.45-0.98).

The magnitude of these reductions was comparable to that in patients without renal dysfunction, said Dr Erdmann.

Bile acid agent reduces A1c and LDL cholesterol levels

The bile acid sequestrant colesevelam HCl not only lowers low-density lipoprotein (LDL) cholesterol levels but reduces hemoglobin A1c in patients with type 2 diabetes who do not reach their glycemic target (A1c < 7%) with metformin, said Harold Bays, MD.

He reported on a randomized, double-blind study in which the lipid and glucose effects of colesevelam were evaluated in 316 patients with type 2 diabetes not adequately controlled on metformin monotherapy or metformin in combination with additional antidiabetic drugs. In the study, patients with A1c levels of 7.5% to 9.5% who were on a stable dose of metformin were randomized to colesevelam, 3.75 g/day, or placebo for 26 weeks.

"A modification in glucose levels is something that has been found with the bile acid sequestrants as a class," said Dr Bays, medical director, Louisville Metabolic and Atherosclerosis Research Center. "An earlier pilot study with colesevelam in 65 patients with type 2 diabetes suggested an improvement in glycemic control, a 0.5% reduction in hemoglobin A1c."

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There were 155 participants in the current study on metformin monotherapy. In these patients, colesevalam recipients experienced a mean reduction in A1c of 0.54% relative to placebo at week 26 ( = .002).

A significant reduction in fasting plasma glucose was also observed with colesevelam compared with placebo, and a greater percentage of patients achieved a reduction in A1c levels of 0.7% or greater from baseline to week 26 with colesevelam.

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In the entire cohort of 316 patients, LDL cholesterol was reduced by 15.9% in patients assigned to colesevelam compared with placebo ( <.001).

The incidence of treatment-emergent adverse events was not different between the colesevelam and placebo groups (51.8% vs 56.6%, respectively), as was the incidence of moderate and severe treatment-related adverse events. In previous clinical trials, gastrointestinal-related side effects have been more common with colesevelam, "but in general it is well tolerated," said Dr Bays. "Perhaps most importantly, because it's a nonsystemic drug, it is thought to be pretty safe."

Although colesevelam specifically has yet to be shown to reduce the incidence of cardiovascular events in an outcomes clinical trial, other agents in this class have done so. "Cardiovascular disease is the number one cause for morbidity and mortality in diabetes, so the improvement in lipid levels would be very important in a patient with diabetes," he said.

"Patients with diabetes not only have macrovascular disease but they have microvascular disease as well, and they often do not achieve either their lipid goals or their glucose goals," he continued. "If you can get improvement in their lipid levels and an additional 0.5% reduction in hemoglobin A1c, then one would hope to get a reduction in microvascular disease. With a single agent, you're reducing 2

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risk factors for complications that occur in patients with diabetes."