Insulin Sensitizers Halve PAD Risk, Amputations in BARI 2D

Marlene Busko

June 10, 2013

The same week that 2 US Food and Drug Administration (FDA) panels voted to keep rosiglitazone (Avandia, GlaxoSmithKline) on the market, a secondary analysis from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial reports that glycemic control with an insulin-sensitizing approach reduces the risk of developing peripheral arterial disease (PAD) in these high-risk patients.

In the 1479 patients in BARI 2D without PAD at study entry, the incidence of any type of new PAD during an average follow-up of 4.6 years was lower among participants who received insulin-sensitizing therapy — metformin or a "glitazone" — than those who received insulin-providing therapy: 16.9% vs 24.1% ( P < .001).

"What this suggests is that the use of an insulin-sensitizing medication might slow or reduce the progression of systemwide atherosclerosis in participants who already have fairly advanced coronary disease," lead author Andrew D. Althouse, MA, from the department of epidemiology at the University of Pittsburgh, Pennsylvania, told Medscape Medical News.

The article is published online June 4 in Diabetes Care.

Asked about the clinical implications given the controversy swirling around rosiglitazone, senior author Maria Mori Brooks, PhD, also from the University of Pittsburgh, commented: "This paper does not address a single drug [but rather looks at] the insulin-sensitizing strategy of not providing insulin to the patient's system…and it appears there may be some beneficial effect…regarding new PAD."

However, one expert not involved in this research said, as ever, the benefits and risks of any therapeutic approach must be balanced. Zachary T. Bloomgarden, MD, from Mount Sinai School of Medicine, New York, said that while there may be a subset of type 2 diabetes patients in whom there are atherosclerotic benefits of using glitazones, other research suggests that for those with existing PAD, there might be an adverse effect with this drug class.

As Many as 1 in 4 High-Risk Patients May Develop PAD

In patients with type 2 diabetes, PAD is very common and progresses more rapidly than in other individuals; those with both conditions are at high risk for losses of mobility and even amputation, the authors write.

Treatment with insulin-sensitizing agents has been proposed as a way to reduce the risk for PAD in type 2 diabetes patients but has not been demonstrated in a randomized controlled trial.

To investigate this, the researchers analyzed data from BARI 2D, a global study that recruited patients from 2001 to 2005 (N Engl J Med. 2009;360: 2503-2515). BARI 2D randomly assigned patients with type 2 diabetes and stable coronary disease (CAD) to medical therapy or revascularization and 2 types of therapy for glycemic control: insulin-sensitizing therapy (n = 735) with a thiazolidinedione (TZD) (rosiglitazone or pioglitazone [Actos, Takeda]) or metformin; or insulin-providing therapy (n = 744) with a sulfonylurea, repaglinide (Prandin, Novo Nordisk), nateglinide (Starlix, Novartis), or insulin itself. Both glycemic-control strategies aimed to achieve an HbA1c level of < 7.0%.

The current post hoc analysis included all patients in BARI 2D who had a normal ankle-brachial index (ABI) at baseline (0.91 to 1.30) and no history of PAD. The participants were aged 61.9 years on average; 72% were male, and 15% were black.

After a mean follow-up of 4.6 years, 303 participants experienced 1 or more of 3 PAD outcomes.

Compared with participants who received insulin-providing therapy, those who received insulin-sensitizing therapy had less:

  • Lower-extremity revascularization (1.1% vs 2.6%, P = .07).

  • Low ABI (16.5% vs 22.7%, P < .001).

  • Amputation (0.1% vs 1.6%, P = .002).

  • Any of these 3 PAD outcomes (16.9% vs 24.1%, P < .001).

Mr. Althouse observed that "essentially, [the patients'] risk of low ABI or lower-extremity revascularization was cut in half, and risk of the more serious complication of amputation was cut even further" with an insulin-sensitizing vs insulin-providing strategy of glycemic control.

In BARI 2D, the combined primary end point of death, MI, and stroke was not statistically different for these 2 glycemic-control strategies, the authors noted.

At 3 years, in the insulin-sensitizing–therapy group, 74.1% of the patients were using metformin, 62.1% of the patients were using a TZD, and 55.1% were using rosiglitazone, Mr. Althouse said. In fact, half of the patients (50.1%) assigned to insulin-sensitizing therapy were taking both TZD medications and metformin during the study, he added.

The difference between glycemic-treatment groups remained significant after adjustment for HbA1c levels, which suggests that insulin sensitizers confer a benefit independent of glycemic control.

"Our results suggest that treatment of type 2 diabetic patients with insulin sensitizers might reduce the morbidity and treatment cost of PAD in this population," the researchers conclude.

"Convincing Analysis"; TZD Therapy for Targeted Patients?

Dr. Bloomgarden, who is also the editor of the Journal of Diabetes, said "the data are very convincingly analyzed, very suggestive of a benefit of prevention of PAD in people in high risk… I don't see any flaws in the concept or the analysis or the discussion.

"But we can't go from this to say, 'Okay, [TZDs are great drugs] for people with PAD,' because, in fact, we have other evidence [from the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) study] that suggests if you have existing PAD, you may paradoxically have an adverse effect" when treated with pioglitazone, a TZD, he added.

And although he acknowledges the use of metformin along with rosiglitazone may somewhat decrease the edema and weight gain in these patients, he said it would seem that "appropriate candidates for TZD have to be chosen very carefully." There "probably is a subset of people in whom there are atherosclerotic benefits that would justify the use of these agents. On the other hand, we do know that there are risks with these drugs."

BARI 2D is funded by the National Heart, Lung, and Blood Institute and the National Institute of Diabetes and Digestive and Kidney Diseases. BARI 2D receives significant supplemental funding from GlaxoSmithKline and additional funding from Lantheus Medical Imaging, Astellas Pharma US, Merck, Abbott Laboratories, and Pfizer. Medications and supplies were donated by Abbott Laboratories, MediSense Products, Bayer Diagnostics, Becton Dickinson, J.R. Carlson Laboratories, Centocor, Eli Lilly, LipoScience, Merck Santé, Novartis, and Novo Nordisk. Unrestricted grant support for the nuclear core laboratory was provided by Astellas Healthcare and Lantheus Imaging. Mr. Althouse and Dr. Brooks have reported no relevant financial relationships. Disclosures for the other coauthors are listed in the article.

Diabetes Care. Published online June 4, 2013. Abstract


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