Within the past year, endocrinologists and federal regulators have become much more conscientious about the risk of cardiovascular (CV) disease with type 2 diabetes patients, due to their natural propensity for CV events, along with the potential adverse events associated with particular medications, such as Avandia.  

The results of the ACCORD and ADVANCE trials have caused the FDA to reassess its approval process for diabetes drugs and altered the method in which many specialists manage their type 2 diabetes patients with oral agents (NEJM 2008; 358:2545-2572).

In the ACCORD trial, more than 10,000 randomized patients with a median glycated hemoglobin (A1c) level of 8.1 percent were assigned to receive intensive therapy (targeting a hemoglobin A1c level below 6 percent) or standard therapy (targeting a level from 7 to 7.9 percent). The intensive-therapy arm was discontinued after 41 CV-related deaths occurred. In an accompanying commentary in the NEJM, Robert G. Dluhy, MD, and Graham T. McMahon, MD, suggested that future studies should focus on targeting near-normal glycemic levels with strategies that carry a lower risk of hypoglycemia.

In the ADVANCE trial, more than 11,000 patients were randomly assigned to undergo either standard glucose control or intensive glucose control—defined as the use of gliclazide-MR (Diamicron MR, Servier) plus other drugs as required to achieve a hemoglobin A1c value of 6.5 percent or less. The ADVANCE results did not reveal a similar pattern of high-risk of death. The authors noted that severe hypoglycemia, although uncommon, was more common in the intensive-control group.

Noting some trial differences, Dluhy and McMahon wrote that thiazolidinediones (TZDs) “were widely prescribed during the ACCORD trial (92 percent in the intensive-therapy group vs. 58 percent in the standard-therapy group, with rosiglitazone [Avandia, GlaxoSmithKline] used almost exclusively), but were administered more sparingly in the ADVANCE trial (17 percent in the intensive-control group vs. 11 percent in the standard-control group).” Pioglitazone (Actos, Takeda Pharmaceuticals) is the other major TZD on the U.S. market.

However, ADVANCE lead author Anushka Patel, MD, from the University of Sydney in Australia, says that no conclusions or recommendations about the use of TZDs can be made for either trial. “It is important to remember that in the two trials, patients were randomized to strategies of care involving multiple treatments, and not to head-to-head comparisons of individual drugs. It is not possible to reliably dissect out any particular beneficial or harmful effect for a component drug. Conclusions can only be drawn about the effects of the overall strategy,” he says.  

Recently, Sonal Singh, MD, et al recommended strong restrictions in the use of TZDs and questioned the rationale for leaving Avandia on the U.S. market (Heart 2008.155507). In a meta-analysis of four long-term trials, researchers found that the use of Avandia was associated both with increased heart attacks and a doubling of heart failure (JAMA 2007; 298:1189–1195). Singh, a professor of public health sciences at Wake Forest University, Winston-Salem, N.C., agrees with Patel that the same conclusion can not be drawn from the ACCORD study because both arms received Avandia. “The only certainty that emerged from ACCORD was that somehow the intensive treatment increased death,” Singh notes.

From clinical to practical

David Nathan, MD, chief of the diabetes unit at Massachusetts General Hospital, says that there was a trend of moving away from prescribing TZDs, specifically Avandia, even before the publication of the ACCORD and ADVANCE trials. “While those studies didn’t point the finger at TZDs, they did not exonerated them either,” he says. Nathan suggests that the popularity once appreciated by Avandia may have shifted to Actos. “The data that exist—which are far from conclusive—could potentially support that there is a benefit of pioglitazone,” he says.
 

Sales of Oral Anti-Diabetes Drugs Soar
As the rate of diabetes increases, sales of oral anti-diabetic drugs will continue to outstrip sales of insulin. Source: IMS Therapy Forecaster

Avandia’s sluggish sales over the past few market quarters also indicate its unfavorable trend in prescriptions. In highlighting his drug of choice, Patel notes that in ADVANCE, almost all intensive group patients received gliclazide-MR, compared to none in the standard care group, so it “appears to be an agent with a good safety profile. But again, major conclusions about overall efficacy and safety must be ascribed to the strategy as a whole, which included gliclazide-MR in all patients.”

Singh says that his first choice is metformin (Glucophage, Bristol-Myers Squibb) due to its long-standing positive outcomes data. Metformin is currently the most popular anti-diabetic drug in the U.S. and one of the most prescribed drugs in the country overall, with nearly 35 million prescriptions filled in 2006 for generic metformin alone (Drug Topics, March 2007).

However, the diabetes drugs in the U.S. have no cardiovascular outcomes data on their label, Singh notes. Due to the adverse events linked with Avandia, an FDA panel voted in July to recommend that pharmaceutical companies conduct long-term studies—up to five years—to produce evidence that would rule out an unacceptable level of CV risk. The panel considered, but rejected, to require the diabetes drugs to show CV benefit. The proposed FDA conditions could slow down the process of newer oral agents entering the U.S. market.

Even with the myriad new drugs that are emerging, the consensus for the treatment of type 2 diabetes is to use older drugs, use them more aggressively and use insulin earlier, Nathan says. He adds that the newer drugs tend to be more expensive since they are all brand names, and they tend to be less powerful than the older drugs. The trend also is to move away from a glucose-centric approach and more toward a cardiovascular risk reduction approach that involves aspirin, blood-pressure lowering drugs and other drugs as well.

While there is a trend toward transitioning to an insulin regimen earlier, Singh notes that oral agents are more convenient and often, less costly. He also adds that the pressure for physicians to achieve the ADA target hemoglobin A1c level of 6.5 percent or lower may not be appropriate for certain patients with CV disease, as shown by the ACCORD trial. For those patients with type 2 diabetes who continue to be treated with oral agents, they often are taking eight to 10 pills on average just for the diabetes and diabetes-related problems alone.

One goal is to have an approach that reduces the number of pills patients must take. “It remains a major burden on our patients, and one that we have not dealt with effectively in the overall management of our patients,” Nathan concludes.