Researchers Raise Doubt Over Major Diabetes Drug Trials
The FDA requires pharmaceutical companies developing diabetes drugs to run trials to guarantee that the drugs will not increase the risk of cardiovascular disease. DPP-4 inhibitors, GLP-1 agonists, and SGLT-2 inhibitors: all of these novel drugs have gone through these cardiovascular outcome trials (CVOTs) and been declared safe.
But now two researchers have questioned the legitimacy of these analyses. Miriam Tucker first relayed the news for Medscape:
“… in an article recently published online in the Journal of Pharmaceutical Policy and Practice, Japanese researchers Rumiko Shimazawa, PhD, of the Department of Clinical Pharmacology at Tokai University School of Medicine, and Masayuki Ikeda, MD, point out that A1c levels were significantly higher in placebo groups than in treatment groups in all of the CVOTs.
Those imbalances, they argue, placed patients in the placebo groups at potentially higher cardiovascular risk and thereby biased the results in favor of the study drug.”
These trials are intended to isolate a drug’s impact on cardiovascular outcomes by equalizing glycemic control between the intervention group and the control/placebo group. But in the dozen significant studies identified by Shimazawa and Ikeda, the control group had consistently and significantly worse glycemic control, thereby muddying the results. Patients with higher blood sugars would naturally experience more diabetes complications, including heart attack and stroke, which could make the drugs in question seem misleadingly safer.
The researchers assert that it should be easy to adjust for these factors in new analyses of the data. Whether it will have a significant effect on the trials’ conclusions remains to be seen. Their full study is available here.
This latest criticism addresses just one notable aspect of what appears to be a larger issue surrounding study design. Major drug trials – which are funded by the pharmaceutical companies themselves – can have other built-in imbalances.
Tucker quotes an American expert, Bruce Leslie, who has criticized the design of SGLT-2 inhibitor trials that have led to claims of remarkable health benefits:
“all the SGLT2 inhibitor CVOTs … contain an unbalanced therapeutic design … that leaves unanswered the question of whether the cardiovascular and renal benefits they describe can be reproduced by inexpensive generic … diuretics.”
The companies funding the research, however, have little incentive to see if their great results could be replicated with cheaper generic medicines.
So what can we do? To start, we can focus on eating a low carb diet, which is often the best treatment for people with Type 2 diabetes. Sometimes, a low carb diet works so well on its own, Type 2 diabetes goes into remission.
*People with Type 1 diabetes taking SGLT2-inhibitors are at risk for DKA.
Studies have shown that patients that take an SGLT2 inhibitor while on a low-carb diet have an increased risk of developing ketoacidosis. A low-carb diet naturally produces a small amount of ketones: this is known as nutritional ketosis, and is perfectly safe. But SGLT2 inhibitors also trigger ketone production, and these two ketone sources can combine and spiral out of control, poisoning the blood.