Jack L. Leahy, MD
University of Vermont College of Medicine
Burlington, VT
Our patient has a family history of type 2 diabetes and metabolic syndrome along with worsening obesity despite attempting lifestyle modification. He also has a documented rise of his A1c plus a fasting glucose value, both of which signal pre-diabetes. Finally, he’s concerned and wants to do whatever possible to prevent full-blown diabetes.
While lifestyle modification or metformin are the most common recommendations for a patient like this, my vote is to also consider a thiazolidinedione (TZD) based on proven efficacy, although side effects and/or cost get in the way of this being recommended very often for patients with pre-diabetes.
Proven Efficacy in Preventing Diabetes
Several clinical trials have used TZD therapy in patients with noteworthy pre-diabetes. The TRIPOD
[1]and PIPOD
[2] studies from Buchanan and coworkers tested a TZD (trogliazone in TRIPOD, pioglitazone in PIPOD) in Hispanic women in Los Angeles who previously had gestational diabetes. The prominence of these studies was due to this population’s extreme risk of moving onto full-blown type diabetes (nearly 50% within five years after delivery), as well as the dramatic findings: 55% reduction in diabetes onset during the 30 months of the TRIPOD study, and continuation of that protection when patients were switched to pioglitazone after troglitazone was taken off the market because of hepatotoxicity. On the other hand, these findings have been questioned due to their relatively few subjects and select patient population involved. The next study--the DREAM study
[3]--lessened those concerns considerably. It was a large (n=5269) worldwide study of subjects with
impaired fasting glucose (IFG),
impaired glucose tolerance (IGT), or both, who received 8 mg of rosiglitazone daily or placebo for a median of three years. Rosiglitazone lowered the diabetes incidence from 25% in the placebo group to 10.6%, i.e., nearly a 60% reduction.
Collectively, these results showed a 55-60% reduction in diabetes incidence. That number is important as it equals the 58% reduction with intensive lifestyle intervention in the US-based Diabetes Prevention Program (DPP)
[4] and the Finnish Diabetes Prevention Study,
[5] that are used to support the general belief that lifestyle intervention has given the best results in type 2 diabetes prevention studies. Even more informative is to closely scrutinize the DPP study. It tested three interventions in more than 3800 subjects with IGT--intensive lifestyle program that included dietary and exercise behavioral support, metformin 850 mg twice daily, or troglitazone 400 mg daily--and compared them to a control arm of standard healthy lifestyle recommendations, with percent conversion to diabetes over the average 2.8 years of the study as the endpoint. However, because the troglitazone arm was stopped early because of a case of fatal liver failure that contributed to that drug’s removal from the market, these subjects were not included in the high profile paper published in the
New England Journal of Medicine.
4 Even so, those results did appear in little known second paper that compared results from all four treatment arms over the average nine months exposure to troglitazone.
[6] Diabetes incidence rate was 3.0 cases per 100 years for troglitazone versus 12.0 for control, in contrast to 6.7 for metformin, and 5.1 in the intensive lifestyle group. In other words, the TZD was the most effective preventive approach, at least initially.
So, score one for TZDs in terms of efficacy, which seems at least as good as the commonly used interventions, if not better.
Mechanism of Action Supporting Beta Cell Protection
A second argument for TZD therapy is a proposed mechanism of action that seems tailor-made for pre-diabetes patients. Cross-sectional and prospective studies of many populations have shown that the progression of normal glucose tolerance to pre-diabetes to diabetes stems from a progressive worsening of beta cell function. As such, the ultimate goal of a prevention therapy should be stabilizing beta cell function. Consistent with this, Buchanan showed that at the start of the TRIPOD study1 that his subjects were insulin resistant but also had a high level of insulin secretion preventing hyperglycemia, a phenomenon known as beta cell compensation. Diabetes resulted when insulin secretion fell relative to the degree of insulin resistance, so-called beta cell failure. Furthermore, troglitazone maintained the original relationship between insulin secretion and sensitivity, thus preventing diabetes through substantial improvements in both insulin sensitivity and insulin secretion. Within this pair of observations, Buchanan’s team focused on the fall in insulin secretion and concluded that troglitazone had induced a beta cell rest effect. Importantly, with this conclusion and additional studies by these and other authors, focus for TZD’s effect in pre-diabetes has shifted from insulin sensitization per se to beta cell preservation. In theory, lifestyle intervention or metformin might act similarly, although neither of these other approaches is as powerful as TZDs in terms of insulin sensitization.
Finally, TZDs act on the
PPAR-gamma signaling pathway in tissues, which a growing literature suggests might play a role in regulating the mass of islet beta cells.
[7] However, it’s too early to know what relevance this might have to the clinical use of TZDs in pre-diabetes.
Score two for TZDs in terms of linking their use to beta cell protection mechanisms.
The Downside
Why haven’t TZDs been advocated for usage in prediabetes--at least on the list of proven agents, if not at the top? The simple answer is that every positive study has been balanced by an editorial or other opinion that looks not only at diabetes prevention, but also at other results such as more weight gain, congestive heart failure, and cost and concludes on balance that other therapies, while perhaps not as effective, are safer and cheaper.
Returning to our patient, he has no cardiac history and is generally healthy, and he’s looking for the best diabetes protection he can get. Based on the above, one can make a strong argument that TZDs fit that bill at least as well, if not better than, lifestyle modification alone or with metformin.
See below for References and Disclosures.