Initial Combination Therapy for Type 2 Diabetes: Is It Ready for Prime Time?

Cancer, HIV, tuberculosis and asthma are complex diseases that are routinely, and immediately upon diagnosis, treated with medication cocktails. Diabetes is complex, too, so clinicians should strongly consider a combination therapy approach for this disease, according to Bernard Zinman, a clinician-scientist at Mount Sinai Hospital in Toronto, Ontario, Canada.

Zinman borrowed from a point made in a journal article about how cellular pathways operate more like webs than like superhighways – meaning there are multiple routes that could be activated in response to inhibition of one pathway.

“If you get blocked one way going to Cleveland from Columbus, there are other ways to get there. The same is true in cellular pathways,” Zinman told attendees at the 2012 Global Diabetes Summit hosted by Ohio State’s Diabetes Research Center at Wexner Medical Center.

That article was pointing to the need for combination therapies for tumors and infectious diseases. “I believe the same principles apply to metabolic pathways and the use of pharmacological interventions,” he said, adding that there are a lot of pathways that lead to excess blood glucose and that the disease is progressive, getting worse over time as beta cells disappear.

This being the case, he said, why wait? Why “treat to failure,” as is the current standard of care for new diabetes cases?

Zinman published a 2011 article in the American Journal of Medicine detailing his rationale for the cocktail approach. His reasoning is that starting with combination therapy could: more rapidly lower hemoglobin A1c, a measure of blood glucose levels in the previous two to three months; avoid clinical inertia associated with the current stepwise approach to therapy; potentially improve beta cell function; set off multiple mechanisms of action that work well together; and allow for less than maximal doses, which could reduce side effects.

“We should start with combination therapy right from the get-go,” he said, also acknowledging, “It’s a major paradigm shift.”

Studies of combination therapies for diabetes have produced mixed results, and often show quick improvements in health measures that disappear over time. Acknowledging that the best evidence doesn’t yet exist to support his argument in favor of early combination treatments, Zinman said the most effective study would be a randomized clinical trial of monotherapy with the existing stepwise approach compared to initial combination therapy.

Current guidelines tend to recommend this stepwise approach, meaning that they recommend clinicians begin treatment with lifestyle interventions and a single drug to combat hyperglycemia. The addition of new therapies is typically recommended when A1c levels reach 9 – though the normal A1c level is 5.6 and 7 or above triggers a diabetes diagnosis. That A1c threshold is too high in Zinman’s estimation.

“Combination therapies with complementary mechanisms of action should be used early in the disease process. The earlier we achieve the target, the better off patients will be,” he concluded.

-Emily Caldwell


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