Debate: Do We Need Triple and Quadruple Therapies in Diabetes?

Aus Alzaid, MD


November 03, 2015

For any responsible physician, the decision to prescribe four different medications for the treatment of a single medical condition is never easy, especially if therapy is expected to be lifelong. After reading the title of this debate[1] -- Do We Need Triple and Quadruple Therapies? -- I thought the organizing committee of the European Association for the Study of Diabetes (EASD) wanted to know whether physicians were comfortable using as many as four diabetes drugs to treat glycemia or preferred to take the short cut, opting for insulin therapy when a couple of agents had failed to produce the right results.

But the intended purpose of the debate was quite different. As you will see, the speakers had a relatively free hand to pick the fight that suited their arguments. This is an account of the two presentations and my own verdict on the subject. Ralph A. DeFronzo, MD, professor of medicine, and chief of the Diabetes Research Unit at the University of Texas Health Sciences Center in San Antonio, argued in favor of triple and quadruple therapies; Thomas R. Pieber, MD, professor and director of the Division of Endocrinology and Diabetes at the Medical University Graz in Austria, argued against.

Dr Ralph A. DeFronzo: Yes! We Do Need Triple and Quadruple Therapies.

Dr DeFronzo opened his presentation by saying that if you treat the underlying defects responsible for type 2 diabetes (T2D), you can be assured of durable glycemic control and inevitably fewer diabetes complications. Furthermore, Dr DeFronzo said he had the evidence to prove his point. Dr DeFronzo outlined the pathogenesis of T2D and described how the defects causing T2D have grown from abnormalities confined to three target tissues (liver, muscle, and β-cell, called the Triumvirate[2],) to a current list of 8 separate players that he has named the Ominous Octet.[3]

"There is absolutely no way in the world that one drug is going to correct all of these abnormalities," declared Dr DeFronzo. Thus, treating T2D with a single drug at a time is a treatment strategy doomed to failure. The United Kingdom Prospective Diabetes Study (UKPDS) study[4] is proof of that, said Dr DeFronzo, as it showed only a temporary relief in glycemic control with each added agent. Given this finding, why not hit hard from the start and use several drugs together to nullify many of the known defects of T2D and preserve β-cell function early, pleaded Dr DeFronzo.

Indeed, Dr DeFronzo and his colleague Muhammad Abdul-Ghani, MD, PhD, followed through with this idea with a clinical trial,[5] choosing metformin + pioglitazone + exenatide as the best combination of agents to counteract the pathophysiologic abnormalities of T2D and sustain normal β-cell function. Keeping β-cells healthy is a central theme to ensuring a lasting glycemic effect, Dr DeFronzo repeated.

Dr DeFronzo presented details of the 3-year follow-up study[5] in newly diagnosed T2D patients. His triple-drug regimen seemed to surpass conventional add-on therapy (metformin, followed by sulfonylureas, followed by insulin) in almost every clinical and laboratory aspect considered: better glycemic control (an impressive mean HbA1c level below 6.0%) and fewer side effects (hypoglycemia and weight gain). Tests for insulin sensitivity improved and β-cell function remained remarkably normal in the triple-therapy group, whereas both parameters declined in the conventional group.

Convinced of his own hypothesis and now supported by the findings from the triple-therapy study, Dr DeFronzo called for abandonment of current practices (embodied in the official American Diabetes Association (ADA)/EASD guidelines[6]) and urged everyone instead to use multiple-drug therapy (three agents or more) as a first-line therapy in the treatment of T2D. Dr DeFronzo seemed more than willing to consider other combinations of diabetes drugs, as long as they did not include sulfonylureas. Aware of the recent arrival on the scene of new antidiabetes classes, Dr DeFronzo said that if he had to do the triple-therapy study again he would now replace metformin with an SGLT-2 inhibitor.

Dr Thomas R. Pieber: No! We Don't Need Triple and Quadruple Therapies.

Dr Pieber's opening remark was simple: "Treat the patient, not the blood sugar." He said he is not against the concept of using of multiple drugs, but that multiple drugs should be used only when they have shown clear benefit to the patient. In fact, he would be happy to use a "quartet" of treatments that included medications such as antihypertensives, statins, and aspirin because plenty of evidence shows that control of hypertension and use of statin therapy reduces cardiovascular complications in people with diabetes. However, he would never advocate the use of four antidiabetes drugs that in themselves offer no cardioprotective properties to control something (glycemia) that results in little or no cardiovascular (CV) benefit.

To support his position, Dr Pieber presented data from major clinical trials and said the CV benefits observed were at best modest and delayed[4] (UKPDS study) and at worst blatantly harmful.[7] He made an additional reference to the ORIGIN study[8] as an example of a good and well-designed "outcome study" that set out in search of CV protection through glycemic control and failed to find any, but instead reported an excessive amount of hypoglycemia suffered by patients in the intervention group.

Dr Pieber then turned his attention to the newly marketed diabetes drugs and asked, "Is it not the idea that before we embrace a new drug for diabetes, we must first establish its superiority over existing therapy?" What is the point of celebrating new diabetes agents if they add nothing to clinical outcome and only lower blood glucose as well as existing medications already do? All the recent CV outcome trials have failed to show an improvement in mortality, said Dr Pieber. It is not acceptable any more to hail a noninferiority status against a placebo as representing a major clinical advantage of new drugs coming to the market. (It is worth mentioning that this debate was held just hours before the release of the positive findings of the Empa-Reg Outcome study.[9])

Dr Pieber's last point seemed to be the one of most concern to him personally: The dangers associated with polypharmacy in diabetes practice. He presented data from the ACCORD study[7] showing that the intensively treated group included a high number of patients taking multiple diabetes drugs and concomitantly a high number of deaths despite optimal glycemic control. Dr Pieber said he did not believe hypoglycemia was responsible for the excess mortality but instead pointed to drug interactions as the likely culprit. He then presented the findings of another recent study[10] in elderly patients with diabetes. It showed an alarming rate of side effects related to overtreatment with diabetes drugs. "So the famous drug cocktail ascribed by Dr DeFronzo could spell danger to our patients," warned Dr Pieber. He concluded that the only way forward is through better clinical outcome data, not dubious glucose-lowering tactics.


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