Combination Therapy in Diabetes Care: A Debate

The American Journal of Managed Care

Four distinguished endocrinologists debated the pros and cons of using combination therapy during the final session of Patient Centered Diabetes Care 2015, presented by and Joslin Diabetes Center.

The American Journal of Managed Care,

The panel featured Helen Feit, MD, medical director with Cigna and a practicing geriatric endocrinologist; S. Sethu K. Reddy, MD, MBA, FRCPC, FACP, MACE, chief of adult diabetes at Joslin Diabetes Center; Ravi Retnakaran, MD, MSc, FRCPC, endocrinologist and scientist at the University of Toronto; and Alexander Turchin, MD, MS, associate director for quality of diabetes care and a practicing endocrinologist at Brigham and Women’s Hospital. Dennis Scanlon, PhD, professor of health policy and administration, Pennsylvania State University, and associate editor of served as moderator.

To start the conversation, Scanlon asked each panelist to comment on the use of combination therapy in diabetes.

Reddy explained that because several different factors may be responsible for hyperglycemia, maintaining the patient on a single medication does not make logical sense. Additionally, elderly persons might suffer from several comorbidities. Reddy said that in contrast to patients who have had a myocardial infarction, for whom aggressive therapy is started right away, the philosophy in diabetes is “treat-to-failure.” He believes, however, that there is room to introduce aggressive clinical therapy in diabetes as well.

Retnakaran agreed with Reddy, adding that combination therapies allow patients to be treated with submaximal doses of a drug, with potentially fewer side effects and the ability to affect multiple aspects of the disease pathophysiology. Referring to the treatment-to-failure approach, Retnakaran said that in the current clinical practice, a new drug is added when the first agent fails, and this process continues until the patient needs permanent insulin therapy. He believes a different approach is needed, and this is his research interest. Retnakaran introduced a 2-step treatment protocol: induction therapy, consisting of an early aggressive treatment followed by maintenance therapy to retain the benefit of the initial treatment. This would call for a slightly different combination therapy approach, he said: a specialist would be in charge of the early treatment, and then the primary care provider would take over.

Combination therapies can take several different form, says Turchin, including fixed-dose oral combinations; multiple therapies early in treatment; insulin combinations, which are mostly injectables; and insulin combined with GLP-1 agonists. A sound understanding of the benefits or drawbacks of each of these combinations is essential, he added. Fixed dose combinations are difficult to titrate, which is a problem, because “Diabetes is not a stable disease.” Patients’ blood glucose levels fluctuate based on diet, losing or gaining weight, and life-style changes. Fixed-dose combinations thus become restrictive, because proper treatment requires the flexibility to be titrated accordingly.

Feit presented another perspective: using lipid-lowering agents in patients with diabetes. She said that while the physician wants to see both a lowering of glycated hemoglobin (A1C) levels and an impact on microvascular outcomes, there isn’t evidence yet on combinations for cardiovascular outcomes.

Reddy and Retnakaran agreed that microvascular risks associated with lowering A1C levels need more attention.

When asked to comment on her specific experiences with the geriatric population, Feit said that the impact of hypoglycemia on cognitive function needs attention. Additionally, polypharmacy is an extremely important issue in the elderly, “If you look at the population that I serve clinically, they’re nearly always on more than 6 drugs—with the side effects and with the drug interactions and with those risks.” Adding another drug into their regimen can cause problems, she said, making it important to consider the risk-to-benefit ratio.

The elderly with renal impairment cannot be administered metformin (which is usually the first therapy given), may not be able to stick to specific meal times (which is important for those on hyperglycemia), or may experience drastic weight fluctuations (which would necessitate dose adjustment). Complicated patients like these need a personalized regimen, she said. “You need to reassess them for their cognitive status, for their risk of hypoglycemia, and along with their caregiver, get the A1C down as low as you can and be safe.”

Scanlon argued that considering all of these issues, a single pill with a fixed-dose combination seems an ideal choice. Retnakaran agreed, but pointed to the lack of evidence on that front. Reddy said that most fixed-dose studies are industry sponsored, and purport to show benefit over existing drugs. Very few long-term studies to evaluate improved adherence with these agents have been conducted, and increased adherence has only been presumed, he said. “Simplifying [treatment regimens] has to be patient-centric, and anything to make it simpler—once a day [pills], reminder systems, etc—will certainly make the efficacy better.”

Turchin warned about the risk of such combination therapies: if a confused patient takes 2 tablets instead of 1, it would double their dose of those medications and greatly increase the risk of hypoglycemia.

When Scanlon introduced the idea of a polypill, Reddy noted that multiple studies with a “superpill” are being conducted in India and the United Kingdom. “There are some data [indicating] that if you put someone on that combination of antihypertensive, ACE [angiotensin-converting enzyme] inhibitor, a little bit of aspirin, diabetes pills, and a statin, you’ll get more patients to target than otherwise,” said Reddy. Turchin agreed with the idea of a superpill, and said it might even present a cost benefit. Feit emphasized, however, the need for evidence that a cost benefit is likely.

Scanlon then played the devil’s advocate and asked: When one talks about tailored treatment for a patient, “Does a polypill really make sense? What kind of study might you use to provide the evidence?” In response, Reddy said that trying each drug individually to arrive at a safe combination that could be individualized for the patient would be an ideal tactic. “That has been my approach in the situations where we do have a combination pill at our disposal,” said Retnakaran. Turchin agreed, saying that he follows the same rule for titrating the medications individually in his clinic to evaluate a patient’s tolerance, before switching to a fixed-dose combination.

However, Turchin and Feit both pointed out that managing adverse reactions in these patients is complicated because it is difficult to pinpoint the source of the problem. “A sequential approach, at least to begin with, does allow you to determine which side effect is due to which medication,” said Feit.

All the panelists agreed on at least 1 point: that the decision-making process should be patient-centric and should consider the patient’s goals.

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