ORLANDO – Whether to start a patient with newly diagnosed type 2 diabetes mellitus on combination therapy or monotherapy should be based on experimentation and observation rather than expert opinion, according to Dr. Alan Garber, president of the American College of Endocrinology and professor of medicine, biochemistry, and molecular and cellular biology at Baylor College of Medicine in Houston.
Monotherapy for type 2 diabetes with stepwise addition of other antihyperglycemic agents has long been the accepted way to initiate therapy in this population. Beginning in the 1990s, investigators began to compare the efficacy of monotherapy with combination therapy, first with metformin and glyburide alone or together, and then testing metformin in combination with glipizide, rosiglitazone, and sitagliptin, he said.
Dr. Alan Garber
For metformin and glyburide, each agent alone lowered glycated hemoglobin (HbA1c), compared with placebo, but adding one to the other enhanced lowering. Combining the two drugs had the greatest benefit for higher HbA1c entry levels (e.g., HbA1c strata of 9%-9.9% or 10% or greater vs. less than 8%). At the highest-entry HbA1c levels, half doses of each of metformin and glyburide (250 mg/1.25 mg, respectively) were more efficacious than full doses of each (500 mg/2.5 mg). “This is called drug sparing,” he said.
In a trial of metformin and rosiglitazone, the combination was superior to either alone, producing significantly greater mean reductions in HbA1c and in fasting plasma glucose (FPG) at 32 weeks from their respective baselines, again, with greater reductions for higher-entry HbA1c levels. The combination was also better than either drug alone in the speed of reducing HbA1c or FPG, and in the final attained levels.
The combination of metformin and a sulfonylurea presents a risk of hypoglycemia, but Dr. Garber said the results are “much cleaner” using combinations of metformin with agents such as a thiazolidinedione, a dipeptidyl peptidase-4 inhibitor, or a sodium/glucose cotransporter-2 inhibitor.
Also noteworthy are findings from the EDICT (Efficacy and Durability of Initial Combination Therapy for Type 2 Diabetes) trial using insulin-sensitizing and insulin-secreting agents metformin/pioglitazone/exenatide in combination vs. escalating doses of metformin with sequential addition of a sulfonylurea and glargine insulin to treat patients with newly diagnosed type 2 diabetes. Over 2 years, the subjects receiving combination therapy had lower HbA1c, a mean weight loss, compared with weight gain, in the sequential therapy group, and a 7.5-fold lower rate of hypoglycemia, compared with the sequential treatment group (Diabetes Obes Metab. 2015;17:268-75).
Although the agents used in the two treatment strategies were not strictly equivalent, “it’s clear that testing multiple therapeutic mechanisms tends to produce better outcomes than fewer therapeutic mechanisms,” Dr. Garber said. The conclusions are fairly straightforward. “Look for evidence to support what strategies you want to use for your patients’ care.”
Using the Kaiser Permanente database, investigators found that the mean time of having an HbA1c above 8% was 3 years before a second agent was added, and the mean HbA1c was 9%. Many people have ascribed this sort of delay to a problem with the physician. But Dr. Garber said it is more related to patients, who often resist prescriptions for more drugs. So starting with two drugs may produce better efficacy faster as well as overcome the psychological issues of trying to add another one later (Am J Manag Care. 2003;9:213-7).
Dr. Daniel Einhorn
Session moderator Dr. Daniel Einhorn, medical director of the Scripps Whittier Diabetes Institute in La Jolla, California, raised the possibility of “subtraction therapy, where you start with three agents no matter what, and then if things go well, you subtract. And so you reverse the situation that Alan discussed.” In the patient’s view, “you have a celebration that night instead of a wake,” he said.
Dr. Garber has received honoraria or consulting fees as a member of the advisory boards of Novo Nordisk, Janssen, and Merck. Dr. Einhorn is on the scientific advisory boards of Eli Lilly, Novo Nordisk, Janssen, Boehringer Ingelheim, Sanofi, and Adocia, is a consultant for Halozyme, Glysens, Freedom-Meditech, and Epitracker, and has research funding from Lilly, Novo, Janssen, AstraZeneca, Mannkind, Freedom-Meditech, Merck, Sanofi, and Boehringer Ingelheim.