Sequential therapy: Far more data, lower cost
Dr. Nathan began by pointing out that the ADA Standards of Care continue to advise use of metformin as first-line therapy for type 2 diabetes “because of its high efficacy in lowering A1c, minimal hypoglycemia risk when used as monotherapy, weight neutrality with the potential for modest weight loss, good safety profile, and low cost.”
He emphasized that he was not arguing “against the use of early or even initial combination therapy when there are co-existent morbidities [such as cardiovascular or chronic kidney disease] that merit use of demonstrably effective medications.” But Dr. Nathan pointed out, those patients are not the majority with type 2 diabetes.
He laid out four main arguments for choosing traditional sequential therapy over initial combination therapy. For one, it “enables determination of efficacy of adding individual medications, while initial combination precludes determining benefits of individual drugs.”
Second, traditional sequential therapy allows for assessment of side effects from individual drugs.
“With Dr. DeFronzo’s algorithm you throw everything at them, and if they get nausea, vomiting, or diarrhea, you won’t know which drug it is ... If they get an allergic reaction, you won’t know which medication it is,” observed Dr. Nathan, who is director of the clinical research center and the diabetes center at Massachusetts General Hospital, Boston.
Moreover, he said, traditional sequential therapy “promotes individualization, with selection of drugs, which is something we’re laboring to achieve. Initial combination obviously limits that.”
Further, sequential therapy is “parsimonious and cost-effective, whereas initial combination therapy is expensive, with modest advantages at most.”
And, there are “lots of data” supporting traditional sequential therapy and relatively little for initial combination therapy.
Dr. Nathan added that when he searched the literature for relevant randomized clinical trials, he found 16 investigating initial combination therapy versus monotherapy, but only three that examined combination versus sequential therapy.
“Very few of them, except for EDICT and VERIFY, actually include the sequential therapy that we would use in practice,” he said.
Moreover, he observed, except for the VERIFY study, most are less than half a year in duration. And in VERIFY, there was an initial 20% difference in the proportions of patients with A1c below 7.0%, but by 12 months, that difference had shrunk to just 5%-6%.
“So, looking over time is very important,” Dr. Nathan cautioned. “We really have to be careful ... Six months is barely enough time to see A1c equilibrate ... You really need to study a long-term, chronic, progressive disease like type 2 diabetes over a long enough period of time to be clinically meaningful.”
Dr. Nathan acknowledged to Dr. DeFronzo that the latter’s EDICT study was “well conducted” and “long enough,” and that the researchers did examine monotherapy versus sequential therapy. However, he pointed out that it was a small study with 249 patients and the dropout rate was high, with 58% of patients remaining in the study with triple therapy versus 68% for conventional treatment. “That’s a bit problematic,” Dr. Nathan noted.
At 2 years, the “trivial” difference in A1c was 6.5% with conventional therapy versus 6.0% with triple therapy. “This is all on the very flat complications curve with regard to A1c,” he observed.
Patients treated with sequential therapy with sulfonylurea and insulin had higher rates of hypoglycemia and weight gain, whereas the combination triple therapy group had more gastrointestinal side effects and edema.
However, the most dramatic difference was cost: the average wholesale price for sequential therapy totaled about $85 per month, compared with $1,310 for initial combination therapy. For the approximately 1.5 million patients with new-onset type 2 diabetes in the United States, that difference comes to an additional cost per year of about $22 billion, Dr. Nathan calculated.
“Although current sequential therapy leaves much to be desired ... initial combination therapy has generally only been tested for brief, clinically insufficient periods.
“And therefore, I think sequential therapy is still what is called for,” he concluded. “Well-powered, acceptable-duration studies need to be performed before we can adopt initial/early combination therapy as the standard of care.”
Dr. DeFronzo has reported receiving research support from Boehringer Ingelheim, AstraZeneca, and Merck; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from AstraZeneca; and participation on a data safety monitoring board or advisory board for AstraZeneca, Intarcia, Novo Nordisk, and Boehringer Ingelheim. Dr. Nathan has reported no relevant financial relationships.
A version of this article appeared on Medscape.com.