After Metformin, Are Newer Drugs Better for Type 2 Diabetes?

Miriam E. Tucker

March 17, 2014

Use of a sulfonylurea as second-line therapy after metformin for type 2 diabetes is just as effective as a newer agent but far less costly, a new study based on claims data finds.

The results were published online February 26 in Diabetes Care by Yuanhui Zhang, a PhD candidate at North Carolina State University, Raleigh, and colleagues.

"In light of an incomplete understanding of the pros and cons of second-line medications and the high cost associated with newer medications, the decision to use newer medications should be weighed against the additional cost burden to patients and/or the health system," study coauthor Brian Denton, PhD, of the University of Michigan, Ann Arbor, told Medscape Medical News.

However, the use of retrospective data means that the study is subject to both ascertainment and physician-choice bias, said Alan J. Garber, MD, PhD, of Baylor College of Medicine, Houston, Texas, when asked to comment for Medscape Medical News.

Moreover, noted Dr. Garber, the study doesn't adequately account for the adverse effects of sulfonylurea-induced hypoglycemia. "Patients value things differently. If you had a hypoglycemic episode and you don't like that, you're willing to pay a lot more of your discretionary income to avoid having another one."

Four Regimens Compared

The researchers explain that there are currently 11 classes of approved glucose-lowering medications. Metformin has a long-standing evidence base for efficacy and safety, is inexpensive, and is regarded by most as the primary first-line treatment for type 2 diabetes.

When metformin fails to achieve or maintain glycemic goals, another agent needs to be added. However, there is no consensus or sufficient evidence supporting the use of one second-line agent over another. And in the past decade, the mix of secondary agents used in the treatment of diabetes has changed significantly, with increasing use of newer glucose-lowering agents such as dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagonlike peptide-1 (GLP-1) agonists in place of older and less expensive drugs such as sulfonylureas, resulting in a dramatic rise in the cost of diabetes medications and management. However, the long-term clinical benefit of this shift is uncertain.

The researchers employed a statistical model derived from an administrative claims database of 37,501 privately insured patients aged at least 40 years with type 2 diabetes, diagnosed between 1995 and 2010. Outcomes were compared for those prescribed sulfonylurea, DPP-4 inhibitor, GLP-1 agonist, or insulin for the intensification of metformin monotherapy.

The model, which simulates natural variation in HbA1c progression, assumed that the sulfonylurea, DPP-4 inhibitor, or GLP-1 agonist was added to metformin when glycemic control worsened to a given HbA1c threshold and that if the goal was exceeded a second time, insulin was added to the regimen to replace the second-line agent. In the case of insulin as a second-line therapy, treatment was intensified by directly adding insulin once HbA1c exceeded the glycemic-control goal. For all regimens, there were no further treatment changes once insulin was initiated, as it was assumed to maintain glycemic control.

Outcome measures included life-years (LYs), quality-adjusted life-years (QALYs), mean time to insulin dependence, and expected medication cost per QALY from diagnosis to first diabetes-related complication (ischemic heart disease, myocardial infarction, congestive heart failure, stroke, blindness, renal failure, amputation) or death. LYs gained were adjusted down to account for the impact of hypoglycemia severe enough to require hospitalization, Dr. Denton told Medscape Medical News.

All regimens resulted in similar LYs and QALYs regardless of glycemic-control goal, but the regimen with sulfonylurea incurred significantly lower cost per QALY and resulted in the longest time to insulin dependence (about 1 year vs 0.53–0.62 years for the other 2 regimens). The latter is "an important factor to be considered by patients who wish to delay insulin initiation as long as possible," the researchers note.

Average medication costs per month were $81.75 for metformin, $54.85 for sulfonylurea, $232.84 for DPP-4 inhibitor, $325.97 for GLP-1 agonist, and $245.70 for insulin.

Expected medication costs per QALY ranged from a low of $2600/QALY for metformin/sulfonylurea in women to a high of $2891/QALY for metformin/GLP-1 agonist in men. Compared with the metformin/sulfonylurea regimen, which was the least expensive, additional cost per QALY incurred with the other second-line agents ranged from $141/QALY for DPP-4 inhibitor in women to $216/QALY for GLP-1 agonist in men.

"The differences in cost per patient among the 4 treatment regimens were substantial and thus of potential importance to patients as well as healthcare providers and payers," the authors comment.

How Relevant Is Cost?

Dr. Denton told Medscape Medical News: "We think the results open up important questions about the value derived from the various second-line treatments. There is a lack of evidence about the long-term effects of the newer medications. All of the medications have pros and cons, but the difference in cost is quite clear."

"In light of this, there is a need to more clearly justify the benefits of newer treatments," he stressed.

However, Dr. Garber said that the study did not adequately adjust for the impact of sulfonylurea-induced hypoglycemia. He pointed to a 2011 study by the US Centers for Disease Control and Prevention, which showed that glucose-lowering drugs are responsible for a quarter of emergency hospitalizations in older adults. And, he noted, in the Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) study, hypoglycemia occurred in more than half of patients randomized to receive sulfonylureas.

"I don't see cost anywhere in the Oath of Hippocrates. What I do see is that we're obliged to prescribe safe and effective treatments. Sulfonylureas have proven safety concerns," Dr. Garber pointed out.

However, Dr. Denton sees it differently. "Our findings suggest that there are open questions about the value of the newer medications in terms of the trade-off between cost and quality-adjusted survival."

GRADE Should Yield Some Answers

"Our findings will be helpful in interpreting the anticipated results of future randomized controlled trials, which should shed more light on the clinical effects of the medications," Dr. Denton adds.

In fact, such a trial is currently under way. Funded by the US National Institutes of Health, the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) will prospectively compare the same 4 classes of second-line agents in combination with metformin in 5000 patients with type 2 diabetes at 45 US clinical sites for a planned 7-year follow-up.

The current study was funded in part by the Agency for Healthcare Research and Quality and is based in part on work supported by the National Science Foundation. The study authors have reported no other relevant financial relationships. Dr. Garber is a consultant to, on the advisory board of, and/or on the speakers' bureau for Novo Nordisk, Merck, Salix, Janssen, Viking Therapeutics, Vivus, Lexicon, Halozyme, Eisai, and Amarin.

Diabetes Care. Published online February 26, 2014. Abstract

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