All-cause mortality showed a similar pattern, with a 60% increased risk in 1997 and a gradual improvement. "Although it’s still on the wrong side of 1.0, it’s not close to being statistically significant."
Overall, 226 patients have now died: 107 in the monotherapy group (40%) and 119 in the combination group (44%). Death from a diabetes-related cause has occurred in 57 of the monotherapy group (21%) and 60 of the combination therapy group (22%), for a nonsignificant risk ratio of 1.18.
There is no significant increase in the risk of myocardial infarction (1.09) or stroke (0.86), whether fatal or nonfatal.
Two more studies are in the works to try and sort out the sulfonylurea-metformin mash-up, Dr. Holman said: GRADE and GLINT. GRADE (Glycemic Reduction Approaches in Diabetes) is a four-arm comparative effectiveness study sponsored by the National Institutes of Health. It will randomize 6,000 patients with type 2 diabetes to metformin and either a sulfonylurea (glimepiride), a DPP-4 inhibitor (sitagliptin), a GLP-1 agonist (liraglutide), or insulin glargine. The groups will be followed for 5 years, Dr. Holman said. "Certainly, if there is a doubling in the risk of death in the sulfonylurea/metformin group, we will see it."
The second study, called GLINT (Glucose Lowering in Non-diabetic Hyperglycemia Trial), is just getting ramped up in the United Kingdom. It’s aimed at patients whose HbA1c is elevated, but not yet in the diabetic range of 6.5%.
The 5-year GLINT aims to recruit nearly 12,000 people aged 40 years and older, who have a 10-year calculated cardiovascular disease risk of at least 20%. Subjects will be randomized to metformin or placebo. The primary endpoint is a composite cardiovascular outcome of death or nonfatal MI or stroke. The first patients are being seen this month, Dr. Holman noted.
The study is also well powered to look at the increased risk of bowel and breast cancers among diabetes patients, he added
"Perhaps this will be the pivotal second study that will help confirm the preeminence of metformin as first-line therapy."
Becton Dickinson, Boehringer Mannheim, Bristol Myers Squibb, Hoechst, Lilly, Lipha, and Novo Nordisk contributed to the funding for the UKPDS study. Dr. Holman had no financial disclosures.
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