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Veterans who developed type 2 diabetes and who were started on monotherapy with metformin rather than a sulfonylurea had a lower risk of dying up to 6 years later — whether their kidney function was normal or mild to moderately impaired, in a new study. The study excluded patients with severe chronic kidney disease (CKD), defined as estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2. Of note, patients with moderate CKD (eGFR 30–44 mL/min/1.73m2) who received metformin as opposed to a sulfonylurea had an even greater absolute benefit than patients with better kidney function. "This is a population in which evidence regarding the health benefits of metformin is limited," say Zachary A Marcum, PharmD, PhD, from the University of Washington, Seattle, and colleagues in their recent paper in the Journal of General Internal Medicine. These findings, together with results from previous studies, support the FDA's guidance from April 2016 "to consider metformin initiation among individuals with an eGFR of 45–59 mL/min/ 1.73 m2 [mild CKD]" and suggests that "metformin initiation may be beneficial among persons" with even worse kidney function (ie, moderate CKD), they note. "What we're seeing here is further evidence of metformin's benefit in individuals with diabetes and CKD," Dr Marcum told Medscape Medical News. However, "it's too soon to say that the FDA should change" the labeling requirement for metformin, since the current findings need to be replicated in other populations," he added. Mortality With Metformin vs Sulfonylurea in Diabetes Plus CKDWhen metformin was approved by the FDA in 1995, it was contraindicated in patients with higher serum creatinine levels, due to fears of lactic-acid acidosis, which had been seen with another drug in the same class, phenformin, Dr Marcum and colleagues explain. But in April 2016, the FDA concluded metformin could be used safely in patients with some kidney impairment, defined by eGFR levels rather than serum creatinine cutoffs. The guidance said that metformin is contraindicated in patients with eGFR below 30 mL/min/1.73 m2. But it can be safely given to patients with mild CKD (eGFR 45–59 mL/min/1.73 m2), and patients who are already on metformin whose eGFR falls to 30 to 44 mL/min/1.73 m2 can remain on the drug if they still benefit from it. Since there have been no randomized clinical trials that specifically evaluate the safety and effectiveness of metformin in CKD, it's necessary to rely on well-conducted observational studies and meta-analyses, the researchers write. They performed an observational study using data from the US Veterans Health Administration, to compare mortality in veterans with type 2 diabetes who received initial monotherapy with metformin or a sulfonylurea between 2004 and 2009, when there was clinical equipoise for choosing either therapy They excluded individuals who had an eGFR < 30 mL/min/1.73m2 or had used a glucose-lowering drug prior to metformin or sulfonylurea. They identified 111,781 patients who received metformin and 63,515 patients who received a sulfonylurea. Patients who received metformin rather than a sulfonylurea were slightly younger (mean age 64 vs 68) and more likely to be male (96% vs 98%) or white (83% vs 82%) and have a higher BMI and a higher eGFR. The patients were followed until they discontinued their initial antidiabetic therapy or received a different prescription — for a mean duration of 1.7 years and a maximum of 6.2 years. The study reflects changes in therapy recommendations. In 2004, 52% of study entrants received metformin and 48% received a sulfonylurea. Following the 2006 consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes recommending the use of metformin as first-line therapy (Diabetes Care. 2006;29:1963-1972), this pattern changed. By 2009, 75% of new study entrants received metformin and 25% received a sulfonylurea. During follow-up, 5121 patients died. After adjustment for potential confounders, metformin monotherapy was associated with a lower hazard ratio for death across all the evaluated eGFR ranges. Risk of Mortality Among Patients Initiated on Metformin vs Sulfonylureaa
a. During a mean follow-up of 1.7 years and a maximum follow-up of 6.2 years b. Adjusted for age, sex, race, BMI, tobacco use, alcohol use, eGFR category, comorbid conditions, cholesterol, creatinine, HbA 1C, and cardiovascular medications c. Per 1000 person-years The survival benefits with metformin vs a sulfonylurea were slightly smaller in patients who were 75 or older or had cardiovascular disease. The study did not have information about dose, so it could not examine potential benefits of, for example, halving the dose in patients with moderate CKD. "Moving forward," said Dr. Marcum, "we need more evidence like this in people who are considered high risk," especially patients with eGFR 30 to 44 mL/min/1.73 m2, to see if the recommendations to restrict metformin treatment among these patients should be reexamined. The study was funded by a grant from the National Heart, Lung, and Blood Institute. The authors have no relevant financial relationships. J Gen Intern Med. Published online November 27, 2017.
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