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Long-term metformin therapy reduces CVD risk in type 1 diabetes
SAN DIEGO — Middle-aged adults with long-standing type 1 diabetes at high risk for cardiovascular disease who added metformin to insulin therapy for 3 years saw reductions in body weight, LDL cholesterol and atherosclerosis progression vs. those assigned placebo, according to a speaker here.
“Type 1 diabetes is associated with reduced life expectancy by 11 to 13 years due to heart disease and stroke,” John Petrie, MD, PhD, professor of diabetic medicine at the University of Glasgow in Scotland, said during a press conference discussing the findings. “Metformin is an inexpensive agent widely used to reduce heart disease in type 2 diabetes, so we hypothesized that it might have similar effects in type 1 [diabetes].”
Risk m arkers trial
U.S. and U.K. guidelines currently recommend adding metformin to insulin therapy in adults with type 1 diabetes and overweight or obesity to improve blood glucose control and reduce insulin dose requirements, Petrie said. However, metformin is not widely used for this off-label indication, and the recommendation is based on short-term studies.
Researchers initiated the REMOVAL study, he said, to assess whether metformin, when added to insulin therapy and standard care, reduced atherosclerosis, as measured by progression of carotid intima-media thickness, in adults aged at least 40 years with type 1 diabetes at increased risk for CVD.
“This is not a [CV] outcomes trial,” Petrie said. “This is a trial looking at markers of [CVD] and risk.”
Petrie and colleagues analyzed data from 428 adults enrolled in removal between December 2011 and June 2014, from 23 hospital diabetes clinics in Australia, Canada, Denmark, the Netherlands and the United Kingdom (mean age, 55 years; mean diabetes duration, 33.8 years; mean BMI, 28.5 kg/m²; mean HbA1c, 8.05%; 34% on insulin pump therapy; 73% on antihypertensive medication; 80% using statin therapy). Researchers randomly assigned participants to 1,000 mg twice-daily metformin (Glucophage, Merck; n = 219) or placebo (n = 209) for 3 years. Adjustments in insulin dose were made at the discretion of site staff; follow-up occurred at 12, 24 and 36 months. Primary outcome was progression of average mean far-wall carotid artery intima-media thickness (measured in millimeters at baseline, 12, 24 and 36 months); secondary outcomes were reductions in HbA1c, LDL cholesterol and body weight, increases in estimated glomerular filtration rate and incident retinopathy, and improvements in endothelial function assessed at baseline, 12 and 36 months. Improvement in two or more of the secondary outcomes was prespecified as clinically meaningful. Tertiary outcomes included frequency of hypoglycemia, treatment satisfaction, progression of average maximal far-wall carotid artery intima-media thickness and vitamin B12 status.
Atherosclerosis , glycemic outcomes
Comparing treatment groups, the difference in mean within-person carotid artery intima-media thickness slopes for the primary outcome was –0.005 mm per year (95% CI, –0.012 to 0.002); there was no treatment-by-sex interaction. However, researchers observed a reduction in atherosclerosis progression as measured by the prespecified tertiary outcome of averaged maximal carotid artery intima-media thickness.
Both treatment groups experienced an increase in average maximal carotid artery intima-media thickness, but those assigned metformin saw reduced progression vs. those assigned placebo (difference in slope, –0.013 mm per year; 95% CI, –0.024 to –0.003).
Participants assigned metformin therapy saw a –0.13% reduction in HbA1c over 3 years vs. those assigned placebo, but this reduction occurred in the 3 months after randomization and was not sustained (P for visit-by-treatment interaction = .0163). Researchers did not observe a reduction in insulin dose requirement over 3 years in those assigned metformin vs. placebo, but they noted evidence of an interaction between treatment and visit (units per kilogram; P = .0018) that began, on average, 6 months after initiation of therapy and was sustained (estimated in post-hoc analyses as –0.023 U/kg; 95% CI, –0.045 to –0.0005).
Compared with participants assigned placebo, those receiving metformin saw a mean –1.17 kg reduction in body weight over 3 years (95% CI, –1.66 to –0.69) and a –0.13 mmol/L reduction in LDL cholesterol (95% CI, –0.24 to –0.03).
“These changes would have met the secondary composite outcome (at least two of the secondary outcomes showing significant improvement) had the primary outcome shown a significant difference,” the researchers wrote in an article simultaneously published in The Lancet Diabetes & Endocrinology.
Researchers also observed an increase in e GFR in those assigned metformin vs. placebo (mean 4 mL/min/1.73 m²; 95% CI, 2.19-5.81). There were no between-group differences observed in endothelial function or retinopathy.
“These data suggest a vital role for metformin in [CV] risk management in our view, but the data do not support use of metformin to improve glycemic control in adults with long-standing type 1 diabetes, as is suggested by the current guidelines,” Petrie said. “Unless and until a [CV] outcomes trial is performed in type 1 diabetes with metformin, physicians have to decide whether to add metformin for people with type 1 based on the results of our REMOVAL trial.” – by Regina Schaffer
References:
Petrie JR, et al. Lancet Diabetes Endocrinol. 2017;doi:10.1016/s2213-8587(17)30194-8.
Petrie JR, et al. Presented at: American Diabetes Association 77th Scientific Sessions; June 9-13, 2017; San Diego.
Disclosures: The JDRF funded the REMOVAL Trial; Merck donated study medication. Petrie reports receiving personal fees, travel support or research grants from ACI Clinical, Eli Lilly, Janssen, Novo Nordisk, Quintiles, Sanofi Aventis and nonfinancial support (donation of EndoPAT equipment, reading services and quality assurance support for the present trial) from Itamar Medical. Please see the full study for the other researchers’ relevant financial disclosures.
Perspective
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Metformin is nearly universally used as first-line therapy for glucose control in type 2, although there is only fairly weak evidence for its use as atherosclerotic cardiovascular disease (ASCVD) prevention with this agent. Thus, further evidence for ASCVD benefits of metformin would be welcome. This trial used carotid intima-media thickness (CIMT) to test for possible anti-atherosclerotic effects of metformin vs. placebo over 3 years in 428 randomized patients. Unfortunately, the trial showed only modest benefit, and changes in CIMT with treatment are only weak predictors of ASCVD events. The clinical impact of the trial is small, providing only modest corroboration of the atheropreventive effects of metformin.
Perspective
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REMOVAL looked at the effect of metformin, a medication for type 2 diabetes, on people with type 1 diabetes. For years, it was perceived that people with type 1 diabetes are not at risk for heart disease as are those with type 2. That’s not the case. People with type 1 disease do have an increased risk for CVD compared with the general population, and nowadays many with type 1 diabetes have obesity and insulin resistance, thus raising the question whether we should treat some of them with antihyperglycemic medications currently approved only for type 2 disease. In REMOVAL, these patients were given metformin in addition to insulin and were evaluated for carotid intima-media thickness, which is a good surrogate for atherosclerosis. Although the researchers observed no significant improvement in glucose control, they saw an improvement in atherosclerosis.
The conclusion from the diabetes CV outcome trials is that medications for diabetes are safe from the standpoint of CVD. In fact, based on some of the randomized clinical trials, as well as real-life observational trials, we’re seeing a superior effect of SGLT2 inhibitors, as well as some GLP-1 receptor agonists, on the reduction of CV morbidity and mortality, not just demonstrating CV safety. At the same time, we recognize that many people with diabetes, not just with type 2 disease, may benefit from medication like metformin, if not for glucose control, for improvement in CV risk.