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Metformin No Help for Atherosclerosis in T1D
— Findings don't support metformin in long-standing type 1 diabetes
by Kristen Monaco, Contributing Writer, MedPage Today June 13, 2017
This article is a collaboration between MedPage Today and:
SAN DIEGO -- Metformin didn't help diminish atherosclerosis in patients with type 1 diabetes, according to results of the REMOVAL trial.
Compared with placebo, 1,000 mg twice-daily of oral metformin didn't reduce mean progression of common carotid artery intima-media thickness (cIMT) over 3 years (-0.005 mm per year, 95% CI -0.012 to 0.002; P=0.1664), John Petrie, PhD, of the University of Glasgow in Scotland, and colleagues reported here at the American Diabetes Association and simultaneously in The Lancet Diabetes & Endocrinology.
Note that this randomized trial found that metformin use in type-1 diabetes was not associated with improved carotid intima-media thickness.
A signal of potential renal benefit of metformin emerged, however, though this was a secondary outcome.
They did find, however, that one of the trial's tertiary endpoints – maximal cIMT -- was significantly reduced among the treatment group (-0.013 mm per year, -0.024 to -0.003; P=0.0093).
Vivian Fonseca, MD, of Tulane University School of Medicine, who wasn't involved with the study, told MedPage Today that this tertiary endpoint represents a "small change, and we don't quite know what that means in terms of long-term cardiovascular outcomes."
Some work has shown that metformin can reduce the need for insulin and improve glycemic control in patients with type 1 diabetes, but less is known about whether it confers cardiovascular protection. To explore that issue, Petrie and colleagues conducted the REMOVAL trial across 23 centers in five countries. The randomized, double-blind study included 428 participants with type 1 diabetes for a minimum of 5 years (n=219 treatment; n=209 placebo). All participants, who had met three out of ten pre-specified CV-risk factors, had endured a 3-month optimization period regarding glycemic and risk factor control prior to randomization.
Regarding the first secondary outcome, HbA1c improved over 3 years among the metformin group versus the placebo (-0.13%, 95% CI -0.22 to -0.037; P=0.006). However, this change was attributed to a reduction after 3 months (-0.24%, -0.34 to -0.13; P<0.0001) and was not sustained long-term, they reported (P=0.0163 for visit-by-treatment interaction).
Three years of metformin treatment was associated with a significant drop in both LDL cholesterol (-0.13 mmol/L, 95% CI -0.24 to -0.03, P=0.0117), as well as a reduction in body weight, they found (-1.17 kg [-2.58 lb], -1.66 to -0.69 [-3.66 to -1.52], P<0.0001).
Petrie's group reported there was no significant change associated with metformin use after 3 years regarding retinopathy, endothelial function (which was assessed by reactive hyperaemia index), or insulin requirement. However, the researchers did find a notable visit-by-treatment interaction regarding insulin requirement with metformin use (P=0.0018).
Use of treatment was also linked to a significant rise in eGFR, they found (4.0 mL/min per 1.73m², 2.19 to 5.82; P<0.0001).
In an accompanying commentary, Eberhard Standl, MD, of Munich Diabetes Research Group at Helmholtz Center in Germany, highlighted this finding as a stand-out, writing that it would have "enormous practical implications" if metformin is linked with renal benefit.
"However, caution should be exercised before expectations are raised too high," he wrote. "The investigators themselves allude to a potential functional (and probably reversible) effect of metformin at the tubular level of the kidney, but why has this phenomenon not been described before now? Clearly, further studies are warranted to elucidate this issue, including exclusion of a potential interaction of the assay used to estimate glomerular filtration rate with metabolic changes related to metformin."
A larger percentage of patients discontinued use of metformin during the trial, compared with placebo, which was mainly attributed to gastrointestinal events (59 metformin [27%] versus 26 placebo [12%], P=0.0002). In total, 7 deaths were reported during the trial -- 5 among the metformin group and 2 in the placebo group, but they were deemed unrelated to the study treatment.
Petrie and colleagues said the results "do not support the assertion by current guidelines that metformin can improve glycemic control in patients with type 1 diabetes, nor do they provide a rationale for restricting its use to those who are overweight or obese."
"However, they do suggest that wider off-label use of metformin might be warranted to improve CVD risk management in type 1 diabetes, and possibly also reduce insulin dose requirement," they concluded.
Fonseca said that for people with type 1 diabetes, "you cannot take the results of this trial to recommend metformin treatment for everybody. I think for a few selected people it might be useful in terms of metabolic management."
The study was funded by JDRF.
Petrie disclosed relationships with JDRF, Novo Nordisk, Sanofi Aventis, Quintiles, Janssen, Merck (Germany), Lilly, ACI Clinical, and Itamar Medical. Other authors also disclosed relevant relationships.
The Lancet Diabetes & Endocrinology
Source Reference: Petrie J, et al ""Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial" Lancet Diabetes Endocrinol 2017; DOI: 10.1016/S2213-8587(17)30194-8.
Source Reference: Standl, Eberhard "Metformin in type 1 diabetes" Lancet Diabetes Endocrinol 2017; DOI: 10.1016/S2213-8587(17)30216-4.