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One of the world's most commonly prescribed drugs, metformin is primarily used to treat type 2 diabetes. New research into its potential advantages in other conditions, as well as emerging concerns about its adverse effects, led to the medication becoming this week's top trending clinical topic. Perhaps most notably, recently released results from a landmark trial were vastly disappointing (see Infographic below).
These results "tell us that metformin is not effective against the most common types of breast cancer and any off-label use [of] this drug for the treatment of these common types of breast cancer should be stopped," lead investigator and medical oncologist Pamela Goodwin, MD, a breast cancer researcher at the Lunenfeld-Tanenbaum Research Institute in Toronto, Canada, said in a press release. The study included 3649 patients with hormone receptor–positive or –negative breast cancer who did not have diabetes. Patients were randomly assigned equally to receive either metformin 850 mg twice daily or placebo for 5 years. Among 2533 patients with hormone receptor–positive disease, the incidence of invasive disease–free survival events was 2.78 per 100 patient-years with metformin vs 2.74 per 100 patient-years with placebo (hazard ratio [HR], 1.01; P = .93). Among 1116 patients with hormone receptor–negative disease, the incidence of invasive disease–free survival events was 3.58 with metformin vs 3.60 with placebo (HR, 1.01; P = .92).
The only potential bright spot: Among the small subset of patients (17% of the total) who had HER2-positive disease, 1.93 disease-free survival events were associated with metformin vs 3.05 events with placebo (HR, 0.64; P = .03), and 0.78 deaths per 100 patient-years were reported in the metformin arm vs 1.43 in the placebo arm (HR, 0.54; P = .04). The benefit was limited to patients with any C allele of the rs11212617 single-nucleotide variant. Results need to be confirmed in a randomized trial, but it's possible that metformin "could provide an additional treatment option for HER2-positive breast cancer," Goodwin said.
Findings from recent research involving older patients with type 2 diabetes and cancer were more encouraging. An analysis of 7725 patients with lung, breast, colorectal, prostate, or pancreatic cancer found that 2981 patients (38.5%) had been prescribed metformin. Patients who took metformin had significantly better overall survival in both unadjusted (HR, 0.73; 95% CI, 0.69-0.76; P < .001) and adjusted models (adjusted HR, 0.77; 95% CI, 0.73-0.81; P < .001). Hazard ratios among those who received metformin were 0.78 (95% CI, 0.69-0.88; P < .001) for colorectal cancer, 0.77 (95% CI, 0.72-0.82; P < .001) for lung cancer, 0.82 (95% CI, 0.72-0.93; P < .001) for pancreatic cancer, and 0.74 (95% CI, 0.62-0.88; P = .002) for prostate cancer.
Metformin has also shown recent promise in mitigating antipsychotic-induced weight gain. A new evidence-based guideline from Ireland suggests that psychiatrists should prescribe metformin early to patients who gain more than 7% of their baseline weight within the first month of antipsychotic treatment. It also endorses metformin when weight gain is established. The proposed starting dosage is 500 mg twice per day with meals, with increments of 500 mg every 1-2 weeks until reaching a target dose of 2000 mg/d. In the case of early intervention, the guideline proposes initially stabilizing the weight gained or, if possible, reverse excess weight. When weight gain is established, the goal is to lose at least 5% of the weight within the next 6 months.
A pair of studies also suggests metformin may have neuroprotective benefits. A preprint study that has not yet been peer-reviewed found that use of the drug probably reduces the risk for Alzheimer's disease in the general population. Genetically proxied metformin use equivalent to a 6.75 mmol/mol (1.09%) reduction in A1c was associated with 4% lower odds of Alzheimer's disease (P = 1.06 × 10-4) in individuals who did not have diabetes. A separate systematic review and meta-analysis of longitudinal data found that metformin may be associated with a broader decreased risk for neurodegenerative disease. Pooled data showed that the relative risk associated with onset of neurodegenerative disease was 0.77 (95% CI, 0.67-0.88) for patients with diabetes who were taking metformin. The effect was greater with longer use, with an relative risk of 0.29 (95% CI, 0.13-0.44) for those who took metformin for 4 years or longer.
From disappointing results to promising findings involving a range of nondiabetic conditions, a wave of metformin research helped turn this popular drug into the most popular clinical topic of the week.
Learn more about metformin.
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Cite this: Ryan Syrek. Trending Clinical Topic: Metformin - Medscape - Jun 17, 2022.