Concerns Also Surface About the Standard Diabetes Treatment
San Antonio, TX — Metformin is like a fine red wine: Its appeal continues to grow over time. More than 70 years after its first clinical use in diabetes, the staple of blood glucose control continues to surprise researchers with unexpected benefits in treating COVID-19, cancer and dementia. Not all the latest news about the common biguanide has been positive, however.
At the VA, understanding the benefits and risks of metformin takes on outsized importance as more than 25% of veterans who receive care through the agency have diabetes. VA/DoD guidelines follow the recommendations of the American Diabetes Association and the American Academy of Clinical Endocrinologist in calling for metformin to be used as the first-line pharmacotherapy for all patients with Type 2 diabetes (T2DM) who are unable to adequately control their blood glucose levels and lack contraindications for the drug. Significantly impaired kidney function is the primary contraindication.
It’s easy to see why metformin has risen to the top of the growing list of therapies available for T2DM. It has long-since lost patent protection, making it widely available as an inexpensive generic. It can be taken orally, avoiding the injections associated with many other diabetes drugs, does not increase weight and seldom causes hypoglycemia. Compared to other common diabetes medications, metformin is also associated with lower risk of cardiovascular disease and death. The most common side effect, gastrointestinal distress, typically wanes over time and can be reduced by using the extended release (ER) formulation.
NDMA Concerns
In the past few months, that extended-release version has faced increasing challenges. Starting in May, the U.S. Food and Drug Administration began alerting healthcare professionals and patients that metformin ER tablets in a range of doses from a growing number of manufacturers—nine as of this writing—may contain N-nitrosodimethylamine (NDMA) above the acceptable limit of 96 nanograms per day.
NDMA is a probable human carcinogen associated with earlier widespread recalls of ranitidine, a common heartburn medication, and multiple angiotensin receptor blockers, frequently prescribed blood pressure drugs. The FDA continues to investigate how NDMA contaminated these medications.
While the recall affects many versions of the metformin ER, many veterans with diabetes can continue to take their pills without worry. “The agency’s testing has not shown NDMA in immediate release (IR) metformin products (the most commonly prescribed type of metformin),” the FDA said. In addition, the agency urged patients to continue to take metformin as prescribed until their doctor or pharmacist provides a replacement or changes their treatment. Physicians were also encouraged to continue to prescribe metformin as clinically appropriate.
Increased Peripheral Neuropathy
Physicians and patients who continue to prescribe and take either formulation of metformin may want to watch carefully for a troubling, but likely manageable, side effect of the drug.
About half of older diabetics will develop some form of nerve damage, with peripheral neuropathy the most common type. While the exact mechanism remains unclear, it appears that high blood glucose levels damage the signaling ability of nerves and weaken the walls of capillaries that provide nerves with essential nutrients and oxygen, according to the Mayo Clinic. Peripheral neuropathy delays significantly increases the risk of lower limb ulcers and amputations.
The usual recommendation for preventing nerve damage from diabetes calls for diligent control of blood glucose levels with pharmacotherapy. Metformin would be the first choice for glucose control in most instances, but researchers at the San Antonio and Atlanta VAMCs and Emory University urged some caution in an article published online in Diabetes Research and Clinical Practice in October.1
For about a decade, evidence has accumulated that indicated metformin could paradoxically increase the risk of peripheral neuropathy (PN) in diabetic patients. The VA/Emory team recently quantified that risk in veterans.
The researchers used a national VA registry of veterans age 50 and older treated at the VA from 2002 to 2015. They found 210,004 veterans who received at least 500 mg/day of metformin for six or more months. Patients had an average age of 66.2 give or take 8.2 years and 96% were male.
“In our study, after a duration of at least six months of metformin prescription, 19% of veterans with T2DM developed PN during the follow up and the average time to develop PN after metformin initiation was 28 months so this suggests that it’s a prevalent problem that can develop relatively quickly following metformin initiation,” lead author Monica C. Serra, PhD, research health scientist in the Geriatrics Research, Education and Clinical Center at the South Texas Veterans Health Care System and associate professor of medicine, at the University of Texas Health Science Center at San Antonio told U.S. Medicine.
After adjusting for age, body mass index, duration of VA care, smoking status, alcohol abuse, and vitamin B12 testing and treatment, the researchers determined that veterans who took metformin for 18 or more months had double to triple the odds of developing peripheral neuropathy compared to those treated between six and 18 months. The adjusted odds ratios were 1.57 (1.51-1.63) for veterans treated 18 to 44 months, 2.05 (1.97-2.14) for those on metformin for 44.1 to 60 months, and 2.69 (2.582.79) for those who took metformin for more than five years.
There might be a simple fix, however. The Diabetes Prevention Program Outcomes Study found that patients with high blood sugar treated with metformin for five years had twice the rate of B12 deficiency (4% vs. 2%) and borderline B12 deficiency (20% vs. 10%) compared to individuals who did not take metformin during that time. Metformin usage also increased anemia. B12 is vital to normal nerve health and function and to normal red blood cell development.2
“There is an elevated risk for the development of new [peripheral neuropathy] with longer duration metformin treatment in older veterans with T2DM, indicating that there may be a need for early vitamin B12 monitoring and intervention among the growing number of older adults with T2DM who are treated with metformin,” Serra noted.
Studies on the impact of B12 on peripheral neuropathy have been “limited due to small study size, short follow-up period and absence of a placebo,” she added. “Future studies are needed to determine whether the risk for peripheral neuropathy may be altered with concomitant B12 supplementation following metformin initiation.” B12 supplementation does improve anemia caused by the vitamin’s deficiency.
COVID-19 Survival Benefit
Now, for the good news.
A study on the preprint server MedRxiv suggests that metformin could sharply reduce mortality in individuals with diabetes who contract the novel coronavirus. Among the 25,326 patients at the University of Alabama Birmingham Hospital tested for COVID-19 between Feb. 25 and June 22, 2020, individuals with diabetes had twice the odds of testing positive. Diabetes increased the odds of death from COVID-19 more than 3.5-fold, even after adjusting for age, race, sex, obesity and hypertension.3
Patients with diabetes accounted for more than 60% of all deaths in the study, but metformin use was strongly correlated with survival. “In fact, with 11% the mortality of metformin users was comparable to that of the general SARS-CoV-2-positive population and dramatically lower than the 23% mortality observed in subjects with diabetes and not on metformin,” the researchers said. Among the 604 diabetic patients with COVID-19, metformin therapy was associated with a 67% reduction in mortality, after adjusting for potential confounders such as metformin contraindications (chronic kidney disease and heart failure).
Similar results were seen in a retrospective study of 775 residents of 134 VHA community living centers who contracted COVID-19 between March 1 and May 13, 2020, published in October. Providence VAMC researchers discovered that residents taking metformin had by far the lowest 30-day mortality rate (12.5%)—nearly half that seen in diabetic patients on insulin (23.3%) or taking no diabetes medications (22.7%), a group that included both individuals without diabetes and those who managed diabetes with diet and exercise. Diabetic patients on other types of antidiabetic medication had a 30-day mortality rate of 17.4%. The reduction in risk of death for patients taking metformin was 52% compared to residents on no diabetes medications.4
Reduced Dementia Risk
While up to 60% of individuals with diabetes ultimately develop dementia, here again, metformin appears to play a protective role. A prospective randomized controlled trial of 1,000 patients published online in Diabetes Care in late September found that metformin slowed the rate of decline in global cognition and executive function and reduced the risk of incident dementia by 81% over six years.5 All study participants were between 70 and 90 years of age and results were controlled for APOE genotype, which is closely linked to risk of Alzheimer’s disease.
“We’ve revealed the promising new potential for a safe and widely used medication, which could be life-changing for patients at risk of dementia and their families. For those with Type 2 diabetes, metformin may add something extra to standard glucose lowering in diabetes care: a benefit for cognitive health,” said first author Katherine Samaras, MBBS, PhD, leader of the Healthy Ageing Research Theme at the Garvan Institute and endocrinologist at St Vincent’s Hospital, both in Sydney, Australia.
The new research supports findings of two large VA retrospective studies. The first compared 17,200 new users of metformin to 11,440 veterans started on sulfonylureas. Patients had a mean age of 73.5 years. With average follow-up of five years, 4,906 veterans received a diagnosis of dementia. Treatment with metformin reduced the risk of dementia by 33% in patients under age 75 and 22% in those 75 years of age and older.6
The second VA study examined the impact of metformin on dementia in African American versus white veterans. Using VHA medical records for 73,761 veterans age 50 or older who received VA care between 2000 and 2015, researchers at the St. Louis VAMC with colleagues from the St. Louis University School of Medicine and the University of Washington in Seattle determined that metformin significantly reduced the risk of dementia in African American veterans compared to sulfonylureas. African Americans with T2DM have a 10% to 18% greater risk of developing dementia than diabetic white Americans.7
Overall, the risk of dementia was reduced 27% in African American veterans taking metformin, with the sharpest reduction, 40%, seen in those between age 50 and 64. Notably, this study did not find an overall reduction in dementia risk in white veterans, though metformin did reduce the risk in both African American and white individuals aged 65 to 74 years.
Reduced Cancer Risk and More
Previous studies have also identified benefits to metformin in cancer. A study in 21,352 veterans with colorectal cancer found that those with diabetes had significantly worse overall survival than those without diabetes. Among the diabetic patients, veterans using metformin had a 13% improved overall survival rate versus those taking other diabetes medications, after correcting for diabetes severity and other factors.8
Metformin has previously been demonstrated to significantly reduce mortality in frail older veterans and pancreatic cancer patients as well as provide benefits in age-related macular degeneration, polycystic ovary syndrome and some types of arthritis. The Targeting Aging with Metformin, or TAME, study is examining the drug’s ability to slow the biological aging process.
- Serra MC, Kancherla V, Khakharia A, Allen LL, Phillips LS, Rhee MK, Wilson PWF, Vaughan CP. Long-term metformin treatment and risk of peripheral neuropathy in older Veterans. Diabetes Res Clin Pract. 2020 Oct 6;170:108486. doi: 10.1016/j.diabres.2020.108486. Epub ahead of print. PMID: 33035597.
- Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ, Bray GA, Schade DS, Temprosa MG, White NH, Crandall JP; Diabetes Prevention Program Research Group. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016 Apr;101(4):1754-61. doi: 10.1210/jc.2015-3754. Epub 2016 Feb 22. PMID: 26900641; PMCID: PMC4880159.
- Crouse A, Grimes T, Li P, Might M, Ovalle F, Shalev A. medRxiv 2020.07.29.20164020; doi: doi.org/10.1101/2020.07.29.20164020
- Lally M, Tsoukas P, Halladay C, O’Neill E, Gravenstein S, Rudolph JL. Metformin is associated with decreased 30-day mortality among nursing home residents infected with SARS-CoV-2. JAMDA. 26 Oct 2020. doi.org/10.1016/j.jamda.2020.10.031 Epub ahead of print.
- Samaras K, Makkar S, Crawford JD, Kochan NA, Wen W. Draper B, Trollor JN, Brodaty H, Sachdev PS. Metformin use is associated with slowed cognitive decline and reduced incident dementia in older adults with Type 2 diabetes: The Sydney Memory and Aging Study. Diabetes Care 2020; DOI: 10.2337/dc20-0892.
- Orkaby AR, Cho K, Cormack J, Gagnon DR, Driver JA. Metformin vs sulfonylurea use and risk of dementia in US veterans aged ≥65 years with diabetes. Neurology. 2017 Oct 31;89(18):1877-1885. doi: 10.1212/WNL.0000000000004586. Epub 2017 Sep 27. PMID: 28954880; PMCID: PMC5664297.
- Scherrer JF, Morley JE, Salas J, Floyd JS, Farr SA, Dublin S. Association Between Metformin Initiation and Incident Dementia Among African American and White Veterans Health Administration Patients. Ann Fam Med. 2019 Jul;17(4):352-362. doi: 10.1370/afm.2415. PMID: 31285213; PMCID: PMC6827650.
- Paulus JK, Williams CD, Cossor FI, Kelley MJ, Martell RE. Metformin, Diabetes, and Survival among U.S. Veterans with Colorectal Cancer. Cancer Epidemiol Biomarkers Prev. 2016 Oct;25(10):1418-1425. doi: 10.1158/1055-9965.EPI-16-0312. Epub 2016 Aug 5. PMID: 27496094; PMCID: PMC5050110.
