Metformin, Aging, and Comorbidities

According to the American Diabetes Association, over 29 million Americans have diabetes, with 11.8 million of the patient population being over the age of 65. Approximately 1.4 million Americans a year are diagnosed with diabetes, and those diagnosed with type 2 diabetes or prediabetes are likely to be started on first-line therapy with metformin. Although a concern of vitamin B12 deficiency is associated with metformin, it is still a choice drug due to its efficacy and limited side effects and may now have additional benefits for diabetes patients.

A study was recently released in the Journal of Diabetes and its Complications that aimed to “…assess the heterogeneity of metformin’s co-development of ARCs (age-related comorbidities) among healthy older adults with T2D” and focused on the prospect of the development of cardiovascular disease, cancer, depression, dementia, and frailty-related disease (FRD). The study population originated from the Veterans Administration Electronic records between the years of 2002-2012 and included men who were age 65 or older, had diagnosis of type 2 diabetes but were naïve to glucose-lowering medication treatment prior to 2003, had one or more outpatient visits per year, and were not diagnosed with any ARC at the beginning of the study period.

The study excluded patients with liver and kidney disease due to metformin’s contraindication in these disease states of increased risk of developing lactic acidosis. Glucose-lowering medications used in the study were: sulfonylureas (glipizide, glyburide, glimepiride, etc), biguanides (metformin), mheglitinides (repaglinide, nateglinide), and alpha-glucosidase inhibitors (acarbose, miglitol, vogilbose). Study subjects were further divided into metformin users (more than 180 days of a prescription for metformin) or non-metformin users who were on any of the other included study medications.

The analysis identified four advanced-related comorbidity trajectory classes that included both metformin and non-users. The majority of the study patients fell into the healthy class, meaning they had a lower chance of developing ARCs. After nine years of the study, metformin was found to have an absolute risk reduction of 2.5% in likelihood of cancer diagnosis (p= 0.02), 6.1% reduction in cardiovascular disease (p= less than 0.01), 5.0% reduction in FRD (p= less than 0.01), and 0.14% reduction in dementia (p= less than 0.01). Consequently, the patients who were classified as non-users of metformin had an approximate increase of 2.8% in likelihood of cancer diagnosis, 6.7% increase in cardiovascular disease, 6.2% increase in FRD, and a 1% increase in depression.

The second most populated class consisted of patients who had the highest risk of developing cardiovascular disease. Metformin non-users had an increase of 74.5% (p less than 0.01) in cardiovascular disease (up from 47.1% in year one of the study) as well as significant increases in likelihood of cancer diagnosis (p less than 0.01), depression (p less than 0.01), dementia (p less than<0 .01="" 0.01="" 1="" 23.6="" 40.1="" 44.4="" 45.5="" 48.2="" 48.6="" 64.7="" a="" above="" across="" all="" an="" and="" arcs="" as="" associated="" being="" both="" by="" cancer="" cardiovascular="" category="" class="" classes.="" classes="" compared="" consequently="" consisted="" decrease="" decreased="" decreases="" depression.="" developing="" diagnosis="" disease="" effect="" final="" followed="" four="" frd.="" frd="" from="" furthermore="" greatest="" had="" high="" highest="" impact="" in="" increase="" increased="" less="" likelihood="" metformin="" mortality="" most="" non-users="" occurrence="" of="" p="" patients="" rate="" reduction="" risk="" seen="" significant="" similarly="" spectrum="" than="" the="" third="" to="" trends="" up="" use="" users.="" users="" was="" well="" who="" with="" year="">

Metformin use was found to reduce the development of ARCs, with significant reduction in patients who are at risk for a particular condition. Limits of this study include the observational design that could lead to bias due to the possibility of unobserved events and confounders, the all-male cohort, and lack of data concerning other medications study participants were taking during the 9-year course observed. This study opens up further potential investigation to confirm the benefit of metformin in reduction of ARCs. Possible beneficial studies would include women as well as looking into the effects of long-term use of glucose-lowering medications used alone or in combination.