Best Med #1: Metformin
Metformin is well known as the first line medication for the treatment of type 2 diabetes. Its history is linked to Galega officinalis (also known as goat's rue), a traditional herbal medicine in Europe, found to be rich in guanidine, which, in 1918, was shown to lower blood glucose. It is now the most prescribed glucose-lowering medicine worldwide.
How exactly metformin regulates blood sugar levels is still an area of scientific debate and research. It seems that it acts on multiple tissues through various underlying mechanisms. It decreases production of glucose by the liver by inhibiting gluconeogenesis. It decreases intestinal absorption of glucose. It also helps sensitize other organs and tissues to insulin, thereby helping them use and control blood sugar levels.
Unlike many other medications that improve glycemic control, metformin does so while also promoting weight loss in both insulin sensitive and insulin resistant patients. Metformin is my first line option for weight loss, even in those who have normal blood glucose levels and hemoglobin A1c’s. Emerging evidence suggests that metformin-associated weight loss is perhaps due to modulation of hypothalamic appetite regulatory centers, alteration in the gut microbiome, and upregulation of GLP-1, a hormone that contributes to satiety. Its immediate impact on appetite control, food intake, and body weight helps to prevent diabetes in the long run. Its ability to improve body mass index, insulin sensitivity, and cholesterol profiles makes it a great therapy for metabolic syndrome and associated conditions like polycystic ovarian syndrome.
Metformin has also been shown to be cardioprotective in patients with diabetes and may be beneficial in the presence of stable congestive heart failure. There is some evidence that metformin can lower cancer risk in diabetic patients but the these study designs do not produce the highest level of evidence. Given these so-called “pleotropic” effects (fancy medical jargon for simultaneously producing more than one benefit), scientists are eager to determine if metformin helps to delay the aging process.
As with all medications, there are some contraindications to taking metformin such as impaired kidney function, progressive liver disease, and active alcohol abuse. When people first start taking the medication, it can cause some nausea and diarrhea if not taken with food. Supplementation with vitamin B12 is strongly recommended for those at higher risk for deficiency, such as those on a vegan diet or who have had bariatric surgery. All told, however, metformin is well tolerated and has an excellent long-term safety profile for the majority of people. In addition, because it has been around for nearly a century, it is dirt cheap (about $4 for a 1-month supply) compared to the new drugs on the market.
Of note, a few small but important trials recently tested the effects of metformin on metabolic responses to exercise. In healthy young subjects, metformin caused a small but significant decline in maximal aerobic capacity. The investigators concluded that “metformin attenuated the increase in whole-body insulin sensitivity and abrogated the exercise-mediated increase in skeletal muscle mitochondrial respiration.” A follow up on this was the MASTERS trial which looked at the effects of metformin with strength training and showed that metformin can negatively impact the hypertrophic response to resistance training in healthy older individuals.
Why exactly this is—especially given metformin’s multitude of benefits—is still a matter of conjecture and hypothesis. One explanation is that exercise creates a stress on the body, which first triggers inflammation and then adaptation. This inflammatory response is essential for subsequent muscle repair and hypertrophy. Given that metformin reduces total body inflammation, it may actually impede the full adaptive response to exercise, thereby attenuating aerobic capacity and muscular hypertrophy. At this time, we still have more questions than answers, such as the effect of different metformin dosages and timing of administration relative to exercise.
Some final thoughts from my end… Based on the current data, it seems that for a younger, metabolically healthy person, metformin is largely unnecessary. In fact, it may even blunt the adaptive response to training. However, for those who are overweight and at increased risk of metabolic syndrome and associated conditions, the benefits of metformin certainly outweigh the risks. And given that aging is the largest risk factor for glycemic dysregulation, metformin should be more widely used for diabetes prevention given its vast, protective effects throughout the body.