Diabetes is a disease that occurs when your blood glucose, also called blood sugar, is too high. Blood glucose is your main source of energy and comes from the food you eat. Insulin is a hormone made by the pancreas and it helps glucose from the food you eat get into your cells to be used for energy. The resistance to insulin in type 2 diabetes typically manifests after prolonged, chronic elevated blood sugar. This continuous assault to the receptors on the cell essentially make the signal weaker and weaker or the pancreas stops producing adequate quantities. Without glucose able to enter the cell and an accumulation in the blood can result in the following problems:

  • heart disease
  • stroke
  • kidney disease
  • eye problems
  • dental disease
  • nerve damage
  • foot problems

Diabetic foot

Metformin as a First Line Approach to Diabetes

For the past few decades, the first-line approach to diabetes management has been the prescription of Metformin. It’s rare that a drug gets the thumbs up from so many different parties, but Metformin, introduced in the US in 1995, has done just that. Studies have found the drug to be safe, effective and cost favorable for the generic version. While the rest of the world has been using the drug for decades, a flawed study in the 40s held up the approval process here out of concerns for lactic acidosis. While moderate-to-severe renal impairment is a contraindication for Metformin, the reported incidence of lactic acidosis is very low (10 in 100,000).

Generally, A1C levels are lowered by 1.5% points by metformin monotherapy which also increases insulin sensitivity.  Treatment with metformin decreases fasting plasma glucose concentrations by 25% to 30% and decreases the production of glucose. Metformin reduces hepatic (liver) glucose production and absorption of glucose in the intestine.

Despite the general acceptance of Metformin, there are several studies that highlight some less than desirable side effects. We commonly find elevated liver enzymes in individuals who have been taking the drug for more than 2 years at moderate to high doses.

Metformin and B12 Deficiency

A small but significant study has linked long term Metformin use to decreases in Vitamin B12 – potentially leading to megaloblastic anemia. Luckily, it is very easy to supplement with the vitamin (4). This is important to replace since depleted B12 levels may increase Homocysteine, an independent risk factor for cardiovascular disease.

Metformin and GI Tract Issues

Treatment with metformin is often associated with gastrointestinal side effects which may decrease quality of life and negatively impact adherence to the treatment. The most common gastrointestinal symptoms are diarrhea, heartburn, and nausea, followed by abdominal pain, bloating, and retching. The mechanism lying under gastrointestinal intolerance caused by metformin is unclear. (5)

FDA Investigation of Metformin

Despite its safety profile in the US, there has been a recent investigation by the FDA into the possible contamination of NDMA – an organic compound linked to cancer and known to be hepatotoxic (damaging to the liver). Although this higher than acceptable level is found in samples tested outside the US, it still warrants investigation for the safety of the millions currently prescribed the drug within the United States.

Metformin and Anti-Aging

Metformin has been extremely popular in the anti-aging community for targeting and delaying aging. With the highest correlation variable of acquiring diabetes being aging itself (about 1,000x increased risk), vs obesity (about 8x), the benefits of metformin may be far more reaching than the treatment of type 2 diabetes (2).

In another study which began in February of this year, researchers recruited the Veterans Affairs’ Investigation of Metformin in Pre-Diabetes on Atherosclerotic Cardiovascular Outcomes (VA-IMPACT), a placebo-controlled study of 7,868 older adults with atherosclerotic CVD and pre-diabetes. The primary outcomes for VA-IMPACT are time to death from any cause, MI, stroke, hospitalization for unstable angina or symptom-driven coronary re-vascularization. The study’s estimated completion date is August 2024 (3).

While the adoption of this drug has been widespread, its long term effects and dosing strategies have not been fully studied from an anti-aging perspective. The real benefits of metformin seem to come from its blood sugar stabilizing properties, however there are natural alternatives that, according to a recent study, may be a safer alternative.

Study Suggests Natural Alternative to Metformin

In one of my most favorite recent studies, researchers investigated the use of a nutraceutical for its Metformin like qualities. This compound is Berberine.

Berberine is a phytochemical that activates AMP-activated kinase (AMPK) – just like Metformin.  AMPK plays a role in energy regulation mostly due to glucose and fatty acid uptake in the cell. It is attributed to a reduction in abdominal fat as well. Unlike Metformin, it upregulates LDL (cholesterol) receptors in the liver and extends the half life of the receptor’s mRNA. In contrast, statin drugs increase transcription of the gene coding for LDL receptors and are well known to decrease CoQ10 and negatively impact mitochondrial/energy pathways (not good).  The typical dosage is 500mg 2-3x/day with the most common side effect being constipation.

Berberine + Astaxanthin

Astaxanthin is a reddish pigment that belongs to a group of chemicals called carotenoids. It occurs naturally in certain algae and causes the pink or red color in salmon, trout, lobster, shrimp, and other seafood. As a side-note, it may be astaxanthin, coupled with higher Omega-3 consumption along coastal civilizations, that bridged the evolutionary gap between the brains of ape and man. Astaxanthin is an extraordinary anti-oxidant for protecting cell membrane oxidative stress. Studies show that Astaxanthin can act as a PPAR(alpha) agonist and reduce the risk of cardiovascular events in patients with metabolic syndrome.


In a recent placebo controlled trial with Type 2 diabetes patients, 8mg/day for 8 weeks achieve significant reductions in serum triglycerides (156->128 mg/dL), serum fructosamine (7.4->5.8 umol/L) and systolic blood pressure (143->132 mm Hg). All these parameters worsened non-significantly in the placebo group. Sources of Astanxantin includes direct supplementation and Krill oil.

Although there are no studies on the benefits Berberine + Astaxanthin in individual without Type 2 diabetes or Metabolic Syndrome, I have personally included these two in my daily regime.


This post does not constitute medical advice. If you are taking Metformin you should not discontinue without first consulting your prescribing physician. 


1. Centers for Disease Control and Prevention. National diabetes statistics report, 2017. Centers for Disease Control and Prevention website. www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-report.pdf External link (PDF, 1.3 MB) . Updated July, 18 2017. Accessed August 1, 2017.

2. Barzilai N, et al. Cell Metab.2016;doi:10.1016/j.cmet.2016.05.011

3. Investigation of metformin in prediabetes on atherosclerotic cardiovascular outcomes (VA-IMPACT). Available at: https://clinicaltrials.gov/ct2/show/NCT02915198.

4.  2016 Apr;101(4):1754-61. doi: 10.1210/jc.2015-3754. Epub 2016 Feb 22.

5. Fatima, M, F., Sadeeqa, S., Nazir, S. Metformin and its Gastrointestinal Problems: A Review. Biomedical Research (2018) Volume 29, Issue 11

6. DiNicolantonio JJ, McCarty M, OKeefe J. Astaxanthin plus berberine: a nutraceutical strategy for replicating the benefits of a metformin/fibrate regimen in metabolic syndrome. Open Heart 2019;6:e000977.