Cardiovascular Diseases

Cardiovascular diseases (CVDs), marked by lipid-rich plaques accumulating in blood vessels, are the leading cause of death globally, claiming around 17.9 million lives per year.28 While CVDs arise from a complex combination of hereditary predisposition and environmental factors including lifestyle, aging is the dominant factor.29 In the US, roughly 70%-75% of people who are 60-79 years old are afflicted with CVDs.30
Dyslipidemia, insulin resistance, and chronic inflammation that commonly occur in older people make them more susceptible to CVDs. AMPK activation by metformin can suppress fatty-acid desaturase (FADS) genes, reducing the circulating levels of lipid metabolites and LDL cholesterol.31 Metformin also improves insulin sensitivity, helps losing weight, and reduces perceived hunger and food intake.32 Recently, growth differentiating factor 15 (GDF15) was found to contribute to the weight loss effect of metformin by interacting with the GFRAL receptor in the central nervous system to suppress appetite. Metformin mediates GDF15 increase by promoting transcription of CHOP and ATF4 most prominently in the liver and gastrointestinal system.33,34 Although metformin does not directly affect coronary artery disease through the GDF-15 pathway, the GDF-15 dependent weight loss effect may contribute to higher insulin sensitivity.35 Metformin also inhibits vascular inflammation that can lead to plaque formation by blockading the PI3K-Akt pathway and its downstream NF-κB pathway.36Furthermore, mitochondria dysfunction and endothelial senescence contribute to higher risks of CVDs, and activated AMPK increases SIRT3 levels and improves mitochondrial biogenesis and function by enhancing trimethylation of H3K79 via the SIRT-DOT1L axis. SIRT3 also delays endothelial senescence by upregulating telomere reverse transcriptase expression.37 Less is known about the protective effects of rapamycin, but a study found that mTOR inhibition suppressed DNMT1 upregulation caused by disturbed flow in the blood vessels bothin vitro and in vivo .38
Metformin’s protective effects have been confirmed in both animal and human studies. Chronic low doses of metformin given to ApoE deficient mice that have poor lipid-clearing capabilities and age-related atherosclerosis showed positive effects as well as reduced recruitment of macrophages into subendothelial space of aorta and decreased levels of pro-inflammatory cytokines.37 Bovine aortic endothelial cells exposed to clinically relevant amounts of metformin have increased activities of nitric oxide synthase (eNOS), endothelium-derived nitric oxide (NO), and AMPK while no such effect is observed in AMPK knockout mice. NO and eNOS have major roles in maintaining vascular homeostasis and its integrity, suggesting that AMPK activation by metformin exerts vascular-protective effects.39,40 Treating 32 weeks old mice with metformin at 200 mg/kg per day for 4 weeks also partially reversed left ventricular dilatation caused by δ-sarcoglycan deficiency: the hearts showed less fibrosis, less cardiomyocyte hypertrophy, and fewer degenerative subcellular changes. At the same time, there were also increased autophagy, increased AMPK activity, and suppressed mTOR phosphorylation.41 Diabetic veterans (mostly white male) who took metformin had lower CVDs and mortality risks compared with those who took sulfonylureas, and similar results were obtained in another clinical trial that compares the CVD risk associated with glipizide and metformin.42,43 Although in these studies it could not be determined whether the result was caused by the benefits of metformin or damages due to sulfonylureas or both, metformin’s protective effects could be more ascertained in the United Kingdom Prospective Diabetes Study (UKPDS), in which metformin treatment conferred a significantly lower incidence of myocardial infraction (33%, P=0.005) compared with dietary therapy for diabetic patients.44 Furthermore, several clinical trials and meta analyses have found metformin to decrease CVD risk for not just diabetic people, but pre-diabetic and non-diabetic people as well.45,46