Not all diabetics develop plaques in their arteries though diabetes is considered equivalent of myocardial infarction, a study has found. More importantly, it found that diabetics on the drug Metformin do not develop the key markers that lead to atherosclerosis (build up of fat and cholesterol in artery walls).
For Ajit S. Mullasari, director (cardiology) at Madras Medical Mission, the discovery was serendipitous. He wondered why some diabetics with no control over their sugar and HbA1c of 11 did not develop atherosclerosis. “When we see diabetic patients it means their risk of heart attack is very high. During our work up of patients in the hospital we found serendipitously that even after 15-20 years of diabetes they had completely clean coronary arteries. It is not like they have well-controlled diabetes.”
A discussion with a fellow researcher in Rajiv Gandhi Centre for Biotechnology in Tiruvananthapuram confirmed his observation and led to the first of a series of studies which began with how macrophages (scavenger cells) in diabetics with atherosclerosis and non-diabetic persons behaved.
“When a macrophage comes in contact with sugar it will get activated and release certain pro-inflammatory proteins. We stimulated the macrophages in vitro and found that one of the 40 proteins, Cyclophilin A, which is very high in diabetics with vascular disease, was lowest in those without vascular disease,” he said. The findings were published in the journal Proteomics. “Cyclophilin A is a marker we use for immune suppression with immunosuppressants in heart transplant (patients),” he explained.
He then expanded his research to 500 patients – 100 with diabetes for five years; 100 with diabetes and vascular disease for 10 years; 100 others with diabetes but no vascular disease; 100 with vascular disease with no diabetes; and 100 with no diabetes or vascular disease.
Their history, blood samples, health parameters including BP, lipids were collected. The samples were tested for Cyclophilin A and other markers such as cholesterol, hsCRP (a protein released by liver in response to inflammation).
“If you have inflamed vessels, which is what diabetes does, you are likely to develop atherosclerosis faster. Inflammation is a very important part for developing atherosclerosis. Unfortunately cardiologists and basic literature were not sure about inflammation till COVID-19 hit. When it hit we realised that inflammation is the most important thing to develop heart attacks, strokes, because by itself it can rip apart the endothelium of the whole body vessels – the brain, kidney, the veins, the heart – that is why you get a heart attack in COVID 19,” he explained.
While people with high cholesterol sometimes do not develop heart disease as their hsCRP is low, the same could not be said for those with border level low density lipoproteins (bad cholesterol) and high hsCRP. Dr. Mullasari’s study conducted between 2012 and 2015 showed a trend. “If your Cyclophilin A was high, it is a sign of inflammation. The higher age of diabetes, the older you are and higher the blood sugar, the possibility was greater. But peculiarly there were certain diabetic patients who did not have inflammation.”
The discovery prompted further investigation “and we found that whether you are diabetic with vascular disease or without vascular disease, patients on Metformin had lower Cyclophilin A. So Metformin was acting as an anti-inflammatory drug. What suddenly came up to us is that Metformin is not a diabetic drug but it could be an anti-inflammatory drug. We were looking for the cause for low Cyclophilin A which is an inflammation marker and we found this,” he added.
A study on animal and mice model confirmed their suspicion. The drug had a good anti-inflammatory effect. “Why this is important is that the effects of Metformin is beyond blood sugar is clear; it is cheap and safe but we need to prove it further,” the cardiologist said.
With the drug now being considered to treat tuberculosis and malignancies it should be studied further, he opined.
