Sometimes there are unintended consequences when using medications. These are often in the form of side effects which can range from minor problems to more serious ones. For this reason any new treatments are extensively tested in clinical trials to ensure their safety and gain approval from the regulatory authorities such as the FDA (food and drug administration) in the USA. Clinical trials are expensive and pharmaceutical companies understandably only do them when they have to. Diabetes is common and increasing in prevalence so there is a large potential market for medications to treat it. However most of the newer medications which target reducing the concentration of blood sugar fail to have any impact on the major cardiovascular complications of diabetes. In fact in some cases these medications increase the risk of heart failure (link to heart failure section of website). This is important as a large proportions of the problems that arise due to diabetes are heart related. Therefore the FDA mandated that any new diabetic medication had to have studies showing that they did not make cardiovascular outcomes worse. When testing the new class of diabetes drugs which are known as SGLT2 inhibitors the pharmaceutical companies were forced to do cardiovascular outcome studies but as they only had to prove the drugs did no harm i.e. non inferior they were able to do so with less patients. However to many people’s surprise the studies, despite not being powered to show a benefit, indicated that cardiovascular outcomes in the patients that received SGLT2 inhibitors were better and reduced the number of heart failure episodes.
Why is this the case? Well when we look at how these drugs work it is not such a surprise. SGLT2 inhibitors work by blocking a receptor in the kidney which reabsorbs glucose (sugar) that the body normally utilises to minimise glucose loss. Therefore SGLT2 inhibitors, make one pass more glucose in the urine thereby reducing the concentrations in blood. Easy to see why that would help with diabetes, but why does it help the heart? Well with glucose, more water will also be passed into the urine due to the osmotic effect of glucose. Heart failure results in increased fluid retention so more fluid loss should protect against heart failure. Also it was found that blood pressure and weight are reduced in patients taking SGLT2 inhibitors which will help reduce the risks of cardiovascular disease.
This surprising result suddenly got cardiologists more interested. Could the effects of the SGLT2 on cardiovascular disease and heart failure have nothing to do with treating the diabetes? To test this hypothesis large clinical trials were carried out in patients with heart failure and reduced left ventricular ejection fraction (reduced pumping action of the heart). They reported last year and showed that regardless of diabetes or what other background medication the patients started on SGLT2 inhibitors lived longer and were less likely to be admitted to hospital with heart failure. This has led to rapid acceptance in the national guidelines and NICE (National Institute of Clinical Excellence) have also issued recent recommendations that these medications are started in all eligible patients. Not to feel left out the Nephrologists (kidney doctors) have also joined in the fun and studies have shown that these medications slow down the deterioration of kidney disease in patients with diabetes potentially reducing the need for dialysis.
In this case unintended consequences have led to a whole new pillar of treatment for heart failure and reduced ejection fraction. Despite some of the simple explanations given earlier for the potential mechanisms of how these drugs work, it is very likely that the reasons for their benefit are multifactorial and are currently an avenue for extensive research. Another unintended consequence of these drugs has been a “coming together” of tribes of physicians usually entrenched in their speciality. Patients with diabetes are the common factor and focusing on one aspect of the multitude of problems caused by the disease is a misguided policy. A coordinated approach which looks more holistically and targets early treatments to prevent the devastating sequelae of under treating diabetes are needed. If we allow the rates of diabetes to continue unabated there will not be enough money to afford the treatment of the heart and kidney related complications that will inevitably arise. Therefore we must re-invigorate effective prevention and aggressive control of even mild disease. In order to achieve this physicians across specialities in primary and secondary care must act decisively together and also advocate for more targeted prevention strategies at a local and national level.