Challenging CV risk in diabetes: ready for a new approach?
Diabetes is increasing in all areas of the world and once you have diabetes, it has a tremendous impact on CV morbidity and mortality. Fortunately, great efforts in CV research over the past years substantially reduced morbidity and mortality rates. Although, emphasised Dr. John Deanfield, there is still a considerable residual CV morbidity and mortality that represents a challenge.
It was recently shown by the Swedish National Diabetes Register that CV mortality mostly occurred in the younger population; the hazard ratio decreased stepwise with age1. Furthermore, CV mortality was predominantly driven by type 2 diabetes as compared to type 1 diabetes2, which suggests the impact of other damaging risk factors on mortality, such as hypertension and hypercholesterolaemia. The multifactorial influence on CV morbidity and mortality was further supported by the notion that multiple risk factors drive CV death in both diabetic and non-diabetic patients. In this regard, the MRFIT trial4 showed that the more risk factors one has, the worse the outcome. This relationship was much more pronounced in diabetic patients compared to non-diabetic patients. The benefit of treating multiple risk factors has been shown in a follow-up of the Steno-2 trial5. This means that not only the lower is better, but also the broader is better, in terms of CV intervention.
“Not only the lower is better, but also the broader is better, in terms of CV intervention”
These data suggest that diabetes should be prevented in the young and in a multifactorial fashion. In this light, there is increasing evidence showing that prevention of obesity and other modifiable risk factors in the young reduced the number of diabetic patients. Moreover, early intervention reversed diabetes and modern treatment reduced CV impact. For example, statin therapy was able to achieve a huge benefit for diabetic patients in terms of myocardial infarction and CV death, which in the CARD study corresponded to a relative risk reduction of 37%3.
Also lowering blood pressure or cholesterol levels showed a very strong association with CV outcome, however a less clear benefit in CV endpoints has been observed with traditional glucose-lowering medication. In contrast, some studies demonstrated that these medications were even associated with an increased risk. So how can we manage glycaemic control?
In the past few years, two classes of glycaemic drugs have been developed that seem to make a difference in terms of CV outcome; GLP-1 receptor agonists and SGLT-2 inhibitors. Liraglutide is a GLP-1 receptor agonists that was tested in the LEADER trial and demonstrated an event and mortality reduction benefit in patients with established diabetes, although this benefit was only notable after 2 years. The second group of drugs is represented by the SGLT-2 inhibitors, which target renal reabsorption of glucose and therefore stimulate glucose excretion in the urine. One of the SGLT-2 inhibitors is empagliflozin, which was evaluated in the EMPA-REG OUTCOME trial6. In this trial, CV death was impressively reduced by 38%, which is equivalent to the effects seen with statins in patients with diabetes. It is hypothesised that the clinical effects seen with SGLT-2 inhibitors are due to haemodynamic changes. Furthermore, it was recently reported that empagliflozin also has an effect on kidney function as it reduced progression of nephropathy as well as a composite renal outcome in diabetic patients. Besides empagliflozin, trials with different SGLT-2 inhibitors are currently ongoing, including canagliflozin and dapagliflozin.