Changing the diabetes treatment paradigm from glucose control to cardiorenal protection

Diabetes is an ancient disease and the first description of this disease has been attributed to Hesy Ra, the chief physician to the Egyptian Pharoah Djoser, nearly 5000 years ago1. Through the centuries, various herbs, chemicals and extreme carbohydrate-restricted diets were used to treat the symptoms of the disease2. Sadly, the prognosis for patients remained uniformly grim until the discovery of insulin by Banting et al3 in Toronto, Canada, 100 years ago in 19214. The introduction of insulin led to a paradigm shift in the management of diabetes and a shift in focus from extreme dietary carbohydrate restriction to effective lowering of blood glucose with the use of insulin. This not only improved glycaemia and ameliorated symptoms but also increased the life span of patients with diabetes. However, it soon became apparent that as patients with diabetes began to live longer, they began to manifest the classic microvascular and macrovascular complications of diabetes5. This occurred despite the introduction of several new classes of effective anti-hyperglycaemic agents and newer insulin preparations into clinical practice.

In the 1990s, several large trials such as the Diabetes Control and Complication Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that tight glucose control has beneficial effects on the microvascular complications of diabetes (retinopathy, nephropathy and neuropathy)6,7. However, tight glucose control has marginal effects on macrovascular disease and unexpectedly increases cardiovascular (CV) and all-cause mortality, as seen in the Action to Control Cardiovascular Risk in Diabetes (ACCORD study group) study8. This is counter-productive since diabetes is itself associated with pre-mature CV disease. An alternative definition of diabetes proposed by Fisher9 states that diabetes is a state of pre-mature CV death which is associated with chronic hyperglycaemia and also with blindness and renal failure.

Clearly, the microvascular complications of retinopathy, nephropathy and neuropathy cause considerable morbidity in patients with diabetes, and early and optimal glucose control greatly reduces the severity and burden of these complications. However, the vast majority of patients with diabetes may die from pre-mature CV disease10. Unfortunately, tight glucose control has marginal or even detrimental effects on CV disease. Concerns regarding the CV safety of anti-diabetic agents were intensified when a meta-analysis suggested that the widely used insulin sensitizer rosiglitazone was associated with an increase in the risk of myocardial infarction (MI) and CV death11. This led to the Food and Drug Administration (FDA) guidance in 2008, under which any new anti-diabetic therapy had to demonstrate that the therapy would not result in an unacceptable increase in CV risk12.

Following the FDA guidance, several large cardiovascular outcomes trials (CVOTs) were conducted, and the results of these studies have truly transformed the landscape of diabetes treatment13. Initially, the results from the CVOTs with the dipeptidyl-peptidase-4 (DPP-4) inhibitors were neutral with regard to CV benefits. However, in 2015, results from the EMPA-REG OUTCOME trial demonstrated that empagliflozin, compared to placebo, significantly reduced the incidence of major adverse cardiovascular events (MACEs) comprising non-fatal MI, stroke and CV death in patients with type 2 diabetes and established CV disease14. These results, which occurred with optimal use of statins, blood pressure agents and renin angiotensin - aldosterone system (RAAS) blockers, surprised many in the diabetes community and were felt to be chance findings. However, the replication of the CV benefits with other compounds in the same class alleviated these concerns13. Further, almost simultaneously, CV benefits were also seen in the CVOTs conducted with the glucagon-like peptide-1(GLP-1) receptor agonists, which have a significantly different mechanism of action. The first positive CV results with GLP-1 receptor agonists were reported in the LEADER trial with liraglutide and have been subsequently confirmed with other agents in this class15,16.

In addition to the CV benefits noted above, another serendipitous finding seen in the CVOTs was the ability of the sodium-glucose transport protein 2 (SGLT2) inhibitors and GLP-1 receptor agonists to improve renal function16. Thus, both classes of medications, in addition to effectively lowering blood glucose levels, also improved clinically significant CV and renal outcomes. In this context, it is important to note that there appear to be differences in the CV and renal benefits seen with SGLT2 inhibitors and the GLP-1 receptor agonists. In the CVOTs to date, the GLP-1 receptor agonists have demonstrated consistent effects to reduce atherosclerotic CVD (ASCVD) events of non-fatal MI, stroke and CV death in patients with and without established ASCVD17. Their effect on renal disease is confined to improvements in albuminuria without preventing progression to end-stage renal disease (ESRD). Further, the GLP-1 receptor agonists do not have beneficial effects on heart failure (HF) in diabetes. In contrast, the SGLT2 inhibitors have modest benefits on atherosclerotic MACE that seems confined to patients with established ASCVD13. More importantly, the SGLT2 inhibitors, unlike GLP-1 receptor agonists, reduce hospitalization for HF and progression to ESRD in those with and without diabetes, as seen in the DAPA HF, DAPA CKD, CREDENCE and the EMPEROR PRESERVED/REDUCED studies16.

The above cardiorenal benefits have led to a major shift in the international treatment guidelines. The American Diabetes Association (ADA) now recommends the use of SGLT2 inhibitors and GLP-1 receptor agonists as the second-line treatment after metformin and lifestyle measures to reduce the risk of cardiorenal complications in individuals at high risk of CV disease, irrespective of baseline and target glucose control18. The European Society of Cardiology (ESC) guidelines recommend either an SGLT2 inhibitor or a GLP-1 receptor agonist as the first-line treatment in people with type 2 diabetes at high or very high CV risk, even ahead of metformin19. However, it is important to note that in the CVOTs, most participants were on at least one glucose-lowering medication at baseline. Hence, the CV benefit of SGLT2 inhibitors or GLP-1 receptor agonists in treatment-naive individuals is uncertain20.

In the context of the burden of CV disease in diabetes, it is ironical to recollect that in 1927 (just six years after the introduction of insulin), Joslin21, the Father of Modern Diabetology, prophetically wrote, ‘‘I believe the chief cause of premature development of arteriosclerosis in diabetes, save for advancing age, is an excess of fat, an excess of fat in the body (obesity), an excess of fat in the diet, and an excess of fat in the blood. With an excess of fat, diabetes begins, and from an excess of fat, diabetics die, formerly of coma, recently of arteriosclerosis”. Clearly, we have come a long way from the 1920s. Today, diabetes has assumed epidemic proportions, especially in the developing world, and is still associated with increased morbidity and mortality. The devastating microvascular complications of diabetes are a major cause of blindness, kidney failure and non-traumatic amputations. Diabetes has been estimated to reduce average life expectancy by about 5-6 years22. However, this grim scenario for patients with diabetes may perhaps become a thing of the past. A hundred year ago, the discovery of insulin heralded a new dawn in the treatment of diabetes. At long last, we now have potent disease-modifying agents which not only improve glycaemia but provide additional robust CV and renal protection along with reduction in all-cause mortality. Cost however, remains a major barrier to the use of these disease-modifying drugs. There is a hope that with the introduction of generic and potentially less expensive SGLT2 inhibitors and GLP-1 receptor agonists, there will be more widespread use of these agents, along with more education of healthcare providers on the risks/benefits of these medications. In addition, dedicated trials will need to be conducted in patients with type 1 diabetes, who have as much to gain from using the SGLT2 inhibitors and GLP-1 receptor agonists as those with type 2 diabetes.