Summary: Natural history of diabetes: focus on microvascular and macrovascular complications
Source, lecture held by prof Kausik Ray, Imperial College, London, United Kingdom
Prevalence, risk factors, progression and impact of diabetes
The prevalence of type 2 diabetes (T2DM) is increasing: 150-200 million new cases are predicted in the next 10-15 years with the heaviest burden in less developed countries. Insulin resistance starts with weight gain and obesity, and can lead to hyperinsulinemia, hypertension, abnormal lipid levels, and altered clotting that can finally lead to T2DM. All of these factors increase cardiovascular (CV) risk in these patients.
An analysis of the Nurses’ Health Study (1) showed that patients with a history of diabetes at baseline had the highest CV risk and those free of diabetes at baseline had the lowest CV risk. Interestingly, the two middle groups in this study suggested a latent period; CV risk increased by ~180% prior to the diagnosis of diabetes and increased again by ~180% after the diagnosis of diabetes. The only difference between these middle groups was the time of diabetes diagnosis, suggesting that diabetes is a progressive disease. Indeed, there is a latent period in which genetic susceptibility, environmental factors, sedentary lifestyle, obesity and inactivity contribute to an increased CV risk. Although it was initially thought that diabetes is a CVD risk equivalent, it turns out that this is not true in the early phase after diagnosis (2). This is important, because in the beginning, it is possible to alter the course and trajectory of disease, for example by improving glycemic control.
When diagnosed with diabetes at the age of 40 years, a person loses half a decade of life, with half of the adverse events being vascular events (3). If one develops diabetes at 90 years, there are fewer life years to lose. Therefore, a different therapeutic approach may apply to older patients who are more vulnerable and frail compared to younger patients, who have much more to gain in number of life years.
Macrovascular and microvascular complications and their relationship
Chronic complications in diabetes include macrovascular disease: myocardial infarction (MI), stroke, need for revascularization, and peripheral vascular disease; and microvascular disease: retinopathy, nephropathy, and neuropathy. In a large United Kingdom (UK) cohort of ~40000 individuals, the association between microvascular disease and CV events was examined (4). Individuals with 1 microvascular complication had a 35-40% increased CVD (CV death, non-fatal MI, stroke) risk, regardless of type of microvascular complication. An increase in the number of microvascular complications resulted in a stepwise increase in the composite of CV death, non-fatal MI, non-fatal stroke, and also in hospitalization for heart failure (HF), CV mortality and all-cause mortality. Thus, the prevention of microvascular disease is very important, as it is an independent risk factor for CV events. Although good control of blood pressure (BP), lipids and glucose reduces CV risk in diabetes patients, including those with microvascular complications, it is more important to prevent development of microvascular disease.
New glucose-lowering agents
It used to be assumed that lowering glucose in diabetes patients could reduce their CV risk. However, the first five trials with glucose-lowering agents did not show a reduction in the composite of CV death, non-fatal MI and stroke. A meta-analysis showed that a reduction of 0.9% in HbA1c over 4.7 years resulted in a 17% reduction in non-fatal MI, a 15% reduction in fatal and non-fatal MI, no reduction in stroke, and no reduction in all-cause mortality (5). It is possible that undesirable effects, such as weight gain and hypoglycemia associated with older treatments may have offset some of their benefits resulting in an increase in CV events. As a consequence, it is now requested that safety of novel glucose-lowering agents is demonstrated in large trials. The therapeutic actions and CV outcomes of these new antidiabetic agents are discussed in detail in chapter 3 and 4.
Novel drug classes show a modest glucose-lowering effect. The results suggest that it matters how glucose is lowered. While lowering glucose with insulin, sulfonylureas (SU) or DPP-4 inhibitors has not resulted in CV benefit, some newer agents have additional effects and favorably affect CV death, non-fatal MI and stroke.
Microvascular disease in diabetes can be prevented by blocking the renin-angiotensin system, either with an ACE inhibitor or ARB. These drugs cause efferent arterial vasodilation, resulting in reduced glomerular pressure and slowing down of the progression of nephropathy. The SGTL2-inhibitor empagliflozin has a different mechanism of action than ACE inhibitors and ARBs: a change in hemodynamics delivers sodium to the distal convoluted tubule, resulting in juxtamedullary apheresis and afferent vasoconstriction, which reduces the pressure on the glomerulus. In the EMPA-REG OUTCOME trial, initially a rapid decline in estimated glomerular filtration rate (eGFR) was observed, similar to that achieved with ACE inhibitors, after which eGFR levels stabilized (6). This is in contrast with traditional glucose-lowering therapy, which shows a steady progression and decline in eGFR.