Summary | Diabetes: How to reduce risk from a cardiovascular perspective?
When trying to understand the mechanisms responsible for the increased CV risk in T2DM patients, it becomes clear that this is a complex situation. It is known, however, that obesity plays a major role. Visceral adiposity is associated with inflammation, insulin resistance, dyslipidemia, and hypertension, which all contribute to vascular damage (18). These mechanisms provide entries for prevention strategies. Indeed, nowadays hyperglycemia, hypertension, dyslipidemia, and obesity are common and important modifiable risk factors in T2DM patients (19). There is a large body of evidence demonstrating that targeting these risk factors reduces CV risk. Anti-hypertensive treatment, control of LDL-c levels and anti-platelet therapy have been demonstrated to be beneficial (20).
Looking more specifically at the effect of anti-hypertensive therapy, even small reductions in BP can reduce CV risk in high-risk individuals. A study on the relationship between systolic BP (SBP) reductions and 5-year CV risk in different strata of patients, showed that the effect of large BP reductions in patients with low CV risk was similar to the benefit of small BP reductions in high-risk patients, including T2DM patients (21). Large trials on statin therapy have demonstrated reduction of CV risk, with a larger benefit in diabetes patients compared with non-diabetes individuals (22).
With regard to glycemic control, controversy exists on its effect on CV risk. Although it makes sense to think that reducing glucose modifies CV risk in T2DM patients, studies with traditional glucose-lowering drugs have not demonstrated large benefits. A pooled analysis of multiple observational studies showed that a fasting blood glucose of ~5.5 or 6% HbA1c resulted in a gradually increased risk of CHD (3). Hyperglycemia has therefore been considered an important risk factor for CV outcomes. A long history of several trials have examined the effect of lowering glucose on CV risk. The first study on glucose lowering was UKPDS, which included patients with newly diagnosed T2DM (23). These patients had very high levels of fasting glucose, much higher than in current clinical practice. Later studies, such as ADVANCE (24) and ACCORD (25), included patients similar to those seen in clinical practice today and lower levels of HbA1c were targeted. Target HbA1c levels in ADVANCE were <6.5% and in ACCORD even <6.0%.
Results of the UKPDS study were slightly disappointing. Although there were clear benefits of lowering glucose on microvascular disease, such as microalbuminuria, retinopathy, and microvascular complications, no large benefit was observed for macrovascular disease, myocardial infarction (MI) and mortality (23). Similar findings were observed in the ADVANCE study 20 years later. In this study, patients were randomized to a regimen of tight glucose lowering or usual care. With a decrease of ~1% in HbA1c over time, no clear benefits were seen for macrovascular events, but there were small benefits for microvascular events, which could potentially be relevant (24). A long-term follow up of 10 subsequent years to examine the effects on mortality and CV mortality over time also showed no macrovascular benefits for the intensively treated group (26). With lower HbA1c target levels in ACCORD, a reduction in non-fatal MI was observed with intensive glucose lowering, but an increase in all-cause mortality (25). This left the investigators puzzled, as HbA1 levels were close to normal and no large CV benefit was observed, in contrast, harm was detected. Altogether, the results of glucose lowering on all-cause mortality or CV mortality in large trials were disappointing (14) and in disagreement with the initial view that diabetes is a glucose problem and glucose lowering should therefore reduce CV risk. One of the explanations may be that these glucose-lowering drugs have side effects that counteract the benefits.
New drugs have been introduced in the past years, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, SGLT2 inhibitors and GLP-1RAs. Results of first clinical trials evaluating these new classes are available and many more are to come. DPP-4 inhibitors and GLP-1RAs have the same mechanism of action, which is primarily stimulating insulin release. Early trials with DPP-4 inhibitors and GLP-1RAs have not been very impressive in terms of CV benefit (27). However, things then changed with the more recently published LEADER trial (28), which is discussed later in this document.
Studies evaluating SGLT2 inhibitors showed that treatment was associated with CV benefit. One of the suggested mechanisms of how SGLT2 inhibitors might lower CV risk in diabetes patients is by diuretic effects, resulting in removal of excess glucose from the body (29). The mechanisms of SGLT2 inhibitors still need further exploration, but besides small effects on glucose and HbA1c, there may be additional effects that cause CV risk reduction (30). The EMPA-REG OUTCOME study evaluated the effect of two doses empagliflozin on CV outcome in high risk diabetes patients. Both doses showed the same effects, therefore most analyses have used pooled data. Treatment with empagliflozin resulted in not very impressive HbA1c decreases of ~0.5% or even less, but still there was a clear benefit for 3-point MACE, and all-cause mortality (31). These findings have gained a lot of interest and led to the perspective that these new drugs will reduce CV events in diabetes patients.
This is a summary of the presentation given by prof. Grobbee, during the PACE symposium entitled 'Preventing Cardiovascular Disease in Patients with T2DM – How to apply novel outcome data with GLP-1RA to clinical practice', held during EuroPrevent in Ljubljana, Slovenia, on May 3, 2018.