Summary | Managing high risk diabetes patient with cardiovascular disease: What works, and what else can we do?August 26, 2017 - Prof. Kausik Ray (London, UK)
Professor Ray set the stage by emphasizing that DM is a global and growing public health challenge. Outcomes in patients with DM remain poor as compared with those not affected by DM, despite the development of many good treatments. DM doubles the risk of coronary heart disease (CHD), increases the risk of cerebrovascular disease by about 80% and death by vascular causes is also increased.1 Ray thus concludes that DM is a vascular disease. Since many first events are fatal, it is important to treat DM quite aggressively directly after diagnosis. A young patient (about 40 years of age) with DM loses about 6 or 7 years of life, and half of those early deaths can be attributed to vascular deaths. With aging, the number of life years lost by DM is lower, because life expectancy is lower. Thus, age may affect treatment strategy. Patients of about 60 years old with DM and pre-existing CVD may lose an additional decade of life, beyond what they would lose just with DM.
The mainstay of treatment of patients with DM to lower their CV risk is lipid lowering, blood pressure (BP) reduction and glucose lowering. Both primary and secondary prevention trials have shown that the relative efficacy of those interventions is similar in those with and without DM, but the absolute benefit is larger in diabetic patients.3-10 In the IMPROVE-IT trial, patients with DM showed a larger risk reduction of the composite CV endpoint than those without DM. It should be noted that, despite achieving LDL-c levels below 53 mg/dL, the 7-year event rate was about 40% in these patients, as compared with 30.2% in those without DM with similar LDL-c levels.11
Diabetics also benefit from BP-lowering: 10 mmHg reduction in systolic BP (SBP) reduces the rate of all-cause mortality, and both macrovascular and microvascular outcomes.12 The question then arises which SBP target should be applied. There are data that suggest that aiming for an SBP lower than what guidelines recommend (140 mmHg), namely 120 mmHg, may be beneficial for at least certain types of events. For instance, the ACCORD trial showed a reduction of stroke events with intensive treatment as compared with standard treatment.13
Historically, the effects of glucose-lowering have actually been fairly disappointing, according to Ray. In a meta-analysis by Ray and colleagues of data of patients achieving 1% HbA1c reduction over 5 years, a significant reduction of non-fatal myocardial infarction (MI) was observed, irrespective of how glucose was lowered. But, while a significant reduction of fatal and non-fatal MI was seen, no significant impact on stroke and all-cause mortality was seen.14 Although the effect of lowering HbA1c is independent and additive to the effect of lipid-lowering and BP-reduction, the absolute benefit is much less than that of the other two interventions.14
Treatment with the newer antidiabetic class of DPP-4 inhibitors does not seem to result in CV benefit,15 in contrast to other new antidiabetic drugs, such as the SGLT2-inhibitor empagliflozin and the GLP-1 receptor agonist liraglutide. It should be noted that these agents have mainly been tested in stable CAD patients, instead of in the post-ACS population. The only trial in a post-ACS population with the GLP-1 receptor agonist lixisenatide did not show a CV benefit.
Other novel agents include PCSK9 inhibition with monoclonal antibodies and the IL-1β-inhibitor canakinumab. The PCSK9 antibody evolocumab was shown to reduce LDL-c levels to about 30 mg/dL, which translates to about 15% relative risk reduction in the overall study population.16 Still, residual CV risk remains, thus targeting additional pathways may pay off. For instance, the vasculature in ACS patients is perturbed; there is inflammation in the vessel wall, systemic inflammation, activation of monocytes and macrophages, as well as perturbed levels of cytokines and chemoattractants. Moreover, the vessel wall has a procoagulant phenotype; there is a tendency towards clot formation and increased production of adhesion molecules. The PROVE-IT trial demonstrated that the higher the concentration of soluble adhesion molecules in the blood, the higher the risk of CV events. High-dose statin therapy attenuated this relationship somewhat, which is known to result in a number of potential beneficial effects on inflammation.17
Studies have attempted to establish the difference of DM patients and why their event rates are so much higher. A number of inflammatory markers, namely CRP, MCP-1 and von Willebrand factor, were examined in patients with or without DM in the OPUS-TIMI 16 study. While higher levels of these markers were associated with higher CV risk in both diabetics and non-diabetics, the relationship was stronger in diabetics.17 Validation of the CRP data in the TACTICS TIMI-18 suggested that there was a possible interaction between hyperglycemia or dysglycemia and inflammation. Indeed, in individuals with an increase of 1 mmol of glucose and a high CRP level, the impact on CV risk was not additive but multiplicative.18
Clearly, there are patients with unmet clinical needs, among them patients at the highest risk, thus those with ACS or DM. Patients with DM often have a low-HDL phenotype, which further increases CV risk. In addition, they often have a heightened inflammation phenotype. The question is whether or how we can improve treatment of these patients. An option to consider may be an approach with a single target and multiple effects, such as the novel epigenetic therapeutic drug apabetalone.