Prevention of macrovascular complications - an update.

Reducing the risk of microvascular and macrovascular sequelae is an important treatment goal in diabetes. In recent years, new modern drugs have entered the market that have demonstrated additional benefits with respect to cardio- and/or cerebrovascular and/or renal sequelae. In particular, these include several agents from the classes of SGLT-2 inhibitors and GLP-1 receptor agonists, as well as a representative of the mineral corticoid receptor antagonists.

There is a worldwide increase in the prevalence of diabetes mellitus, especially type 2 diabetes. And data from the Emerging Risk Factors Collaboration show that diabetes, stroke and heart attack can significantly shorten lives. The effects are particularly great when patients suffer from two or three of these diseases at the same time [1]. In diabetics, life-threatening cardio- and cerebrovascular diseases occur far more frequently than in non-diabetics, reported Prof. Oliver Schnell, MD, of the Diabetes Research Group at Helmholtz Zentrum München [2].

Current data shows: Diabetics are a risk group

Up to three-quarters of diabetic patients ultimately die from myocardial infarction or stroke [3]. And with regard to heart failure or kidney disease, among other things, a large multinational cohort study of diabetics without initially known cardiovascular or renal disease shows that incidence rates are above average compared with the general population [2]. There has been great progress in the areas of prevention and treatment. “But still the challenge remains that these complications are far more common in the population of people with diabetes compared with people without diabetes,” the speaker emphasized [2].

Current understanding is that the most effective approach to preventing macrovascular complications is multifactorial reduction of risk factors. In addition to glycemic control, and treatment of hypertension and lipid management, lifestyle factors such as diet, exercise, and smoking cessation are also included. Regarding drug interventions, data from several large cardiovascular outcomes trials (CVOT) are available showing that certain antidiabetic agents are associated with a lower risk of serious cardiovascular events such as myocardial infarction and stroke [4]. In addition, several modern drugs have demonstrated nephroprotective effects.

Evidence-based added benefit of SGLT-2 inhibitors and GLP-1-RA.

In the randomized DELIVER trial – one of the large cardiovascular endpoint studies – the SGLT-2 inhibitor dapagliflozin was shown to have cardioprotective effects in both diabetic and non-diabetic patients. Treatment with dapagliflozin significantly reduced the risk of cardiovascular death or clinical heart failure exacerbation (primary composite endpoint) by 18% compared with placebo in heart failure patients with an LVEF >40% [5]. “The difference in the combined endpoint was driven by less frequent worsening of heart failure,” Prof. Schnell explained. A meta-analysis based on data from the DAPA-HF (in HFrEF) and DELIVER (in HFmrEF and HFpEF) trials in a total of 11 007 patients confirmed the prognostic efficacy of dapagliflozin in a wide range of LVEF (≤40% and >40%) [6]. Extrapolation of the results of the DELIVER trial (n=6263) showed that in a 65-year-old patient treated with dapagliflozin, the median survival time without the occurrence of the primary endpoint was 12.1 years, compared with 9.7 years with placebo [7]. This corresponds to a gain in event-free survival of 2.3 years (p=0.002) (Fig. 1). If a patient is 55 years old at baseline, the estimated event-free survival is 11.8 years with dapagliflozin compared to 9.8 years with placebo (p=0.14).

GLP-1-RAs reduced major adverse cardiovascular events (MACE) by 14% (HR=0.86; 95% CI: 0.79-0.94; p=0.006) in a meta-analysis of cardiovascular trials (CVOTs) compared with placebo in both patients with and without pre-existing cardiovascular disease [8]. Figure 2 shows a comparison of the CVOTs included in the meta-analysis [8]. Moreover, GLP-1-RA reduced the risk of cardiovascular mortality by 13% (p=0.016), non-fatal stroke by 16% (p=0.007), heart failure-related hospitalization by 10% (p=0.023), all-cause mortality by 12% (p=0.012), and composite renal endpoint by 17% (p=0.012) [8].

Cardiorenal protection in CKD patients: Empagliflozin and Finerenone Data

In patients with chronic kidney disease, despite effective therapies such as renin-angiotensin-aldosterone system (RAAS) blockade, there is still a significant risk that renal injury will progress to end-stage renal failure. Current data on both the SGLT-2 inhibitor empagliflozin and the nonsteroidal mineral corticoid receptor antagonist (MRA) finerenone demonstrate evidence-based nephroprotective and cardioprotective effects.

In the EMPA-KIDNEY study, the use of the SGLT-2 inhibitor empagliflozin successfully halted the progression of renal disease and reduced the risk of cardiovascular events in both diabetic and non-diabetic patients (46% of the study population had diabetes) [9]. The primary endpoint of the EMPA-KIDNEY trial referred to, first, progression of renal disease (end-stage renal failure, renal-related death, sustained eGFR decline to <10 mL/min/1.73^m2, or eGFR decline by ≥40%) and, second, cardiovascular death. During study follow-up (median two years), events of this composite endpoint affected 13.1% in the empagliflozin group and 16.9% in the placebo group. The difference corresponds to a significant 28% relative risk reduction in favor of empagliflozin (hazard ratio: 0.72; 95% CI: 0.64-0.82; p<0.001) [9]. Renal patients with and without type 2 diabetes benefited equally from empagliflozin therapy.

In the FIDELITY trial, a prespecified pooled analysis of the FIDELIO-DKD and FIGARO-DKD trials, finerenone improved cardiorenal outcomes in type 2 diabetic patients who had a urinary albumin/creatinine ratio of 30-5000 mg/g and an eGFR of 25 ml/min per 1.73^{m2 or} greater and who were treated concomitantly with RAAS inhibitors [10,11].

Congress: Diabetologie grenzenlos

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«Diabetesassoziierte mikro- und makrovaskuläre Folgeerkrankungen: Update 2023», Prof. Dr. Oliver Schnell, Diabetologie grenzenlos, 03.02.2023.
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