Systematic review and meta-analyses on the optimal interventions to reduce adverse cardiovascular events for cardiovascular diseases and diabetes mellitus

Abstract

Atherosclerotic cardiovascular disease, hypertension, and diabetes mellitus are three leading causes of global morbidity and mortality that are closely associated with each other, as risk factors and coexisting complications. Reducing cardiovascular diseases in patients with hypertension and diabetes mellitus is as important as lowering blood pressure and blood glucose. However, the optimal treatment strategies for these diseases with maximum cardiovascular protection and minimum adverse events all remain unknown due to the limited or contradicted evidence. This thesis designed four studies aiming to fill the evidence gap with the latest evidence released and add more insights to current clinical guidelines.

Percutaneous coronary intervention with drug-eluting stents implantation has been widely used in the treatment of atherosclerotic cardiovascular disease. A certain period of dual antiplatelet therapy is needed to reduce thrombotic complications. The optimal duration of dual antiplatelet therapy and the optimal antiplatelet P2Y12 inhibitor involved are always debated. In the first and second studies, two systematic review and network meta-analyses were performed to compare the efficacy and safety of different durations of dual antiplatelet therapy and P2Y12 inhibitors used in the therapy (clopidogrel, ticagrelor, prasugrel, and cangrelor). Short-term dual antiplatelet therapy less than 12 months was shown to be non-inferior to 12-month and longer durations beyond 12 months in reducing ischaemic events and deaths while with fewer excessive bleeds, so was more favourable for most patients. Ticagrelor found with a better net efficacy and safety profile was preferred over the other newer P2Y12 inhibitors in combination with aspirin as dual antiplatelet therapy.

Antidiabetic drugs may have direct cardiovascular effects independent of their glucose-lowering effects. Among the latest second-line antidiabetic drug classes, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), sodium-glucose co-transporter-2 (SGLT-2) inhibitors, and dipeptidyl peptidase-4 (DPP-4) inhibitors, which drug class can provide the best cardiovascular protection for diabetic patients is unclear due to the absence of direct comparative trials. In the third study through systematic review and network meta-analysis, SGLT-2 inhibitors and GLP-1 RAs were proved to be superior to DPP-4 inhibitors in reducing cardiovascular events and deaths while SGLT-2 inhibitors were found to be more beneficial in reducing hospitalisation for heart failure and renal events.

The latest hypertension guidelines have recommended a lower blood pressure treatment goal with intensive blood pressure control. Uncertainties have been raised regarding the necessity and safety of more intensive blood pressure-lowering strategies. In the final study, a systolic blood pressure of <130 mmHg was demonstrated to reduce cardiovascular events more than the other blood pressure levels, which could be regarded as an appropriate treatment target for most hypertensive patients. More aggressive blood pressure lowering to <120 mmHg was associated with the lowest risk of stroke, which could be considered for patients who can tolerate the therapy to reduce stroke.

These identified optimal treatment strategies should always be tailored for different patients after considering their benefit-risk profile in clinical practice.