VOLUME 20 NUMBER 2 • NOVEMBER 2023 29 SA JOURNAL OF DIABETES & VASCULAR DISEASE REVIEW The cardiovascular benefits of new diabetes drugs Abstract Diabetes is associated with a significantly increased risk of cardiovascular disease. The emergence of novel antidiabetic medications not only aims to control blood glucose levels, but also shows the potential to mitigate the cardiovascular risks and long-term complications associated with the disease. The potential cardiovascular benefits and clinical implications of these antidiabetic drugs are examined in this article. The results of ongoing clinical trials and additional observational studies will further augment the development of newer drugs with added cardiovascular benefits and lead to more widespread use of these newer agents. This was a secondary analysis of various trials using new diabetes drugs, focusing on cardiovascular benefits and safety profile. Among these new antidiabetic drugs, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists have been shown to be effective in reducing major adverse cardiovascular events. Conversely, dipeptidyl peptidase-4 inhibitors, although effective in controlling blood glucose levels, have not consistently shown significant cardiovascular benefits. Keywords: diabetes mellitus, cardiovascular disease, antidiabetic drugs, type 2 diabetes, chronic kidney disease, myocardial infarction, major adverse cardiovascular events SGLT2 inhibitors Diabetes is a chronic disease that affects millions of people worldwide and is a major cause of cardiovascular disease (CVD), which is the leading cause of death for diabetic patients.1,2 With the advent of new antidiabetic medications, significant progress in the treatment of diabetes has recently been made.3 It has been shown that the new antidiabetic drugs, such as sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) not only help to regulate blood glucose levels but also provide cardiovascular benefits for diabetic patients.4-6 This research provides a summary of the potential cardiovascular benefits offered by newer antidiabetic drugs, shedding light on their clinical implications. SGLT2 is a low-affinity transporter located in the proximal renal tubules and responsible for glucose re-absorption.7 Essentially, SGLT2 inhibitors are pharmaceutical compounds that block SGLT2, leading to glucose elimination in the urine (Fig. 1).7,8 Common SGLT2 inhibitors, such as canagliflozin, dapagliflozin and empagliflozin, have been frequently used in conjunction with metformin to improve glucose control.9,10 Large-scale clinical trials such as the EMPA-REG OUTCOME, CANVAS Program and DECLARE-TIMI 58 have shown that SGLT2 inhibitors can significantly reduce the risk of major adverse cardiovascular events (MACE) in patients with type 2 diabetes, including myocardial infarction (MI), stroke and cardiovascular death.10-12 Notably, empagliflozin reduced heart failure (HF) admissions, and this was a major change from the older generation hypoglycaemic medications that either were not beneficial or increased the incidence of HF (Table 1).13,14 In addition, SGLT2 inhibitors have also been proven in trials such as the EMPEROR-Reduced and DAPA-HF to lower the risk of HF hospitalisation and cardiovascular death in individuals with HF, irrespective of their diabetes status.15,16 Similarly, studies such as CREDENCE and DAPA-CKD have revealed that SGLT2 inhibitors can slow the progression of chronic kidney disease (CKD), lower the risk of end-stage renal disease, and even enhance renal outcomes in both diabetic and non-diabetic individuals (Table 1).17 A collective meta-analysis of the DAPA-HF and DELIVER trials indicated that dapagliflozin reduced the risk of cardiovascular death, hospitalisation for HF and MACE across a range of left ventricular ejection fractions of 25 to 65%.15,18 However, trial results did reveal some known adverse effects of SGLT2 inhibitors (Table 1). Those who received canagliflozin had an increased risk of amputation, specifically at the toe or metatarsal.19 Canagliflozin should be avoided by patients at higher risk for amputation, according to the American Food and Drug Administration (FDA).19,20 Since canagliflozin induces glycosuria, the incidence of superficial genital mycotic infections is common, especially in women and uncircumcised men.21 In addition, their use is linked to an increased risk of urinary tract infection and euglyacemic diabetic ketoacidosis.20,22 A MANEY, K HANMONTH Correspondence to: A Maney Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa e-mail: avishkarmaney@gmail.com K Hanmonth Charlotte Maxeke Academic Hospital, Johannesburg, South Africa S Afr J Diabetes Vasc Dis 2023; 20: 29–33 Fig. 1. Mechanism of action of SGLT2 inhibitors.23
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