VOLUME 20 NUMBER 2 • NOVEMBER 2023 31 SA JOURNAL OF DIABETES & VASCULAR DISEASE REVIEW (SAVOR-TIMI 53, EXAMINE and TECOS, respectively), showed that when compared to a placebo, these drugs did not increase the risk of MACE or overall mortality. However, there were no significant cardiovascular benefits associated with their use (Table 2).27 Saxaglipitin was associated with an increased incidence of HF hospitalisations, according to SAVOR-TIMI 53.28 The most common side effects observed with sitagliptin and saxagliptin were headache, nasopharyngitis, arthralgia, and urinary and upper respiratory tract infections.29 Other side effects, although rare, included hypersensitivity responses, notably anaphylaxis and angiooedema. Pancreatitis and Stevens-Johnson syndrome have been reported in a few cases.28,29 GLP-1 receptor agonists The final class of newer antidiabetic agents reviewed in this article are the GLP-1 RAs. GLP-1 is a hormone that stimulates glucosedependent insulin release from the pancreatic islets.30 GLP-1 has an incretin effect, delaying gastric emptying and inhibiting inappropriate post-meal glucagon release and reduced food intake (Fig. 2).31 Patients with type 2 diabetes have an impaired insulin response to GLP-1, which is hypothesised to be related to a reduction in postprandial GLP-1 secretion.32 GLP-1 RAs stimulate GLP-1 receptors, leading to insulin secretion and decreased glucagon secretion.33 Trials using GLP-1 RAs have shown a significant reduction in MACE, however, there is conflicting evidence on their benefits in patients with HF and CKD.34 The LEADER trial in 2016 and the REWIND trial in 2019 evaluated liraglutide and dulaglutide, respectively, and indicated that there was a relative reduction in MACE with the use of both these drugs.35 Semaglutide was evaluated in the SUSTAIN trial and showed a reduction in MACE, CKD progression and total stroke in patients.36 The evaluation of this drug in the PIONEER 6 trial, however, showed that oral semaglutide did not reduce MACE (Table 3).37 Current guidelines support the use of dulaglutide, liraglutide and semaglutide (injectable, not oral) for reduction of ischaemic events in patients with type 2 diabetes.36,38 The most recent trial is the SELECT trial that evaluates the cardiovascular effects of semaglutide on overweight or obese patients with prior cardiovascular disease. The trial completion date was the end of September 2023.39 The potential side effects encountered with the use of these agents are important to note whenever prescribing these agents, and could lead to discontinuation of use. Gastrointestinal discomforts such as nausea, bloating and abdominal pain are noted as common side effects, and this is a leading cause of treatment discontinuations.40 The more serious side effects of GLP-1 RAs are pancreatitis and pancreatic cancer.40 Transient tachycardia may result from stimulation of GLP-1 receptors found in the sino-atrial node, most likely due to β-adrenergic stimulation and subsequent vasodilation.41 Since the 2008 FDA regulations, numerous CVOTs have shown not only the cardiovascular safety of new antidiabetes medications but also cardiovascular benefits to patients. SGLT2 inhibitors and GLP-1 RAs caused a significant reduction in fatal and non-fatal ischaemic events among patients with diabetes and atherosclerotic CVD.42 SGLT2 inhibitors have been shown to reduce hospitalisations and mortality in HF patients as well as slowing CKD progression.10,11 DPP-4 inhibitors have been shown to be inferior to GLP-1 RAs and SGLT2 inhibitors and cardiovascular outcomes have not been observed with their use.43 The American Diabetes Association 2020 has recommended metformin as the first-line agent for type 2 diabetes.44 In patients with the risk of atherosclerotic CVD, GLP-1 RAs are the preferred choice, and for patients with CKD or HF, the preferred choice is SGLT2 inhibitors. For those patients without risk factors or established CKD/CVD or HF, any of the DPP-4 inhibitors, GLP-1 RAs, SGLT2 inhibitors or sulphonylureas can be used.44 The European Society of Cardiology 2019 guideline recommends the first-line option for CVD or high cardiovascular risk is SGLT2 inhibitors, and GLP-1 RAs are recommended with metformin for low cardiovascular risk.45 Despite the recommendations, the real-world uptake of the newer agents remains limited, especially outside endocrinology Table 3. GLP-1 receptor analogues Benefit Outcome Study name outcome Inclusion hazard and drug measure criteria ratio (HR) Reference LEADER Death from CV Patients with Primary 35 Liraglutide causes, non-fatal T2D > 50 outcome: HR = MI, or non- years with 0.87, p = 0.01 fatal stroke established CV death: HR = (primary CVD, CKD 0.85, p = 0.007 composite stage 3 or Non-fatal stroke outcome) higher or > 60 = 0.89, p = 0.30 years with one or more CVD risk factors HARMONY Death from CV T2D with The primary 53 OUTCOMES causes, MI and HbA1c > 7.0% outcome, CV Albiglutide stroke and > 40 death, non-fatal years, with MI or stroke, established HR = 0.78, p < coronary 0.0001 cerebrovascular or peripheral arterial disease EXSCEL Primary Patients with Primary 54 Exenatide outcome: first T2D at any outcome: occurrence of level of CV HR = 0.91, death from CV risk, including p = 0.001 causes, non- established fatal MI or CV disease non-fatal stroke REWIND Primary T2D patients > Primary 54 Dulaglutide outcome: first 50 years, with outcome: episode of either previous HR = 0.88, non-fatal MI, CV risk factors p = 0.026 non-fatal or event stroke, and death from CV or unknown causes PIONEER 6 MACE, Patients ≥ 50 MACE: HR = 37 Semaglutide consisting of years with 0.79 p < 0.001 death from CV established CV death: HR = causes (undeter- CV or CKD, 0.49, 95% CI: mined causes or ≥ 60 years 0.27–0.92 included), non- with CV Non-fatal MI, fatal MI or non- risk factors HR = 1.18. 95% fatal stroke only CI: 0.73–1.90 CV, cardiovascular; MI, myocardial infarction; T2D, type 2 diabetes; CVD, cardiovascular disease; MACE, major adverse cardiovascular events; ACS, acute coronary syndrome.
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