30 VOLUME 20 NUMBER 2 • NOVEMBER 2023 REVIEW SA JOURNAL OF DIABETES & VASCULAR DISEASE DPP-4 inhibitors The next class of drugs are the dipeptidyl peptidase-4 (DPP-4) inhibitors. These are oral antidiabetic agents that block incretin degradation by DPP-4, thereby inhibiting breakdown of GLP-1, the gastric inhibitory peptide, and other incretins, leading to postprandial insulin release (Fig. 2).24,25 The commonly used agents in this class are saxaglipitin, aloglipitin and sitaglipitin. These drugs exhibit modest glycated haemoglobin (HbA1c) reductions while posing minimal risks of hypoglycaemia and weight gain.24 DPP-4 inhibitors have been widely used because of their notable safety profiles, minimal risk of hypoglycaemia and good tolerability. However, cardiovascular outcome trials (CVOTs) have failed to demonstrate a significant prognostic advantage.24-26 Clinical trials with three of these agents, saxaglipitin, aloglipitin and sitaglipitin Table 2. Summary of DPP-4 inhibitors Benefit Outcome Study name outcome Study hazard and drug measure design ratio (HR) Reference SAVOR-TIMI CV death, non- T2D patients CV death: HR = 46 53 fatal MI, with either a 1.16, p = 0.66 Saxagliptin or non-fatal history of MI: HR = 1.12, ischaemic recognised p = 0.52 stroke CVD or with Stroke: HR = multiple risk 1.11, p = 0.38 factors for vascular disease EXAMINE Time to first T2D adults CV death 48 Alogliptin occurrence of with high CV overall: HR = non-fatal and renal 0.96, p = 0.62 MI or non-fatal risk MI overall: HR stroke = 1.12, p = 0.30 Stroke overall: HR = 0.92, p = 0.53 TECOS First confirmed T2D patients > Primary 49 Sitagliptin event of CV 50 years, with outcome: 0.98, death, non-fatal established p < 0.001 MI, non-fatal CVD Secondary stroke or outcome: 0.99, hospitalisation p < 0.001 for unstable angina (primary outcome) Secondary outcome: CV death, non-fatal MI or non-fatal stroke CV, cardiovascular; MI, myocardial infarction; T2D, type 2 diabetes; CVD, cardiovascular disease; MACE, major adverse cardiovascular events; ACS, acute coronary syndrome. Table 1. Summary of SGLT-2 inhibitors Benefit Inclusion Study name outcome Outcomes and hazard and drug measure criteria ratio (HR) Reference EMPA-REG Death from CV CV events in Reduced death 50 OUTCOME causes, non-fatal adults with from CV cause: Empagliflozin myocardial T2D at high HR = 0.66, p = infarction, or risk 0.001 non-fatal stroke Death rate and HF hospitalisations: HR = 0.61, p = 0.001 CANVAS A composite of T2D patients > Reduced death 51 Canaglifozin death from CV 50 years with > from CV cause: causes, non-fatal two CVD risk HR = 0.86, p < MI or non-fatal factors or > 30 0.001 for non- stroke years with a inferiority history of Hospitalisation symptomatic rate for HF: HR = atherosclerotic 0.68 95% CI: CV disease 0.51–0.90 DAPA-HF Worsening HF or Adults with an CV outcomes 51 Dapagliflozin death from CV ejection fractionreduction: HR = causes ≤ 40%, and 0.74, p = 0.001 NYHA class II–IV EMPEROR - Time to first Chronic HF Reduced CV 52 Reduced event of CV (NYHA class II– death: Empagliflozin death or IV) and reduced HR = 0.75, hospitalisation ejection fraction p = 0.001 for HF and elevated NT-proBNP levels CREDENCE A composite of CKD patients CV death: HR = 15 Canagliflozin doubling of (eGFR 30–90 0.78 p = 0.05 serum creatinine ml/min/1.73 Doubling of levels from m2 and urinary serum creatinine: baseline, end- ACR 300– 0.60 mg/dl, p = stage kidney 5 000 mg/g 0.001 disease or death End-stage renal from CV or renal disease: 0.68, p = disease 0.002 DECLARE- MACE (CV T2D patients CV death or 52 TIMI 58 death, MI or with multiple reduction in HF Dapagliflozin ischaemic risk factors for hospitalisations: stroke) ASCVD HR = 0.83, p = (10 186) 0.005 or established ASCVD (6 974) CV, cardiovascular; MI, myocardial infarction; T2D, type 2 diabetes; HF, heart failure; NYHA, New York Heart Association; CKD, chronic kidney disease; CVD, cardiovascular disease; eGFR, estimated glomerular filtration rate; ACR, albumin to creatinine ratio; MACE, major adverse cardiovascular events; ASVD, atherosclerotic cardiovascular disease; ACS, acute coronary syndrome. Fig. 2. Flow diagram showing the mechanism of DPP-4 and GLP-1 analogues.
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