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Table 1 Summary of commonly used anti-hyperglycaemic agents

From: Consensus recommendations for management of patients with type 2 diabetes mellitus and cardiovascular diseases

Drug class Anti-hyperglycaemic agents Estimated HbA1c reduction (%) Route of administration Mechanism of action Impact on CV events Advantages Disadvantages Contraindications Comments CV favourability
Biguanide Metformin 1 Oral Activates AMPK Reduction in MI, all-cause mortality Extensive experience, no hypoglycaemia, inexpensive Diarrhoea, nausea, GI symptoms, vitamin B12 deficiency, lactic acidosis (rare) Acidosis, severe CHF, hypovolaemia, if intravenous contrast to be used, hold on the day of study and restart 48 h after the contrast if eGFR > 30 mL/min/1.73 m2 Modest weight loss, reduced CV event rates, caution to be exercised or dose adjustment for CKD stage 3B (eGFR 30–44 mL/min/1.73 m2) Favourable
GLP-1 receptor agonist Liraglutide, semaglutide, exenatide, lixisenatide, dulaglutide, albiglutide 0.8–1.5 Injectable Activate GLP-1 receptor, ↑ insulin secretion, ↓ glucagon secretion Reduction in CV mortality, all-cause mortality, MI/stroke (liraglutide, semaglutide, Dulaglutide) No hypoglycaemia as monotherapy, ↓ weight, excellent postprandial glucose efficacy for meals after injections, improves CV risk factors (liraglutide, semaglutide, Dulaglutide) Higher rates of retinopathy with semaglutide, frequent and transient GI side effects, modestly ↑ heart rate, acute pancreatitis (rare/uncertain), very high cost History of pancreatitis, personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2, not to be used with DPP4 inhibitors   Favourable
DPP-4 inhibitor Sitagliptin, linagliptin, saxagliptin, alogliptin 0.6–0.8 Oral Prevent degradation of GLP-1 Increased HF hospitalization (saxagliptin) No hypoglycaemia, weight neutral, well tolerated Nausea (generally resolves), upper respiratory tract complaints Rare urticaria/angioedema, pancreatitisa, arthralgiaa, bullous pemphigoida No increase in CV risk (except hospitalisation for HF) compared to other agents in high risk patients (SAVOR-TIMI53), dose adjustment/avoidance for renal disease depending on agent (except for Linagliptin) Neutral (exception: saxagliptin–unfavourable)
SGLT2 inhibitors Canagliflozin, dapagliflozin, empagliflozin 0.5–0.6 Oral Block glucose reabsorption in proximal renal tubule Reduction in CV mortality only with empagliflozin (EMPA-REG), reduction in HF hospitalization with empagliflozin (EMPA-REG), canagliflozin (CANVAS) and dapagliflozin (DECLARE-TIMI 58) No hypoglycaemia, ↓ weight, ↓ blood pressure, effective at all stages of T2DM with preserved glomerular function, ↓ MACE, CKD with some agents GU infections, polyuria, hypovolaemia/hypotension/dizziness, ↑ LDL-C, ↑ creatinine (transient), euglycaemic ketoacidosis (rare), Fournier’s gangrene (very rare), expensive, canagliflozin: increased risk for amputation [canagliflozin (0.6% vs. 0.3% in placebo)], bone fracture, severe PVD, neuropathy, and DFU. No increased risk of amputation seen for empagliflozin or dapagliflozin to date Severe renal impairment, ESRD or dialysis Dose adjustment/avoidance for renal disease, use lower doses of canagliflozin and empagliflozin if eGFR < 60 mL/min/1.73 m2 Favourable
Thiazolidinedione Pioglitazone 0.5–1.4 Oral Bind PPAR-γ, decrease insulin resistance and increase glucose utilization Increased risk of HF; pioglitazone associated with reduced MACE Low risk for hypoglycaemia, durability, ↑ HDL-C, ↓ triacylglycerol (pioglitazone), ↓ ASCVD events (pioglitazone: in a post-stroke insulin- resistant population and as a secondary endpoint in a high-CVD-risk diabetes population), lower cost Weight gain, peripheral oedema/HF in patients with underlying disease, bone loss, ↑ bone fractures, ↑ LDL-C, bladder cancera, macular oedemaa Severe heart disease at risk for CHF, NYHA Class III or IV HF, liver disease Increased risk of fluid retention. Pioglitazone is neutral to beneficial for composite CV outcomes (PROactive) Favourable for MACE but increased risk of HF
α-Glucosidase Inhibitor Acarbose, miglitol 0.5–1.0 Oral Reduces absorption of dietary carbohydrate Improve the CV risk factors ↓ postprandial glucose excursions, non-systemic mechanism of action, CV safety, lower cost GI discomfort, flatulence, diarrhoea, elevated transaminases, frequent GI side effects, frequent dosing schedule Chronic intestinal disorders, moderate to severe renal impairment (creatinine > 2 mg/dL), caution in cirrhosis May reduce CV risk in patients with impaired glucose tolerance, dose adjustment/avoidance for renal disease Favourable
Basal insulins (long acting) Degludec, glargine 1.0–1.7 Injectable Activate insulin receptor, ↓ glucose production Neutral CV effects Nearly universal response, once daily injection Hypoglycaemia, weight gain, training requirements, frequent dose adjustment for optimal efficacy, high cost Not reported Severe hypoglycaemia may increase the risk of death for up to 1 year after occurrence Neutral
  1. AMPK 5ʹ adenosine monophosphate-activated protein kinase, ASCVD atherosclerotic cardiovascular disease, CHF congestive heart failure, CKD chronic kidney disease, CVD cardiovascular disease, eGFR estimated glomerular filtration rate, ESRD end-stage renal disease, GI gastrointestinal, GU genitourinary, HDL/LDL high density lipoprotein/low density lipoprotein, HF heart failure, MACE major adverse cardiovascular event, DFU diabetic foot ulcer, NYHA New York Heart Association, PVD peripheral vascular disease, T2DM type 2 diabetes mellitus, DPP-4 dipeptidyl peptidase 4, GLP-1 glucagon like peptide 1, PPAR peroxisome proliferator-activated receptor, SGLT-2 sodium–glucose cotransporter 2. Full names of all the cardiovascular outcome trials stated in this table have been mentioned in the ‘abbreviations’ section of the manuscript
  2. aIncidence rate under observation
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Diabetology & Metabolic Syndrome

ISSN: 1758-5996

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