Table 1.
Summary of commonly used anti-hyperglycaemic agents
| 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 |
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
aIncidence rate under observation