Table 1.

Overview of the effect of different drug classes on multiple outcomes [21, 50].

(Adapted with permission from American Diabetes Association [21] © 2019 The American Diabetes Association)

		Efficacy	Hypoglycaemia	Weight change	Cardiovascular effects		Cost	Oral/SC	Renal effects		Additional considerations
					ASCVD	CHF			Progression of DKD	Dosing/use considerations
Metformin		High	No	Neutral (potential for modest loss)	Potential benefit	Neutral	Low	Oral	Neutral	Contraindicated with eGFR < 30	Gastrointestinal side effects common (diarrhoea, nausea) Potential for B12 deficiency
SGLT2i		Intermediate	No	Loss	Benefit: canagliflozin, empagliflozina	Benefit: canagliflozin, empagliflozina	High	Oral	Benefit: canagliflozin, empagliflozin, dapagliflozin [50]	Renal dose adjustment required (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin)	FDA Black Box: risk of amputation (canagliflozin) Risk of bone fractures (canagliflozin) DKA risk (all agents, rare in T2D) Genitourinary infections Risk of volume depletion, hypotension ↑ LDL cholesterol Risk of Fournier’s gangrene
GLP-1RA		High	No	Loss	Neutral: lixisenatide Benefit: liraglutidea > semaglutide > exenatide extended release	Neutral	High	Oral/SC	Benefit: liraglutide	Renal dose adjustment required (exenatide, lixisenatide) Caution when initiating or increasing dose due to potential risk of acute kidney injury	FDA Black Box: risk of thyroid C cell tumours (liraglutide, albiglutide, dulaglutide, exenatide extended release) Gastrointestinal side effects common (nausea, vomiting, diarrhoea) Injection site reactions Acute pancreatitis risk
DPP4i		Intermediate	No	Neutral	Neutral	Potential risk: saxagliptin, alogliptin	High	Oral	Neutral	Renal dose adjustment required (sitagliptin, saxagliptin, alogliptin); can be used in renal impairment No dose adjustment required for linagliptin	Potential risk of acute pancreatitis Joint pain
Thiazolidinediones		High	No	Gain	Potential benefit: pioglitazone	Increased risk	Low	Oral	Neutral	No dose adjustment required Generally not recommended in renal impairment because of potential for fluid retention	FDA Black Box: congestive heart failure (piogloitazone, rosiglitazone) Fluid retention (oedema; heart failure) Benefit in NASH Risk of bone fractures Bladder cancer (pioglitazone) ↑ LDL cholesterol (rosiglitazone)
Sulfonylureas (2nd generation)		High	Yes	Gain	Neutral	Neutral	Low	Oral	Neutral	Glyburide not recommended Initiate gliplizide and glimepiride conservatively to avoid hypoglycaemia	FDA Special Warning on increased risk of cardiovascular mortality based on studies of an older sulfonylurea (tolbutamide)
Insulin	Human insulin	Highest	Yes	Gain	Neutral	Neutral	Low	SC	Neutral	Lower insulin doses required with a decrease in eGFR; titrate per clinical response	Injection site reactions Higher risk of hypoglycaemia with human insulin (NPH or premixed formulations) vs analogues
	Analogues						High	SC

For agent-specific dosing recommendations, please refer to the manufacturers’ prescribing information

ASCVD atherosclerotic cardiovascular disease, CHF congestive heart failure, CVD cardiovascular disease, DKA diabetic ketoacidosis, DKD diabetic kidney disease, DPP4i dipeptidyl peptidase 4 inhibitors, eGFR estimated glomerular filtration rate, FDA US Food and Drug Administration, GLP-1RA glucagon-like peptide 1 receptor antagonists, LDL low-density lipoprotein, NASH non-alcoholic steatohepatitis, NPH neutral protamine Hagedorn, SC subcutaneous, SGLT2i sodium–glucose cotransporter 2 inhibitors, T2D type 2 diabetes mellitus

^aFDA approved for CVD benefit