Table 3: Adverse Effects of Sodium–glucose Cotransporter 2 Inhibitors.

Adverse Effect	Risk Factors and Recommendations*
Infections[22–24,36,37,83,86]	Related to glycosuria Genital mycotic infections: balanitis and vulvovaginitis UTIs: rare cases of pyelonephritis and urosepsis, sometimes requiring hospitalisation Necrotising fasciitis of the perineum (Fournier’s gangrene). Discontinue SGLT2Is and start treatment immediately with broad-spectrum antibiotics and surgical debridement if necessary Risk factors: women, previous genital fungal infections, uncircumcised males Monitor and treat infections as appropriate Avoid SGLT2Is in patients with previous history of complicated UTIs, indwelling urinary catheter and recurrent genital mycotic infections SGLT2Is may decrease quality of life in men with prostatic hypertrophy and women with urinary incontinence
Volume depletion	Risk factors: elderly, patients with dehydration, hypovolaemia, renal impairment, low BP or taking diuretics or nephrotoxic drugs Assess volume status and BP before initiating treatment -SGLT2Is should be used with caution or discontinued in the presence of hypovolaemia to avoid worsening of renal function -Delay SGLT2I therapy in hypovolaemic or hypotensive individuals until fluid status and BP are corrected When SGLT2Is are combined with vasodilators or thiazide diuretics it may be necessary to reduce dose by 50%
Hypoglycaemia	Glucose is not being filtered in the glomerulus when glycaemia is normal; thus, the risk of hypoglycaemia with SGLT2Is is low Risk of hypoglycaemia when combined with insulin or sulfonylureas
Hypotension	In combination with hypovolaemia can cause dizziness and orthostatic hypotension and may increase the risk of falls and fractures The risk of symptomatic hypotension increases in the elderly, patients with renal impairment, low BP or treated with antihypertensives, diuretics or vasodilators Monitor for signs and symptoms of hypotension
Acute kidney injury[17,36,37,101]	Appears within 1 month of starting therapy with canagliflozin and dapagliflozin Risk factors: volume depletion, hypotension, diuretics, ACE inhibitors, ARBs, NSAIDs, or nephrotoxic drugs Monitor for signs and symptoms of acute kidney injury SGLT2Is are contraindicated in patients with eGFR <45 ml/min/1.73 m2 (dapagliflozin when <60 ml/min/1.73 m2), severe renal impairment, end-stage renal disease, or dialysis
Diabetic ketoacidosis[19,36,37,87–89]	Appears with mildly elevated glucose levels (<13.9 mmol/L) which can delay diagnosis and therapy Osmotic diuresis may worsen the hypovolaemic state of DKA, particularly in patients with nausea and decreased oral intake Risk factors: hypovolaemia, acute illness or surgery, alcohol abuse, carbohydrate restriction, low insulin secretory capacity, increased glucagon secretion, previous episodes of ketosis, latent autoimmune diabetes in adults and T1D (SGLT2 are not approved for use) SGLT2Is should be stopped during acute illness and at least 48 h before any planned surgical procedure SGLT2Is are contraindicated in patients with DKA
Lower-limb amputations[23,28,29,90–94]	Canagliflozin may increase the risk of lower limb (toe or metatarsal) amputations. SGLT2Is produce haemoconcentration and volume depletion and decrease in BP, effects that may reduce limb perfusion and produce tissue ischaemia. Canagliflozin activates AMP kinase, which inhibits complex I of the respiratory chain and favours tissue ischaemia Risk factors: men, prior history of lower-limb amputation, advanced peripheral vascular disease, peripheral neuropathy, and diabetic foot ulcers. EMA recommends careful monitoring of all patients receiving SGLT2Is, emphasising foot care. Consider stopping treatment if patients develop lower-extremity infections, new pain or tenderness, sores, ulcers, infection, osteomyelitis, or gangrene. Avoid canagliflozin (all SGLT2Is) in patients at the highest amputation risk until more safety data are accumulated
Bone fractures[95–99]	Canagliflozin (not empagliflozin or dapagliflozin) increases the rate of all-bone and low-trauma fractures within the first weeks of treatment Independent of changes in bone mineral density or alterations in calcium homeostasis Fractures possibly related to: increased parathyroid hormone and FGF23 excretion and orthostatic hypotension and postural falls due to volume depletion Canagliflozin (possibly all SGLT2Is) should be used with caution in patients with fragility fractures or established osteoporosis, or at risk of falling
Increase of LDL cholesterol levels[54,57]	The clinical meaning is uncertain. Monitor and treat as appropriate T2D and established CVD
Cancer100	Avoid dapagliflozin in patients with active bladder cancer (and empagliflozin)?

*Recommendations according to the FDA and/or EMA.

ACE = angiotensin-converting enzyme; ARBs = angiotensin receptor blockers; BP = blood pressure; CVD = cardiovascular disease; DKA = diabetic ketoacidosis; eGFR = estimated glomerular filtration rate; EMA = European Medicines Agency; FDA = Food and Drug Administration; FGF = fibroblast growth factor; NSAIDs = non-steroidal anti-inflammatory drugs; SGLT2I = sodium–glucose cotransporter 2 inhibitor; T1D = type 1 diabetes; T2D = type 2 diabetes; UTI = urinary tract infection.