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SGLT-2 inhibitor; oral glucosuric agent; flozin

Indications: - diabetes mellitus type 2 - may be more effective as 2nd line agent than sulfonylureas or DPP-4 inhibitors [42] - heart failure [38] - may help with weight reduction - may lower risk for gout & gout flares in patients with type 2 diabetes [15] - renoprotective [10,16]; slow progression of diabetic nephropathy * flozins lowest in cardiovascular mortality < GLP-1 agonists < DPP-4 inhibitors (no mention of metformin) [6,19] * cardiovascular risk reduction [10,11] - benefits greatest in patients with pre-existing CV disease - benefit for hospitalization with heart failure [10] - benefit for patients with HFrEF or HFpEF with or without diabetes [24,26] - intermediate to low-value for patients with HFpEF [31] - cost-effective only if mortality benefit [31] - lower risk of recurrent ischemic stroke [46] * may lower risks for heart failure, all-cause death, major cardiovascular events, & cardiovascular death [14] independent of diabetes status [18] or renal function [43] * benefit for heart failure & cardiovascular death across cardiometabolic spectrum [44] * no significant effect on myocardial infarction in the general population [43] * no effect on stroke [43] * may improve maximal exercise capacity & quality of life in patients with heart failure HFrEF or HFpEF [38] * use as 1st line rather than metformin may reduce risk of hospitalization for heart failure, but not myocardial infarction, stroke, or all-cause mortality [25] * dapagliflozin 10 mg QD reduces hospitalization (all cause) & death in patients with chronic kidney disease with & without type 2 diabetes (RR ~0.8) [27] * only canagliflozin & empagliflozin may lower cardiovascular risk; dapagliflozin & ertugliflozin may not [25] * flozins appear safe in elderly >= 75 years of age [29] * cardiovascular benefits persist across full spectrum of glycemic control HbA1c <7.5% to > 9% [30] * efficacy, safety & tolerability same in elderly > 70 years vs younger patients [37] Contraindications: - diabetes mellitus type 1 (not FDA-approved) - diabetic ketoacidosis - renal impairment: GFR < 30 ml/min/1.73 m2 [3]; maybe not* [39] - endstage renal disease * flozins on list of drugs to avoid [5] * flozins are associated with a lower risk for dialysis, cardiovascular events, diabetic ketoacidosis, & acute kidney injury in patients with type 2 diabetes & stage 5 chronic kidney disease [39] Dosage: - stop flozin 3 days prior to surgery Adverse effects: - hypotension [3], orthostatic hypotension [37] - SGLT-2 inhibitors have little effect on blood pressure & may be used at any time during hospitalization for acute heart failure [45] - ketoacidosis (RR=2] [1,9,17], class effect [17]; serum glucose may be normal [3] - euglycemic DKA - urinary tract infections [2] (candidiasis) [3] - no increased risk of severe urinary tract infections [13] - genital infections (vulvovaginal candidiasis) [3] - increased risk for balanitis & vulvovaginitis related to glucosuria [28] - see vulvovaginal candidiasis for management - renal insufficiency - nocturia [23] - reports of nephrolithiasis* [4] - SGLT2 inhibitors are associated with lower risk for serious renal events than DPP-4 inhibitors [16] - hypersensitivity reactions [3] - increased risk of foot amputations & toe amputations (RR=2.1) [9] osteomyelitis (RR=1.4); absolute risk low [7] - no increased risk of fractures in older adults with type 2 diabetes [22,32] - sepsis [12] - necrotizing fasciitis of the perineum, Fournier's gangrene (rare) [8,12] - 70% of victims are men [12] - increased risk of frailty [41] - no evidence of dose-dependent overall safety observed in clinical usage of SGLT2 inhibitors [20] - no additional risk of adverse effects in patients with elevated HbA1c levels [30] * FDA decides no action necessary [4] Drug interactions: - increased risk of hypoglycemia in combination with insulin & insulin scretagogues - increased risk of hypotension & hypovolemia in combination with diuretics [33,34,35] Mechanism of action: - reduction of blood glucose by increasing glucosuria - all flozins inhibit sodium-glucose cotransporter 2 (SGLT2) thus inhibiting reuptake of glucose by the renal tubules - can lower systolic blood pressure 4-8 mm Hg [35] Notes: - empagliflozin more effective than dapagliflozin in reducing hospitalization or all-cause mortality [40] - compliance with guideline recommended administration of SGLT2 inhibitor to eligible hospitalized patients with HFrEF, including patients with comorbid chronic renal insufficiency & diabetes mellitus type-2 [36]

Interactions

drug interactions drug adverse effects (more general classes)

Related

Na+/glucose cotransporter 2; Na+/glucose cotransporter like; low affinity Na+ glucose cotransporter; solute carrier family 5 member 2 (SLC5A2, SGLT2)

Specific

bexagliflozin (Brenzavvy) canagliflozin (Invokana) dapagliflozin (Farxiga, Xigduo XR) empagliflozin (Jardiance) ertugliflozin (Steglatro) sotagliflozin (Zynquista) velagliflozin (Senvelgo)

General

enzyme inhibitor oral hypoglycemic agent

References

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  2. FDA Safety Alert. Dec 4, 2015 SGLT2 Inhibitors: Drug Safety Communication - Labels to Include Warnings About Too Much Acid in the Blood and Serious Urinary Tract Infections. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm475553.htm
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