DIAB Module 6 Infographic — SGLT-2 Inhibitors

SGLT-2 Inhibitors

Mechanism · Cardiovascular Trials · Renal Protection · Safety

Mechanism: Proximal Tubule Glucose Reabsorption Block

SGLT-2 blocked in proximal tubule S1/S2

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Glucose reabsorption reduced by ~70%

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Osmotic glycosuria (~60–80 g/day excreted)

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Blood glucose lowered

Downstream Effects

Osmotic diuresis → BP ↓ 3–5 mmHg
Natriuresis → volume load ↓
Weight loss 2–3 kg
Tubuloglomerular feedback restored

HF Benefit Mechanism

Preload reduced (diuresis)
Volume overload ↓ (natriuresis)
Intraglomerular pressure ↓
Myocardial ketone utilization ↑

Insulin-Independent

Works regardless of beta cell function
Effective in type 1 and type 2 DM
CV/renal benefit persists at low eGFR
even when glucose lowering minimal

Key Outcome Trials by Agent

Trial	Agent	Population	Result	Key Outcome
EMPA-REG	Empagliflozin	T2DM + ASCVD	CV Benefit	38% CV mortality reduction; 35% HHF reduction
CANVAS	Canagliflozin	T2DM + high CV risk	CV Benefit	14% MACE reduction; amputation risk increased
DECLARE	Dapagliflozin	T2DM broad	HHF Benefit	HHF reduced; MACE neutral in primary prevention
VERTIS-CV	Ertugliflozin	T2DM + ASCVD	Neutral	CV safety confirmed; no superiority
CREDENCE	Canagliflozin	T2DM + CKD	Renal Benefit	30% renal composite reduction; stopped early for efficacy
DAPA-HF	Dapagliflozin	HFrEF (±DM)	CV Benefit	25% CV death/worsening HF reduction
EMPA-KIDNEY	Empagliflozin	CKD (±DM)	Renal Benefit	Renal protection independent of diabetes status

ASCVD = atherosclerotic cardiovascular disease; HHF = heart failure hospitalization; CKD = chronic kidney disease; HFrEF = heart failure with reduced ejection fraction; DM = diabetes mellitus.

Safety Signals

Genital mycotic infections: 5–10% (most common)
Euglycemic DKA: hold 3–4 days before surgery; check ketones if symptomatic
Fournier gangrene: rare, fatal if missed; discontinue immediately
Canagliflozin: lower extremity amputation risk (FDA boxed warning)
Volume depletion: caution in elderly and with diuretics

Renal Dosing Thresholds

eGFR above 45: full glycemic + cardiorenal benefit
eGFR 30–45: reduced glycemic efficacy; cardiorenal benefit persists
eGFR below 30: glycemic benefit negligible; cardiorenal benefit may persist (trial data down to eGFR 20)
Guideline: use for cardiorenal protection even at low eGFR where glycemic benefit is minimal