PharmacologyTier 1Medical Sciences concept

SGLT2 inhibitor metabolic effects (BP, weight, lipids, cardiovascular benefit)

Core concept

SGLT2 in the early proximal tubule (S1/S2) reabsorbs ~90% of the ~180 g/day filtered glucose (SGLT1 does the rest distally)
Inhibition -> glycosuria ~60-80 g/day + natriuresis
- dec plasma glucose, insulin-independent -> works at any beta-cell reserve, no hypoglycaemia alone
- ~200-300 kcal/day urinary loss -> 2-3 kg weight loss, mostly visceral fat
- Osmotic diuresis + natriuresis -> SBP dec 3-5 mmHg without reflex tachycardia
Tubuloglomerular feedback is the renal mechanism
- inc distal NaCl delivery to the macula densa -> adenosine -> afferent arteriolar vasoconstriction -> dec intraglomerular pressure
- ACEi/ARB act on the efferent arteriole - different vessel, additive effect

Effect	Magnitude
HbA1c	dec 0.5-0.8% (glucose-dependent, less at low HbA1c)
Weight	dec 2-3 kg
Systolic BP	dec 3-5 mmHg
Uric acid	dec (URAT1/GLUT9 inhibition by luminal glucose)
Triglycerides	Small dec
LDL and HDL	Both rise slightly - no net adverse CV signal
Haematocrit	inc (haemoconcentration + inc erythropoiesis)

Initial eGFR dip of 3-5 mL/min in the first 2-4 weeks is haemodynamic, expected, and reversible - do not stop the drug
- Mirrors ACEi initiation; the long-term slope of eGFR decline is flatter
Outcome benefit is largely independent of glycaemia - present in HF and CKD without diabetes
- dec HF hospitalisation across HFrEF and HFpEF, dec CV death, dec CKD progression and ESKD
Proposed non-glycaemic mechanisms: dec cardiac preload/afterload, dec renal cortical oxygen consumption, ketones as an efficient myocardial fuel, dec inflammation and fibrosis, dec sympathetic tone
Adverse effects
- Genital mycotic infection (commonest), UTI, volume depletion, rare Fournier gangrene
- Euglycaemic DKA - inc glucagon:insulin ratio + glycosuria masking the glucose rise
- Withhold 3 days before surgery or during acute illness
- inc amputation and fracture signal was canagliflozin-specific and not replicated

Indications now extend well beyond diabetes
- HFrEF and HFpEF - dapagliflozin, empagliflozin, regardless of diabetes
- CKD with albuminuria - dapagliflozin, empagliflozin, initiate down to eGFR ~20-25
- Type 2 diabetes with ASCVD or high risk
"Sick day rules" - stop during vomiting, sepsis, fasting, surgery; euglycaemic DKA is the exam trap
- Ketones, not glucose, make the diagnosis
Uricosuric effect is a genuine bonus in gout with diabetes or CKD
Do not double up the diuretic effect - reduce loop diuretic dose on initiation in euvolaemic HF
Glycosuria makes urine dipstick glucose uninterpretable

Diabetes drug mechanisms by class; novel renoprotective drug targets in DKD
Renal tubule segment function; renal blood flow autoregulation and tubuloglomerular feedback
Diuretic classes - site and mechanism
Evidence-based pharmacotherapy in HFrEF
Euglycaemic DKA; arterial blood gas interpretation

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