Diabetes drugs- SGLT2i

Question 1

SGLT2 inhibitors - Pharmacology (4)

Answer 1

Phlorizin
-Very poorly absorbed orally
-Non-specific – inhibits SGLT1 – resulting in osmotic diarrhoea

SGLT2i
Modified from phlorizin to increase oral bioavailability and to be specific for renal isoform (SGLT2

Question 2

SGLT2 inhibitors – molecular mechanism

Answer 2

decrease uptake of sugar by about one quarter

make you pee sugar!

Some homeostatic regulation results in plateauing of weight loss

Question 3

SGLT2i physiology

Answer 3

SGLT2i increase renal glucose loss – resulting in glucose reduction and weight loss

Question 4

SGLT2i Physiology – beyond glucose 1 (4)

Answer 4

Direct effects of SGLT2i

-Glucose loss results in osmotic diuresis
Inhibition of SGLT2i reduces Na reabsorption. BOTH – result in a mild diuretic action. May explain some of the reduction in heart failure.

-Urate excretion is increased – reduction in plasma urate concentrations

-Complex -Increased sodium delivery to distal convoluted tubule = increased Na uptake by Na/K/Cl transporter at macula densa = Increase in adenosine secretion = reduction in renal afferent vasodilation = reduced filtration pressure = renal protection

Question 5

SGLT2i Physiology – beyond glucose 2 (5)

Answer 5

Indirect effects

Glucose reduction
Reduction in insulin and increase in glucagon

Increase in lipolysis
Increase in FFA results in increase Ketone body production

FFA and Ketones are a fuel to cardiac myocytes – improves cardiac bioenergetics. Cardiac benefit

But this can increase Ketosis and risk of ketoacidosis

Question 6

SGLT2i - simply

Answer 6

Increased renal glucose losses, result in lowering of blood glucose and loss of calories resulting in weight loss

Complex consequences of this
-Diuresis
-Improved myocardial energetics
-Renal protection

Question 7

SGLT2i – clinical use (4)

Answer 7

Moderate efficacy – HbA1c reduction ~11mmol/mol. More potent that DPP4i; similar to GLP-1RA; not as effective as metformin or sulphonylureas.

Glucose lowering effect relies on renal glucose filtration. Efficacy falls off below eGFR of 90ml/min; no glucose benefit if eGFR <45ml/min. BUT renal benefits seen below this.

Blood pressure – 3-6mmHg SBP and 2-3mmHg DBP reduction

Lipids – slight increase in LDL and HDL Cholesterol

Question 8

SGLT2i – MOST COMMON (3)

Answer 8

3 in common use – Dapagliflozin, Canagliflozin, Empagliflozin. A number of other ‘flozins’ available.

Most common in Tayside = Empagliflozin 10 mg od; little glycemic benefit from increasing to 25mg od.

Question 9

SGLT2i – side effects

Answer 9

(thrush) – secondary to glycosuria
10% of women and 4% of men
Usually mild and readily treatable

Fournier Gangrene
Rare but severe. 15/100,000 SGLT2i vs ~10/100,000 person years with DPP4i

Hypovolemia and hypotension
-Due to diuretic effect
-Caution in patients on other diuretics or with low blood pressure

Diabetic Ketoacidosis
~double risk of DKA compared to DPP4i.
-Can occur despite normal glucose (Euglycaemic Ketoacidosis)
-Due to increased ketone body production (low insulin, increase glucagon)

Question 10

SGLT2i and renal outcomes

Answer 10

SGLT2i are beneficial for most renal outcomes – results her for empagliflozin. Similar for cana and dapa