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

SGLT2 inhibitors decrease uptake of sugar by about one quarter

So SGLT2 inhibitors make you pee sugar!

This does not continue indefinitely!
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