Endocrinology AJGPs and Checks Flashcards
Mechanism of action
SGLT2i
AJGP 2021
- SGLT2 transporters, located in the proximal renal tubule, are responsible for >90% of renal glucose reabsorption (remainder via SGLT1)
- Glycosuria occurs above glycaemic threshold of 10mmol/L
- People with** T2D have higher thresholds and greater SGLT2 expression**
AJGP 2021 Current evidence and practical guidance for the use of sodium–glucose co-transporter-2 inhibitors in type 2 diabetes
Cardiovascular benefits of SGLT2 inhibitors and when to prescribe them
AJGP 2021, MJA 2022
- T2DM patients who are at high cardiovascular risk due to associated atherosclerotic cardiovascular disease, multiple cardiovascular risk factors or macroalbuminuric chronic kidney disease (eGFR >30 mL/min/1.73 m2 but PBS criteria states eGFR > 25 to initiate dapaglifozin to decrease the risk of developing heart failure
- SGLT2 inhibitor (dapagliflozin or empagliflozin) is recommended in patients with HFrEF (LVEF ≤ 40%) to decrease mortality and decrease hospitalisation for heart failure
- SGLT2i (empagliflozin) should be considered in patients with HFmrEF (LVEF 41–49%) to decrease cardiovascular mortality or hospitalisation for heart failure
- SGLT2 inhibitor (empagliflozin) should be considered in patients with HFpEF (LVEF ≥ 50%) to decrease cardiovascular mortality or hospitalisation for heart failure
AJGP 2021 Current evidence and practical guidance for the use of sodium–glucose co-transporter-2 inhibitors in type 2 diabetes
MJA 2022 Consensus statement on the current pharmacological prevention and management of heart failure
Renal benefits of SGLT2i
- SGLT2 inhibition reduces resorption of glucose and also sodium from the glomerular filtrate in the proximal kidney tubule. This leads to urinary excretion of glucose and osmotic diuresis.
- key proposed mechanism for renoprotective effects is reduction of intraglomerular pressure through tubuloglomerular feedback. In this mechanism, SGLT2 inhibitors cause more sodium to pass along the nephron, which is sensed by macula cells that act via adenosine to constrict afferent glomerular arterioles
- enhanced sodium excretion in the urine (natriuresis) and osmotic diuresis, coupled with reductions in extracellular volume and plasma volume, contribute to the blood pressure (BP)-lowering efficacy of SGLT2 inhibitors, which may preserve kidney function
- may also improve kidney oxygenation and promote anti-inflammatory and antifibrotic pathways, thereby slowing the progression of kidney function decline
- 2020 DAPA-CKD trial looked 4304 patients from 21 countries with an eGFR 25–75 mL/min/1.73 m2 and urine ACR 22.6–565 mg/mmol already on ACEi or ARB for at least 4 weeks:
a) reduced worsening kidney function ( decline of at least 50% in eGFR or onset of kidney failure (dialysis, kidney transplant or GFR < 15))
b) reduced risk of all-cause mortality by 31% - dapagliflozin would be an addition to standard care in CKD, administered concurrently with an ACE inhibitor or ARB, unless contraindicated
- no recommended treatment target
NPS 2022 Dapagliflozin for chronic kidney disease
Considerations for starting dapaglifozin for CKD patients
Dosing:
* 10 mg taken once daily, with or without food.
* No adjustments are required for those with reduced kidney function, mild-to-moderate hepatic impairment or based on age.
* Not recommended to be initiated if: eGFR < 25 mL/min/1.73 m2 (note: may continue established dapagliflozin therapy at 10 mg once daily unless dialysis is commenced), patient has a history of hypotension or dehydration with diuretic therapy OR patient is currently experiencing an acute illness.
Contraindications:
* with polycystic kidney disease; lupus nephritis; ANCA-associated vasculitis; or those requiring or with a recent history of immunosuppressive therapy due to expected lack of effectiveness in these groups
* with severe hepatic impairment (Child–Pugh class C)
* < 18 years old
* with a known hypersensitivity to any of the ingredients
* with type 1 diabetes
* for the treatment of diabetic ketoacidosis.
Precautions:
* Surgery
* Volume-depleted patients
* Patients with a history of hypotension
* History of diabetic ketoacidosis while taking a SGLT2 inhibitor
* eGFR < 45 mL/min/1.73 m2 (glucose-lowering effect is reduced)
* eGFR < 25 mL/min/1.73 m2: starting treatment with dapagliflozin is not recommended; treatment may be continued if eGFR falls below this unless dialysis is commenced.
Not recommended during pregnancy or breastfeeding women
Adverse effects:
* Genitourinary infections
* Hypoglycaemia
* Dehydration (volume depletion)
* Hypotension
* Transiently reduced kidney function
* Euglycaemic ketoacidosis
* Fractures and amputations
NPS 2022 Dapagliflozin for chronic kidney disease
Important potential adverse effects of SGLT2 inhibitors and considerations for clinical practice
DKA
* result of the insulin-independent effect of SGLT2 inhibition on glycaemia, a significant proportion of DKA cases occur with only slightly elevated blood glucose levels, which may lead to delayed diagnosis and management
* risk increased in people who are acutely unwell, fasting, perioperative or have a history of excess alcohol consumption
* In the event of acute illness that warrants medical attention (especially in the setting of nausea, vomiting or abdominal pain), measurement of capillary blood ketone or blood beta-hydroxybutyrate levels should be considered.
* Urine ketone testing may be unreliable because of altered urinary ketone excretion
Genital and urinary infections
* As a result of the glycosuric effect of SGLT2i, there is an increased risk of genital infections
* Of concern is the risk of Fournier’s gangrene
* For candidiasis, a single course of a topical antifungal is usually effective
Polyuria, volume depletion and hypotension
* degree of polyuria is typically higher in people with more marked hyperglycaemia
* diuretic effect can lead to volume loss and potentially hypotension
* 20% decline in eGFR should be tolerated in the first month, provided that there is no clinical evidence of hypovolaemia or an alternate pathology that could be contributing to AKI
* more severe or prolonged decline in eGFR should prompt further investigation
AJGP 2021 Current evidence and practical guidance for the use of sodium–glucose co-transporter-2 inhibitors in type 2 diabetes
Sick day and perioperative mangagement for patients on SGLT2i
AJGP 2021 Current evidence and practical guidance for the use of sodium–glucose co-transporter-2 inhibitors in type 2 diabetes
