sodium glucose co-transporter 2 (SGLT2) inhibitors
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- glucose filtration by the kidney and the role of sodium glucose co-transporter
2 (SGLT2)
- glucose is normally filtered in the kidney and is reabsorbed in the
proximal tubules
- glycosuria occurs when the renal threshold of glucose (blood glucose
of approximately 10 mmol/l (160-180 mg/dl) has been reached
- at this threshold the proximal tubule cannot reabsorb all of the filtered glucose, resulting in glycosuria
- in total, 98% of the urinary glucose is transported across the membrane of the proximal tubule by SGLT2
- a naturally occurring mutation in the SLC5A2 gene, resulting in
a defective SGLT2 protein, produces significant glycosuria
- individuals who have this mutation have not been seen to have significant problems related to the glycosuria, such as urinary tract infections (UTIs) (1)
- a therapeutic option in type 2 diabetics is to mimic the effect
of the SLC5A2 mutation and prevent the reabsorption of renal-filtered
glucose back into the circulation, thereby reducing hyperglycaemia,
without the side effects of weight gain or hypoglycaemia
- glycosuria occurs when the renal threshold of glucose (blood glucose
of approximately 10 mmol/l (160-180 mg/dl) has been reached
- glucose is normally filtered in the kidney and is reabsorbed in the
proximal tubules
- SGLT2 inhibitor drugs:
- SGLT2 inhibitor drugs (dapagliflozin, canagliflozin, empagliflozin,
ertugliflozin)
- SGLT2 inhibitors correct a novel pathophysiological defect, have an
insulin-independent action, are efficacious with glycosylated hemoglobin
reduction ranging from 0.5% to 1.5%, promote weight loss, have a low incidence
of hypoglycemia, complement the action of other antidiabetic agents, and
can be used at any stage of diabetes (2)
- a systematic review of these dapagliflozin and canagliflozin drugs being
used as second or third line drugs has been undertaken (1)
- Seven trials were reviewed.
- dapagliflozin 10 mg reduced HbA1c by -0.54% (weighted mean differences (WMD), 95% CI -0.67 to -0.40) compared to placebo, but there was no difference compared to glipizide
- canagliflozin reduced HbA1c slightly more than sitagliptin (up to -0.21% vs sitagliptin)
- both dapagliflozin and canagliflozin led to weight loss (dapagliflozin WMD -1.81 kg (95% CI -2.04 to -1.57), canagliflozin up to -2.3 kg compared to placebo)
- the study authors concluded that dapagliflozin appears effective
in reducing HbA1c and weight in type 2 diabetes, although more safety
data are needed
- Seven trials were reviewed.
- adverse effects (2):
- generally well tolerated
- however, due to side effects, such as repeated urinary tract
and genital infections, increased hematocrit, and decreased blood
pressure, appropriate patient selection for drug initiation and close
monitoring after initiation will be important
- genital infections
- an increase in genital infections in the dapagliflozin groups
compared with controls in almost all the studies, with the
incidence increasing with higher doses of dapagliflozin
- reported incidence varied from 3% to 13% versus 0% to 5% in the placebo group
- when dapagliflozin monotherapy was compared with metformin monotherapy, the incidence of genital infections was 2%-7% versus 2%, respectively
- an increase in genital infections in the dapagliflozin groups
compared with controls in almost all the studies, with the
incidence increasing with higher doses of dapagliflozin
- UTIs
- reported urinary tract infection rates were 1%-12.9% in
the dapagliflozin groups versus 0%-6.2% in controls and 9%
on metformin monotherapy
- reported urinary tract infection rates were 1%-12.9% in
the dapagliflozin groups versus 0%-6.2% in controls and 9%
on metformin monotherapy
- genital infections
- the Committee for Medicinal Products for Human Use of the European Medicines Agency has recommended approval of dapagliflozin for the treatment of type 2 diabetes as an adjunct to diet and exercise, in combination with other glucose-lowering medicinal products, including insulin, and as a monotherapy for metformin-intolerant patients (2)
- SGLT2 inhibitor drugs (dapagliflozin, canagliflozin, empagliflozin,
ertugliflozin)
Consult the Summary of Product Characteristics before prescribing this drug.
Notes:
- use in renal impairment
- efficacy of dapagliflozin is dependent on renal function, and efficacy
is reduced in patients who have moderate renal impairment and likely absent
in patients with severe renal impairment. Forxiga (dapagliflozin) is not
recommended for use in patients with moderate to severe renal impairment
(patients with creatinine clearance [CrCl] < 60 ml/min or estimated glomerular
filtration rate [eGFR] < 60 ml/min/1.73 m2
- efficacy of dapagliflozin is dependent on renal function, and efficacy
is reduced in patients who have moderate renal impairment and likely absent
in patients with severe renal impairment. Forxiga (dapagliflozin) is not
recommended for use in patients with moderate to severe renal impairment
(patients with creatinine clearance [CrCl] < 60 ml/min or estimated glomerular
filtration rate [eGFR] < 60 ml/min/1.73 m2
- recommended dose is 10 mg dapagliflozin once daily for monotherapy and add-on combination therapy with other glucose-lowering medicinal products including insulin. When dapagliflozin is used in combination with insulin or an insulin secretagogue, such as a sulphonylurea, a lower dose of insulin or insulin secretagogue may be considered to reduce the risk of hypoglycaemia
Reference:
- 1) Clar C et al.Systematic review of SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes. BMJ Open. 2012 Oct 18;2(5).
- 2) Kim Y, Babu A. Clinical potential of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes Diabetes Metab Syndr Obes. 2012; 5: 313-327.
Last edited 05/2019 and last reviewed 07/2021
Links:
- NICE guidance - dapagliflozin in combination therapy for treating type 2 diabetes
- role of SGLT 1 and SGLT 2 in glucose metabolism
- NICE guidance - canagliflozin in combination therapy for treating type 2 diabetes
- NICE guidance - empagliflozin in combination therapy for treating type 2 diabetes
- EMPA - REG trial - empagliflozin in type 2 diabetes patients with high cardiovascular risk (EMPAREG)
- SGLT 2 inhibitors and diabetic ketoacidosis
- SGLT2 inhibitors and weight loss
- SGLT 2 and renal absorption of glucose in the kidney
- CANVAS Program - Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes
- SGLT2 inhibitors and Fournier's gangrene
- NICE guidance - ertugliflozin as monotherapy or with metformin for treating type 2 diabetes
- Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF)
- SGLT2 inhibitors and monitoring ketones in blood during treatment interruption for surgical procedures or acute serious medical illness
- SGLT2 inhibitors versus DPP4 inhibitors - comparing cardiovascular risk benefits
- SGLT2 inibitors comparison with GLP1 agonists - cardiovascular and renal benefits
- SGLT2 inhibitors in comparison to sulphonylureas (SUs) - comparison of all-cause mortality
- SGLT2 inhibitors and retinal vein occlusion