SGLT2 Inhibition in the Diabetic Kidney (1)
SGLT2i is a group of medicines that emerged as one of the most popular oral antidiabetic agents in recent years due to the recent findings in efficacy and benefits. Examples of SGLT2i available in the market include empagliflozin, canagliflozin, dapagliflozin and ertugliflozin.
Below are summaries of the following:
Mechanism of action of SGLT2i
What are the recommended roles of SGLT2i in type 2 diabetes?
Evidence from meta-analysis
Choice of the agent, adverse drug reactions, normal dose, dose adjustment, contraindications, precautions
Mechanism of action of SGLT2i
Sodium-glucose Co-transporter expressed at the proximal tubule of the nephron is responsible for the reabsorption of sodium and glucose molecules from the tubular lumen back into the bloodstream. SGLT2i works by inhibiting this reabsorption process and hence encourage the excretion of glucose through the urine. This leads to a reduction in blood glucose level and hence HbA1c level. (2)
What are the recommended roles of SGLT2i in type 2 diabetes?
Standards of Medical Care in Diabetes-2021: Pharmacologic Therapy for Type 2 Diabetes published by the American Diabetic Association (ADA) (3)
SGLTi with demonstrated cardiovascular disease (CVD) benefit is recommended for patients with established atherosclerotic cardiovascular disease (ASCVD) or indicators of high risk (such as patients ≥55 years of age with coronary, carotid, or lower-extremity artery stenosis >50% or left ventricular hypertrophy), heart failure, or CKD, independent of A1C, independent of metformin use, and in consideration of patient-specific factors.
2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD (4)
Whether patients are treatment-naive or already on metformin:
Empagliflozin, canagliflozin, or dapagliflozin are recommended in patients with type 2 diabetes (T2DM) and CVD, or at very high/high CV risk, to reduce CV events
Empagliflozin is recommended in patients with T2DM and CVD to reduce the risk of death
Evidence from meta-analysis
Three major conclusions can be drawn from “SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials” (5):
SGLT2i reduced major adverse cardiovascular events (composite of myocardial infarction, stroke, or cardiovascular death) by 11% (p=0·0014), with benefits only seen in patients with atherosclerotic cardiovascular disease and not in those without.
SGLT2i reduced the risk of cardiovascular death or hospitalisation for heart failure by 23% (p<0·0001), with a similar benefit in patients with and without atherosclerotic cardiovascular disease and with and without a history of heart failure.
SGLT2i reduced the risk of progression of renal disease by 45% (p<0·0001), with a similar benefit in those with and without atherosclerotic cardiovascular disease.
Choice of the agent, adverse drug reactions, normal dose, dose adjustment, contraindications, precautions
In patients with type 2 diabetes and a prior history of atherosclerotic CVD, the agent of choice is empagliflozin (had more pronounced effect than that of canagliflozin or dapagliflozin; canagliflozin had an increased risk of amputation and bone fractures). (2,5)
In patients with type 2 diabetes and heart failure or kidney disease, all SGLT2 inhibitors have shown salutary effects; choice of agent depends on provider preference, cost and availability of drugs. (2)
Common adverse drug reactions for SGLT2i include vulvovaginal candidiasis, Urosepsis and pyelonephritis. (2)
Summary of the normal dose, dose adjustment for renal or hepatic impairments, contraindications and some of the important precautions as below: (2,6)
Conclusion
SGLT2i, specifically empagliflozin should be started as monotherapy, or added to metformin in T2DM patients with established CVD. As patients with T2DM patients are often at increased risk of CVD, heart failure or CKD, an SGLT2i can be the agent of choice as a monotherapy, or as an add-on to metformin to achieve the target HbA1c.
References
van Bommel EJ, Muskiet MH, Tonneijck L, Kramer MH, Nieuwdorp M, van Raalte DH. SGLT2 Inhibition in the Diabetic Kidney-From Mechanisms to Clinical Outcome. Clin J Am Soc Nephrol. 2017;12(4):700-710.doi:10.2215/CJN.0608061
DeSantis A. Sodium-glucose co-transporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus. Uptodate. https://www.uptodate.com/contents/sodium-glucose-co-transporter-2-inhibitors-for-the-treatment-of-hyperglycemia-in-type-2-diabetes-mellitus?search=sglt2+inhibitors&source=search_result&selectedTitle=2~95&usage_type=default&display_rank=1#H4130796457. Accessed August 28, 2021.
American Diabetes Association. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2021. Diabetes Care. 2021;44(Suppl 1):S111-S124. doi:10.2337/dc21-S009
Cosentino F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines on DIABETES, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: The Task Force for DIABETES, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the study of Diabetes (EASD). European Heart Journal, Volume 41, Issue 2, 7 January 2020, Pages 255–323, https://doi.org/10.1093/eurheartj/ehz486. Accessed August 28, 2021.
Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials [published correction appears in Lancet. 2019 Jan 5;393(10166):30]. Lancet. 2019;393(10166):31-39. doi:10.1016/S0140-6736(18)32590-X
MIMS gateway. MIMS Gateway. https://online1.mimsgateway.com.my/. Accessed August 28, 2021.
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