Dr. Anant Patil answers ten questions on SGLT2 inhibitors drugs used in the management of type 2 diabetes.

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Question 1: What are SGLT2 and SGLT2 inhibitors?

Dr. Anant Patil: Normally, glucose filtered by the glomerulus is reabsorbed in the kidney tubules resulting in no appearance of glucose in the urine. Sodium glucose cotransporter-2 (SGLT2) located in the proximal tubule is responsible for the reabsorption of most of the filtered glucose. [1]

SGLT2 inhibitors are the drugs used in the management of type 2 diabetes mellitus. These drugs inhibit glucose reabsorption in the renal proximal tubule which results in increase in glycosuria. [1,2] The examples of SGLT2 inhibitors are empagliflozin, canagliflozin, dapagliflozin and ertugliflozin. [1]

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Question 2: How do SGLT2 inhibitors differ from each other?

Dr. Anant Patil: Drugs in the class of SGLT2 inhibitors differ in their pharmacokinetic profile i.e. bioavailablity, elimination half-life, metabolism and excretion. SGLT2 inhibitors are given by oral route but they differ in dosage. [3]

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Question 3: What is the place of SGLT2 inhibitors in the management of type 2 diabetes?

Dr. Anant Patil: SGLT2 inhibitors have an important place in the management of type 2 diabetes mellitus. The recommendations from different guidelines regarding use of SGLT2 inhibitors are given below:

• American Diabetic Association (2020): Metformin is the preferred initial treatment for type 2 diabetes. SGLT2 inhibitors are one of the agents recommended for combination with metformin in patients not achieving HbA1 target after approximately three months of metformin therapy. Patient-centered approach considering cardiovascular comorbidities, risk of hypoglycaemia, cost of therapy, potential adverse events, and patient preference is recommended for selecting the pharmacological therapy. The guideline recommends SGLT2 inhibitor with demonstrated benefit for cardiovascular disease in type 2 diabetes patients having established arhterosclerotic cardiovascular disease or those with high risk of it, patients with established renal disease or heart failure. [4]
• RSSDI-ESI Clinical Practice Recommendations (2020): Metformin should be started with lifestyle modifications at the time of diagnosis. SGLT2 inhibitor is one of the options for initial treatment in patients having contraindications for use of metformin or if a patient is not able to tolerate metformin. It can be used as a component of dual or triple therapy in patients who are not able to achieve glucose control target. SGLT2 inhibitors are also among the agents that may be considered in patients having issues of postprandial hypoglycaemia. [5]
• European Society of Cardiology (ESC) guideline (2019) developed in collaboration with the European Association for the Study of Diabetes (EASD): In type 2 diabetes patients with atherosclerotic cardiovascular disease or those with high or very high cardiovascular risk, SGLT2 inhibitors are recommended as initial treatment. [6]

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Question 4: What are the advantages of SGLT2 inhibitors in the management of type 2 diabetes?

Dr. Anant Patil: SGLT2 inhibitors are effective in the management of type 2 diabetes mellitus as demonstrated by their effects on glycaemic parameters including glycosylated haemoglobin, fasting blood glucose and post-prandial blood glucose. The risk of hypoglycaemia is low with SGLT2 inhibitors. [1] These agents are also useful to decrease post-pradial glucose excursions. [6]

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Question 5: What are the benefits of SGLT2 inhibitors beyond glycaemic control in patients with type 2 diabetes?

Dr. Anant Patil: SGLT2 inhibitors offer several benefits beyond glycaemic control in patients with type 2 diabetes mellitus. Obesity or overweight is common in patients with type 2 diabetes. [7] SGLT2 inhibitors cause weight reduction. [1,6,7] Another issue common in patients with type 2 diabetes is arterial hypertension. [7] SGLT2 inhibitors also improve blood pressure. [1,7] Patients with type 2 diabetes are also at higher risk of cardiovascular or renal complications. [7] These drugs offer benefits related to cardiovascular and renal effects. All these benefits make SGLT2 inhibitors an attractive option in the management of type 2 diabetes mellitus.

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Question 6: What are the cardiovascular benefits of SGLT2 inhibitors in patients with type 2 diabetes mellitus?

Dr. Anant Patil: Many cardiovascular outcome trails showed cardiovascular benefits with use of SGLT2 inhibitors in patients with cardiovascular disease, or those at very high or high risk of cardiovascular disease. [6] SGLT2 inhibitors decrease the major cardiac events in adult with type 2 diabetes and established cardiovascular disease. They also reduce the risk of heart failure hospitalisation in adults with type 2 diabetes irrespective of existing cardiovascular disease. [2] Empagliflozin and canagliflozin provide benefits related to atherosclerotic cardiovascular disease and heart failure and dapagliflozin provides benefits related to heart failure. [4]

In addition to approval as an adjuvant to diet and exercise for improving glycaemic control in type 2 diabetes patients, empagliflozin is also approved by the US-FDA to decrease the risk of cardiovascular death in adult patients with type 2 diabetes mellitus and established cardiovascular disease. [8]

Similarly, canagliflozin is approved for reduction in the risk of major adverse cardiovascular events in adults with type 2 diabetes mellitus and established cardiovascular disease. [9] Dapagliflozin is approved to reduce the risk of hospitalisation for heart failure in adult type 2 diabetes patients with established cardiovascular disease or multiple cardiovascular risk factors.[10]

The guidelines (2019) by the ESC6 recommend empagliflozin, canagliflozin, or dapagliflozin to reduce risk of heart failure hospitalisation.

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Question 7: What are the benefits of SGLT2 inhibitors related to diabetic kidney disease?

Dr. Anant Patil: Cangliflozin, empagliflozin and dapagloflozin provide benefits related to progression of diabetic kidney disease. [4] The ESC guideline (2019) recommends use of SGLT2 inhibitors for reducing progression of diabetic kidney disease. [6]

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Question 8: What are the adverse events associated with SGLT2 inhibitors?

Dr. Anant Patil: Generally SGLT2 inhibitors are well-tolerated by patients with type 2 diabetes mellitus. Based on the mechanism of action of higher amount of glucose in the urine, it is expected that these agents may predispose patients to risk of urinary tract infection. However, available data are conflicting. Some reports showed higher risk of urinary tract infection and others did not show significant difference in the rates of urinary tract infection with these drugs as compared to placebo or active comparative arm. [1]

Risk of genital infection associated with SGLT2 inhibitors is more in females and in those with a history of previous genital infection. Genital infections are usually not severe and do not need treatment discontinuation. [1]

Other reported adverse events include hypotension, dizziness, increase in LDL cholesterol and fractures (rare) in susceptible patients.[3] Some considerations with SGLT2 inhibitors include risk of amputation (canagliglozin), [9] diabetic ketoacidosis, and Fournier’s gangrene. [1]

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Question 9: How common is the risk of hypoglycaemia with SGLT2 inhibitors?

Dr. Anant Patil: The risk of hypoglycaemia is low with SGLT2 inhibitor monotherapy. Concurrent administration may increase the hypoglycaemic effects of insulin or insulin secreatogogues (e.g. sulfonylureas). [3]

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Question 10: What are the dosages of SGLT2 inhibitors in patients with type 2 diabetes mellitus?

Dr. Anant Patil: The dosages of SGLT2 inhibitors are given in table below

SGLT2 inhibitor	Dose
Canagliflozin[9]	Initial dose: 100 mg once daily before first meal of the day. Dose can be increased to 300 mg once daily if 100 mg once daily is well tolerated Patient has eGFR of 60 mL/min/1.73 m2 or more and Need better glycaemic control
Dapagliflozin[10]	Type 2 diabetes: Initial dose: 5 mg once daily in morning, with or without food Dose can be increased to 10 mg once daily if Additional glycaemic control is needed and Patient tolerates initial dose To reduce risk of hospitalisation for heart failure in type 2 diabetes patients and established cardiovascular disease or multiple cardiovascular risk factors: 10 mg once daily.
Empagliflozin[8]	Initial dose: 10 mg once daily in morning with or without food Dose can be increased to 25 mg if additional glycaemic control is needed and if patient tolerates the initial dose.
Ertugliflozin[11]	Initial dose: 5 mg once daily, in morning, with or without food Dose can be increased to maximum 15 mg if additional glycaemic control is required and if patient tolerates the initial dose.

Assessment of renal function is required before starting SGLT2 inhibitors and periodically thereafter. In patients with renal impairment, decision to start and discontinue SGLT2 inhibitors should be taken based on the severity of renal dysfunction as indicated by estimated glomerular filtration rate (eGFR) of the patient. If the patient has volume depletion, it should be corrected before starting the SGLT2 inhibitor. [8-11]

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Disclaimer: The content is for educational purpose only. For agent specific information, healthcare providers are requested to refer the updated prescribing information.

The views and opinions expressed in this article are those of the author and do not necessarily reflect the official policy or position of M3 India.

The author, Dr. Anant Patil is Assistant Professor of Pharmacology.