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Original Article

A Practical, Simple Approach to Prescribing SGLT-2 Inhibitors for Glycemic Control, Heart Failure, or Chronic Renal Disease in Patients with and without Type 2 Diabetes Mellitus

Olivia Cook, MD, FRCPC, Ally Prebtani, BScPhm, MD, FRCPC*

Professor of Medicine, Division of Endocrinology & Metabolism, Department of Medicine, McMaster University

Abstract

The indications for SGLT-2 inhibitors have expanded beyond glycemic control in type 2 diabetes mellitus and now include chronic kidney disease and heart failure. These broadened indications mean more health care providers will be prescribing this class of medication on top of best evidence guideline directed therapy to improve cardiac and renal outcomes. This article reviews the effectiveness of SGLT-2i and outlines key considerations when prescribing to mitigate adverse events.

Résumé

Les indications des inhibiteurs du SGLT-2 se sont étendues au-delà du contrôle de la glycémie dans le diabète de type 2 et incluent maintenant les maladies rénales chroniques et l’insuffisance cardiaque. Ces indications élargies signifient qu’un plus grand nombre de fournisseurs de soins de santé prescriront cette classe de médicaments en plus du traitement dirigé par les meilleures données probantes pour améliorer les résultats cardiaques et rénaux. Cet article passe en revue l’efficacité du SGLT-2i et présente les principales considérations à prendre en compte lors de la prescription pour atténuer les effets indésirables.

Key words: SGLT-2 inhibitors, heart failure, diabetes mellitus, chronic kidney disease

Corresponding Author: Ally Prebtani: prebtani@mcmaster.ca

Submitted: 20 June 2022; Accepted: 12 September 2022; Published: 19 October 2022

DOI: 10.22374/cjgim.v17iSP2.644

All articles published in DPG Open Access journals
This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)(https://creativecommons.org/licenses/by-nc/4.0/).

Case

Ms. Happy is a 65-year-old female referred to your clinic for type 2 diabetes mellitus (T2DM) management. She has a known history of congestive heart failure (HF) with an ejection fraction (EF) of 45%, hypertension, obesity (body mass index 31 kg/m2), and chronic kidney disease (CKD) with an estimated glomerular filtration rate (eGFR) of 55 mL/-minute/1.73 m2 and urine albumin to creatinine ratio (uACR) of 12 mg/mmol. She is currently on degludec 10 units, metformin 1000 mg twice daily, metoprolol 50 mg twice daily, furosemide 40mg twice daily, perindopril 8 mg daily, and rosuvastatin 10 mg daily. Her most recent HbA1C is 8.5%, with a continuous glucose monitor time range (between 3.9-10.0 mmol/L) of 48%. You wonder if adding an SGLT-2 inhibitor (SGLT-2i) would be an appropriate next step?

General

In T2DM, metformin is traditionally and typically the first medication used for glycemic control.1 Because T2DM is a progressive disease, second-- and third-line agents are frequently required to achieve glycemic control. As recent cardiovascular (CV) and renal outcome trials evaluating glucose-lowering therapies, particularly SGLT-2i and GLP-1 receptor agonists, have shown significant cardiorenal benefits, it is important to consider the presence of CV and renal risk factors, established atherosclerotic cardiovascular disease, and history of HF or CKD in patients before choosing agent(s) for additional benefits beyond glycemic control.

Indications SGLT-2i

Indications for SGLT-2i include any of the following: T2DM for glycemic control or with elevated CV risk, CKD with an eGFR 25–75 mL/minute/1.73m2 and uACR > 22mg/mmol, or HF with either HFrEF (HF with Ef < 40%) or HFpEF (HF with Ef > 40%).1-4 The HF and CKD indications exist with or without T2DM.

Glycemic Control and Other Metabolic Effects

It is currently thought that SGLT-2i acts by reducing glucose reabsorption in the kidney leading to increased urinary excretion and overall lowering of blood glucose levels.1 In managing T2DM, SGLT-2i have reduced HbA1C by approximately 0.5–0.7% and are not associated with hypoglycemia.1 SGLT-2i are not very effective at lowering HbA1C in patients with an eGFR of <60 mL/minute/1.73m2.5

CKD

SGLT-2i reduces intraglomerular pressure and hyperfiltration, thereby preventing the progression of renal disease. In CKD, SGLT-2i exhibit renal protection in patients with diabetic CKD and non-diabetic CKD.6,7 Specific benefits include slowing the decline of renal function, rates of end-stage kidney disease, reduction in major adverse cardiac events, HF hospitalizations, and death from renal and CV causes as a composite outcome.6,7

Heart Failure & CVD

In the treatment of HF, cardiovascular outcome trials have demonstrated reduced CV events, CV mortality, and HF hospitalization in patients with and without T2DM.6,8-11 Meta-analyses of these trials report that SGLT-2i, as a class, reduces the risk of HF hospitalization by 31% in patients with T2DM, both with and without known CV disease.12 The benefit of SGLT-2i also extends to HF (class II-IV) with HFpEF or HFrEF with or without diabetes.4 Empagliflozin and dapagliflozin lowered the risk of CV death and hospitalization in this population.4,13 In the management of CKD and HF, it is essential that SGLT-2i are added to best evidence guideline-directed therapy.

Contraindications and Caution

Ms. Happy meets two indications for initiation of SGLT-2i including suboptimal glycemic control and symptomatic HFpEF. Although other glucose-lowering therapies, such as sulphonylureas or incretins could be considered, because of her HFpEF an SGLT-2i is preferred. Now that it is established that she has an indication for SGLT-2i, we must ensure that she does not have contraindications for its use. Current contraindications to SGLT-2i use include type 1 diabetes mellitus, pregnancy/breastfeeding, dialysis, eGFR < 20 mL/min, and previous hypersensitivity to SGLT-2i.1-3 Use caution if the patient has a significant history of recurrent urinary tract infections. The label warning for critical limb ischemia has recently been removed from canagliflozin; however, it is important to be aware of the association previously seen in initial trials.9 SGLT-2i start should also be delayed until the following conditions are corrected: volume depletion, active genital mycotic infections, symptomatic hypotension, and diabetic ketoacidosis (DKA).1-3

SGLT-2i Availability and Cost

You confirm that Ms. Happy has no contraindications to SGLT-2i use and would like to start one today. There are three SGLT-2i approved for use in Canada: canagliflozin, dapagliflozin, and empagliflozin. They are all once daily, oral, and available in combination pills with metformin. Ideally, the choice should be based on the evidence for each particular indication (Table 1).4,6-11,14 Since Ms. Happy has T2DM, any SGLT-2i would be appropriate to prescribe. Given her additional history of HFpEF you elect to start empagliflozin 10 mg daily. As Ms. Happy is 65 years old, the SGLT-2i will likely be covered under most provincial or territorial drug benefit programs in Canada. However, if Ms. Happy did not have coverage, a 30-day supply for any SGLT-2i is approximately one-hundred Canadian dollars.15

Table 1. Selecting appropriate SGLT-2i based on indication

SGLT-2i T2DM HFrEF* HFpEF* CKD
Empagliflozin X X X
Dapagliflozin X X X X*
Canagliflozin X X

*In patients with & without T2DM

Full details regarding each SGLT-2i can be found in the product monograph.

Pharmacologic Considerations

When starting an SGLT-2i you may need to adjust other medications. Ms. Happy, for example, appears euvolemic with a blood pressure of 115/77. She takes furosemide 40 mg twice daily and perindopril 8 mg daily. Knowing that SGLT-2i can have a diuretic effect and lower systolic blood pressure by 3–5 mm Hg, you decide to simultaneously reduce her furosemide to 20 mg twice daily.1,2 Additionally, if a patient’s HbA1C is <7% and they have a history of diabetes, you may consider reducing other glucose-lowering medications that risk causing hypoglycemia, such as sulphonylureas or meglitinides by 50%, and insulin by 10–20%.1,2 Since Ms. Happy’s HbA1C is 8.5%, you decide not to make such adjustments.

Patient Counselling for Side Effects and Complications

Ms. Happy should also be counselled on the side effects and suggestions to reduce these adverse effects. She may experience increased urine output, weight loss (2-3kg), symptoms of hypotension, genital mycotic infections, and rarely euglycemic DKA.1,2 SGLT-2i are part of the sick day medication list “SADMANS” (S: sulfonylureas, A: angiotensin--converting enzyme inhibitors or angiotensin neprilysin inhibitors, D: diuretics, M: metformin, A: angiotensin receptor blockers, N: nonsteroidal anti-inflammatory drugs, S: SGLT-2i) and must be held if experiencing a dehydrating illness or planned surgery to prevent euglycemic DKA and hypovolemia.1,2

Back to the Case…

You see Ms. Happy back in the clinic in 3 months. She is doing well and has tolerated the SGLT-2i nicely. Her repeat HbA1C is 8.1% and she has lost 1 kg. Her blood pressure is stable and she has no symptoms of hypotension. You therefore, increase empagliflozin to 25 mg daily to target a greater HbA1C lowering effect which may be marginal with the dose increase and more dietary counselling. Remember that in patients with an eGFR <60 mL/minute/1.73m2 the glycemic lowering benefits of SGLT-2i are limited.5 As Ms. Happy’s eGFR is 55 mL/minute/1.73m2 she may require other hypoglycemic agents soon in addition to lifestyle modifications.

Hospital Complications & Management

Three months later Ms. Happy is admitted to hospital for pneumonia and an acute kidney injury (AKI) with an eGFR of 25 mL/minute/1.73m2. Given her dehydration, poor oral intake, and renal injury the SGLT-2i is held. A major restriction in the initiation or continuation of SGLT-2i in hospitalized patients is any risk factor for precipitating euglycemic DKA or hypovolemia. Such factors include prolonged fasting, dehydration, sepsis, surgery, trauma, and AKI.16 SGLT-2i reduces plasma glucose levels, insulin release, and glucagon concentrations. This increases glucagon to insulin ratio, promoting gluconeogenesis and enhancing lipolysis. This is no problem for people living with T2DM who are normally non-insulinopenic. However, in the context of the above risk factors which further increase counterregulatory hormones, this can push patients into DKA.16 Therefore, it is essential to hold or delay initiation of SGLT-2i in patients with any risk factor for this adverse event. In patients who develop euglycemic DKA on an SGLT-2i, restarting the medication will depend on if the precipitant of DKA is identified. If a clear precipitant is known, then after the resolution of DKA and the underlying precipitant, the SGLT-2i could be resumed.17 Of course, the patient needs to receive sick day management education and clearly understand when to stop the SGLT-2i in the future. However, if the cause is not clear and the risk of future DKA is high, then discontinuation of the SGLT-2i is warranted.17 There are limited published studies evaluating the initiation of SGLT-2i in admitted patients. Given its benefit for T2DM, CKD, and HF, starting an SGLT-2i in a stable inpatient may be helpful. By initiating this medication in hospital, the team will be able to adjust doses of hypoglycemic medications, diuretics, and antihypertensives.16

Summary

SGLT-2i are a safe and effective medication class that benefits patients with T2DM, CKD with albuminuria, and HF. We are at a time where we need to emphasize personalized medicine based on patient and therapeutic characteristics with respect to glycemia, CV risk, and CKD risk. SGLT-2i are a classic example of how to promote this. For a step-by-step guide on safely prescribing SGLT-2i (see Figure 1).

Figure 1. Step-by-step guide on how to safely prescribe SGLT-2i.

Key Points

  • Indications for SGLT-2i include T2DM for glycemic control or with high CV risk, CKD with an eGFR 25-75mL/minute/1.73m2 and urine albumin to creatinine ratio > 22mg/mmol, or HF with either reduced or preserved ejection fraction.4,6-11,13,14 On top of best evidence guideline directed therapy to improve cardiac and renal outcomes.

  • SGLT-2i have proven to be a safe medication class. The most common side effects include genital fungal infections and volume depletion.18 A rare, but important side effect is euglycemic diabetic ketoacidosis. Counsel patients on these side effects and prevention methods, including proper genital hygiene and holding the medication if experiencing sepsis, a dehydrating illness or planned surgery.1

  • Look for medication interactions when initiating an SGLT-2i and make necessary adjustments. To prevent dehydration/hypotension, consider reducing antihypertensives and diuretics.1 If a patient’s HbA1C is <7% and they have a history of diabetes, consider lowering other hypoglycemic medications that have the risk of causing hypoglycemia, such as sulphonylureas, meglitinides, and insulin.1

  • After starting an SGLT-2i, monitor weight, blood pressure, renal function (as clinically indicated), and glucose (if the patient has T2DM).

  • If adding or restarting SGLT-2i in hospital, ensure any risk factors for developing euglycemic DKA have resolved and ensure the patient is euvolemic and eating/drinking well before the start.16

REFERENCES

1. Lipscombe L., Butalia S, Dasgupta K, et al. Pharmacologic Glycemic Management of Type 2 Diabetes in Adults: 2020 Update. Can J Diabet. 2020;44(7):575–591. 10.1016/j.jcjd.2020.08.001

2. Coates PT, Devuyst O, Wong G, et al. KDIGO2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Internat. 2020;98(4):S1–S115. 10.1016/j.kint.2020.06.019

3. O’Meara E, McDonald M, Chan M, et al. CCS/CHFS Heart Failure Guidelines: Clinical Trial Update on Functional Mitral Regurgitation, SGLT2 Inhibitors, ARNI in HFpEF, and Tafamidis in Amyloidosis. Can J Cardiol. 2020;36(2):159-169. doi:10.1016/j.cjca.2019.11.036

4. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N Engl J Med. 2021;1–11.

5. Miyoshi H, Kameda H, Yamashita K, et al. Protective effect of sodium-glucose cotransporter 2 inhibitors in patients with rapid renal function decline, stage G3 or G4 chronic kidney disease and type 2 diabetes. J Diabet Investig. 2019;10(6):1510–1517. 10.1111/jdi.13064

6. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295–2306. 10.1056/nejmoa1811744

7. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436–1446. 10.1056/nejmoa2024816

8. Packer M, Anker SD, Butler J, et al. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med. 2020;383(15):1413–1424. 10.1056/nejmoa2022190

9. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644–657. 10.1056/nejmoa1611925

10. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(4):347–357. 10.1056/nejmoa1812389

11. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019;381(21):1995–2008. 10.1056/NEJMoa1911303

12. Arnott C, Li Q, Kang A, et al. Sodium-glucose cotransporter 2 inhibition for the prevention of cardiovascular events in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. J Am Heart Assoc 2020;9:e014908.

13. Solomon SD, de Boer RA, DeMets D, et al. Dapagliflozin in heart failure with preserved and mildly reduced ejection fraction. N Engl J Med. 2022;23(7):1217–1225.

14. Zinman B, Wanner C, Lachin J, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22).

15. Steiner S. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2016;13(1),17–18. 10.1056/nejmoa1504720

16. Koufakis T, Mustafa OG, Ajjan RA, et al. The use of sodium-glucose co-transporter 2 inhibitors in the inpatient setting: Is the risk worth taking? J Clin Pharm Therapeut. 2020;45(5):883–891. 10.1111/jcpt.13107

17. Zhang L and Tamilia M. Euglycemic diabetic ketoacidosis associated with the use of a sodium glucose cotransporter-2 inhibitor. CMAJ: Canadian Medical Association Journal 2018;190(25): E766–E768. 10.1503/cmaj.171319

18. Qiu M, Ding LL, Zhang M, Zhou HR. Safety of four SGLT2 inhibitors in three chronic diseases: A meta-analysis of large, randomized trials of SGLT2 inhibitors. Diabetes Vasc Dis Res. 2021;18(2):10–2.