A Few Key Points Can Guide SGLT2 Inhibitor Management

Increasingly, pharmacists and technicians are seeing patients with and without diabetes who take novel antihyperglycemic drugs.^1-4 The sodium-glucose cotransporter 2 (SGLT2) inhibitors (Table 1^5-9) have proven benefits in diabetes and are also used to reduce cardiovascular and renal morbidity and mortality; treat heart failure and chronic kidney disease (CKD) in individuals without diabetes; and improve proteinuria, body weight, blood pressure, and blood glucose in kidney transplant recipients.^1-4

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Pharmacists need to remember a few clinical pearls when patients present with prescriptions for SGLT2 inhibitors.

Clinical Pearl No. 1: SGLT2 Inhibitors Are Protective

Many guidelines now indicate that SGLT2 inhibitors are a standard of care for cardiovascular, renal, and metabolic protection in individuals with type 2 diabetes (T2D).^3,10,11 They have primary and secondary preventive actions in addition to their glucose-lowering benefits. In diabetes, good glucose control continues to be the preferred way to prevent microvascular complications. However, after a sclerotic cardiovascular disease episode, in all types of heart failure and in CKD, the SGLT2 inhibitors are considered preventive. That means clinicians now have tools to address macrovascular complications.¹¹ Very recent data indicate that adding finerenone (Kerendia; Bayer), a nonsteroidal mineralocorticoid receptor agonist that has demonstrated efficacy in delaying CKD progression, to empagliflozin leads to a greater reduction in CKD progression.¹²

Clinical Pearl No. 2: Start With Metformin, Add an SGLT2 Inhibitor

All major guidelines still consider metformin the drug of choice for patients with T2D. Once patients are stabilized on metformin, however, adding an SGLT2 inhibitor is considered prudent because of the systemic benefits. This is especially important if a patient’s cardiovascular risk is equal to or greater than 10%, the patient’s estimated glomerular filtration rate is 20 mL/min/1.73 m² to 60 mL/min/1.73 m², and/or the patient has albuminuria regardless of the hemoglobin A1C. However, pharmacists need to know that the SGLT2 inhibitors’ glycemic benefits are reduced once the estimated glomerular filtration rate falls below 45 mL/min/1.73 m². The preventive actions are durable.¹¹

Adverse Effects Are Related to the Mechanism of Action

All SGLT2 inhibitors have the suffix “-flozin,” reflecting that they shift the flow of glucose through the renal system. More specifically, they shift reabsorption of large amounts of glucose from the kidneys’ early proximal tubule (where SGLT2 is at play) to tubular segments located downstream; these segments express SGLT1. Inhibiting SGLT2 creates a situation in which nonreabsorbed glucose spills into the urine, and osmotic diuresis further moves glucose out of the bloodstream.¹³

Early in the development of this medication class, it appeared that urinary tract infections might be common. However, it is more likely that patients will develop mycotic genital infections related to the increased concentration of glucose in the urine.¹⁴ Therefore, it is essential to remind patients to have excellent personal hygiene. Again, SGLT2 inhibitors cause osmotic diuresis that usually presents as thirst, polyuria, lightheadedness, or fatigue. Patients need to consume an adequate amount of water. Recommending 8 glasses of clear fluids daily is appropriate, but these liquids should not include tea, coffee, or alcohol. Serious adverse drug reactions are rare.^5-8,14,15

Clinical Pearl No. 4: Euglycemic Diabetic Ketoacidosis Is Possible

FDA officials identified a rare adverse effect in patients taking SGLT2 inhibitors: euglycemic diabetic ketoacidosis (DKA).¹⁶ In most cases of garden-variety DKA, patients have elevated blood glucose levels.¹⁷ In patients taking SGLT2 inhibitors, blood glucose levels can be completely normal while ketone levels are elevated. Patients need to know the signs and symptoms of DKA (thirst or a very dry mouth, frequent urination, fatigue, dry or flushed skin, fruity odor on the breath, confusion, vomiting).^17,18 They must either test their own ketones using ketone strips or call their prescriber’s office, especially if they have a fever or vomiting. Patients with type 1 diabetes are at greatest risk and may develop DKA at rates 5 to 17 times higher than patients without type 1 diabetes.¹⁹ Risk factors in all patients with diabetes include diets very low in carbohydrates, prolonged fasting, dehydration, and excessive alcohol intake.²⁰

Clinical Pearl No. 5: Provide Sick Day Guidance

All patients who take medications to reduce blood glucose need to be aware that if they experience a dehydrating illness, they must implement a sick day protocol.²¹ Dehydrating illnesses include diarrhea/vomiting, fever, infection, nausea, and poor appetite. This means they need to temporarily pause those medications during the acute phase of those illnesses.²¹ Table 2²² provides a mnemonic that lists the medications patients should pause. Patients should never stop insulin, however. Patients also need to know that once they resume eating and drinking normally, they need to restart these medications.

Conclusion

With 10 years of experience using SGLT2 inhibitors, clinical researchers find the class has much more utility than expected. With adverse effect profiles that are much better than the old drugs, SGLT2 inhibitors are here to stay.

REFERENCES

1. McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardiovascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol. 2021;6(2):148-158. doi:10.1001/jamacardio.2020.4511

2. Cosentino F, Cannon CP, Cherney DZI, et al; VERTIS CV Investigators. Efficacy of ertugliflozin on heart failure–related events in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease: results of the VERTIS CV trial. Circulation. 2020;142(23):2205-2215. doi:10.1161/CIRCULATIONAHA.120.050255

3. Roddick AJ, Wonnacott A, Webb D, et al. UK Kidney Association clinical practice guideline: sodium-glucose co-transporter-2 (SGLT-2) inhibition in adults with kidney disease 2023 UPDATE. BMC Nephrol. 2023;24(1):310. doi:10.1186/s12882-023-03339-3

4. Van Loon E, Gillard P, Naesens M. SGLT2 inhibitors fulfill their expectations in diabetic kidney transplant recipients. Kidney Int. 2025;107(6):966-969. doi:10.1016/j.kint.2025.02.019

5. Steglatro. Prescribing information. Merck; 2017. Accessed June 20, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209803s000lbl.pdf

6. Farxiga. Prescribing information. AstraZeneca; 2024. Accessed June 20, 2025. https://den8dhaj6zs0e.cloudfront.net/50fd68b9-106b-4550-b5d0-12b045f8b184/0be9cb1b-3b33-41c7-bfc2-04c9f718e442/0be9cb1b-3b33-41c7-bfc2-04c9f718e442_viewable_rendition__v.pdf

7. Invokana. Prescribing information. Janssen; 2018. Accessed June 20, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/204042s027lbl.pdf

8. Brenzavvy. Prescribing information. TheracosBio; 2023. Accessed June 20, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/214373s001lbl.pdf

9. Jardiance. Prescribing information. Boehringer Ingelheim; 2023. Accessed June 20, 2025. https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/204629s033lbl.pdf

10. KDIGO 2022 clinical practice guideline for diabetes management in chronic kidney disease. Kidney Int. 2022;102(suppl 5S):S1-S127. Accessed June 18, 2025. https://kdigo.org/wp-content/uploads/2022/10/KDIGO-2022-Clinical-Practice-Guideline-for-Diabetes-Management-in-CKD.pdf

11. American Diabetes Association Professional Practice Committee. 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes-2025. Diabetes Care. 2025;48(1 Suppl 1):S181-S206. doi:10.2337/dc25-S009

12. Agarwal R, Green JB, Heerspink HJL, et al. Finerenone with empagliflozin in chronic kidney disease and type 2 diabetes. N Engl J Med. Published online June 5, 2025. doi:10.1056/NEJMoa2410659

13. Vallon V. State-of-the-art-review: mechanisms of action of SGLT2 inhibitors and clinical implications. Am J Hypertens. 2024;37(11):841-852. doi:10.1093/ajh/hpae092

14. Talyshinskii A, Nedbal C, Somani BK. Urological impact of flozins (SGLT2 inhibitors): an EAU Endourology review of risks, side effects and clinical considerations. Curr Opin Urol. Published online May 24, 2025. doi:10.1097/MOU.0000000000001306

15. Nuffield Department of Population Health Renal Studies Group, SGLT2 inhibitor Meta-Analysis Cardio-Renal Trialists’ Consortium. Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials. Lancet. 2022;400(10365):1788-1801. doi:10.1016/S0140-6736(22)02074-8

16. FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. FDA. Updated March 16, 2022. Accessed June 18, 2025. https://www.fda.gov/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious

17. Qiu H, Novikov A, Vallon V. Ketosis and diabetic ketoacidosis in response to SGLT2 inhibitors: basic mechanisms and therapeutic perspectives. Diabetes Metab Res Rev. 2017;33(5). doi:10.1002/dmrr.2886

18. Diabetes & DKA (ketoacidosis). American Diabetes Association. Accessed June 18, 2025. https://diabetes.org/about-diabetes/complications/ketoacidosis-dka/dka-ketoacidosis-ketones

19. Li M, Liu Z, Yang X, et al. The effect of sodium-glucose cotransporter 2 inhibitors as an adjunct to insulin in patients with type 1 diabetes assessed by continuous glucose monitoring: a systematic review and meta-analysis. J Diabetes Complications. 2023;37(12):108632. doi:10.1016/j.jdiacomp.2023.108632

20. Danne T, Garg S, Peters AL, et al. International consensus on risk management of diabetic ketoacidosis in patients with type 1 diabetes treated with sodium-glucose cotransporter (SGLT) inhibitors. Diabetes Care. 2019;42(6):1147-1154. doi:10.2337/dc18-2316

21. SGLT-2 inhibitors – handout for patients. Duke University Nephrology. Accessed June 18, 2025. https://sites.duke.edu/nephfellow/files/2021/07/SGLT2-Inhibitors-Handout-for-patients.pdf

22. Leung C. If you have diabetes, do you know about SADMANS? Drug Opinions. August 19, 2020. Accessed June 18, 2025. https://drugopinions.wordpress.com/2020/08/19/if-you-have-diabetes-do-you-know-about-sadmans/