Emergence of SGLT-2 Inhibitor-Induced Myopathy

Kimmy Nguyen
Jun 6
4 min read

Written by Qabas Al-Jobori, PharmD Candidate and Adenike Atanda, PharmD, BCACP, CDCES, CTTS

Drug-induced myopathy manifests as myalgia, muscle weakness, or, in severe cases, rhabdomyolysis following medication exposure. It may also present as asymptomatic elevation of serum creatine kinase (CK), with resolution achieved following the discontinuation of the offending agent (1). While mechanisms such as direct myotoxicity and, more rarely, immune-mediated myopathy explain some cases, there is limited data regarding its emergence in relation to sodium-glucose cotransporter 2 inhibitor (SGLT2i) therapy (2).

SGLT2is inhibit glucose reabsorption in the proximal tubule, reducing plasma glucose via glucosuria. Initially approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus (T2DM), SGLT2is also play a role in cardiovascular and renal protection, expanding their use to heart failure and chronic kidney disease treatment regardless of diabetes status (3). Common class effects include urinary tract infection and dehydration, while serious adverse effects include ketoacidosis and genitourinary infections (4). Although myopathy is not commonly considered an adverse effect of this medication class, emerging case reports suggest a possible correlation, particularly with empagliflozin and dapagliflozin.

The cases described in Table 1 highlight a temporal relationship between SGLT2i initiation and the onset of muscle-related symptoms, with improvement following discontinuation. While there were some notable confounders, such as in Case 2 where the patient had a history of statin-induced rhabdomyolysis and concurrent evolocumab use, the rapid symptom resolution post-empagliflozin discontinuation suggests that it was the primary causative agent. Additionally, dapagliflozin in Case 3 was rechallenged, confirming its role in symptom recurrence, strongly supportive the SGLT2i-induced myopathy hypothesis.

Table 1: Patient Case Reports (5-7)

Abbreviations: T2DM – type 2 diabetes mellitus; HFpEF – heart failure with preserved ejection fraction; COPD – chronic obstructive pulmonary disease; SGLT2i – sodium-glucose cotransporter 2 inhibitor; IV – intravenous; CK – creatine kinase; MRI – magnetic resonance imaging.

Despite most published cases reporting on empagliflozin-induced myopathy, the FDA Adverse Events Reporting System (FAERS), shows that most reported incidents are associated with dapagliflozin, as shown in Graph 1. It is important to note that while this does present a trend worth further investigating, the surveillance system includes consumer and healthcare professionals’ submissions which may contain incomplete, inaccurate or unverified information. Prevalence cannot be solely determined based on this data due to potential under-reporting and lack of certainty of causation. Additionally, the number of incidents can also be directly correlated to how frequently a drug is prescribed since less incidents might be reported due to infrequency of use (8).

Figure 1. FAERS Data Report

This graph includes data from each SGLT2i’s year of approval (2014, 2014, and 2013, respectively) up to 2024. Data is pooled based on reported incidents under the brand and generic trade names.

While data pertaining to the mechanism by which SGLT2is may potentiate this effect is limited, sarcopenia, the age-related loss of skeletal muscle mass, might play a role. The risk of developing this condition is reported to be 3-fold higher in patients with T2DM versus those without (9). It has been proposed that SGLT2is precipitate sarcopenia via the decreased utilization of glucose by insulin, leading to decreased uptake into the muscles and increased glucagon-mediated proteolysis, creating a catabolic effect. However, findings remain inconclusive due to inconsistent data (10).

Though rare, pharmacists should consider SGLT2i-induced myopathy when evaluating patients with musculoskeletal symptoms. Rhabdomyolysis should be ruled out, and a temporal connection to the patient’s exposure to a drug or illicit substance should be confirmed. Laboratory diagnostics, such as CK or myoglobin, can indicate muscle injury but lack specificity. Muscle imaging via ultrasound and MRI provides information about structural changes and muscle wasting, allowing for a more in-depth assessment (1). In confirmed cases it is imperative that the offending agent be discontinued, and supportive treatment is tailored to presenting symptoms. The current data is insufficient to determine risk factors, however, SGLT2i use in older adults at risk for age-related muscle loss or patients on concomitant myotoxic therapy, such as statins, colchicine, and corticosteroids, should be approached with the necessary precautions and assessments (1). Proactive measures such as baseline labs, outpatient follow-ups, and counseling on side effects can help mitigate the risk of progression into rhabdomyolysis. By staying vigilant, pharmacists can ensure timely intervention and optimal patient care.

1. Janssen L, Allard NAE, Saris CGJ, Keijer J, Hopman MTE, Timmers S. Muscle Toxicity of Drugs: When Drugs Turn Physiology into Pathophysiology. Physiol Rev. 2020;100(2):633-672. doi:10.1152/physrev.00002.2019.

2. Naddaf E, Bhai S, Dimachkie M. Drug-Induced Myopathies. In: UpToDate, Connor RF (Ed), Wolters Kluwer. Accessed on February 21, 2025.

3. Zelniker TA, Braunwald E. Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review [published correction appears in J Am Coll Cardiol. 2020 Sep 22;76(12):1505. doi: 10.1016/j.jacc.2020.08.010.]. J Am Coll Cardiol. 2020;75(4):422-434. doi:10.1016/j.jacc.2019.11.031.

4. Adverse events of SGLT2i: FDA Drug Safety Communication: FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. https://www-fda-gov.proxy.unthsc.edu/drugs/drug-safety-and-availability/fda-revises-labels-sglt2-inhibitors-diabetes-include-warnings-about-too-much-acid-blood-and-serious. Published December 4, 2015. Accessed August 25, 2020.

5. Gao F, Hall S, Bach LA. Myopathy secondary to empagliflozin therapy in type 2 diabetes. Endocrinol Diabetes Metab Case Rep. Published online April 12, 2020. doi:10.1530/EDM-20-0017.

6. Khan S, Broce A. Empagliflozin-induced Myopathy. JCEM Case Rep. 2024;2(12):luae216. Published 2024 Nov 28. doi:10.1210/jcemcr/luae216.

7. Mohapatra, P., Kar, D. M., Rath, K., & Pal, A. (2024). Causality analysis of myopathy secondary to dapagliflozin therapy in type II Diabetes – A case study. Multidisciplinary Science Journal, 7(3), 2025130. https://doi.org/10.31893/multiscience.2025130.

8. U.S. Food and Drug Administration. FDA Adverse Event Reporting System (FAERS) Public Dashboard. Accessed February 21, 2025. https://www.fda.gov/drugs/fdas-adverse-event-reporting-system-faers/fda-adverse-event-reporting-system-faers-public-dashboard.

9. Wu CN, Tien KJ. The Impact of Antidiabetic Agents on Sarcopenia in Type 2 Diabetes: A Literature Review. J Diabetes Res. 2020;2020:9368583. Published 2020 Jul 9. doi:10.1155/2020/9368583.

10. Gupta R, Alcantara R, Popli T, et al. Myopathy Associated With Statins and SGLT2 – A review of Literature. Curr Probl Cardiol. 2021;46(4):100765. doi:10.1016/j.cpcardiol.2020.100765.