What adverse effects are unique to sodium-glucose co-transporter 2 inhibitors?

Background

Sodium-glucose co-transporter 2 (SGLT2) is found in the proximal renal tubule and its function is to reabsorb filtered glucose from the urine.1,2  The SGLT2 inhibitor(s) (SGLT2i) (canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin) are a class of antihyperglycemic medications that block this glucose reabsorption process, promoting the renal excretion of glucose and thereby resulting in the blood glucose lowering effect.2

Safety issues associated with SGLT2i

Adverse effects that are unique to SGLT2i include volume depletion/hypotension, acute kidney injury, urinary tract infections (UTIs), ketoacidosis, necrotizing fasciitis of the perineum (Fournier’s gangrene), bone fractures, and genital mycotic infections.1,3,4  Table 1 summarizes some of the adverse effects identified in post-marketing surveillance and the safety issues listed in the warnings and precautions section of the prescribing information for SGLT25-8  Most of the safety issues from Table 1 are less common or rare, except for volume depletion/hypotension and genital mycotic infections.4  Additional details on some of these safety issues and adverse reactions are provided below Table 2.

Table 1. Warnings, precautions, and post-marketing adverse effects of SGLT2i.5-8

  Invokana® (canagliflozin)5 Farxiga® (dapagliflozin)6 Jardiance® (empagliflozin)7 Steglatro™ (ertugliflozin)8
Volume depletion/hypotension ✓ ✓ ✓ ✓
Acute kidney injury ✓ ✓ ✓ ✓
Ketoacidosis ✓ ✓ ✓ ✓
Urosepsis and pyelonephritis ✓ ✓ ✓ ✓
Fournier’s gangrene ✓ ✓ ✓ ✓
Genital mycotic infections ✓ ✓ ✓ ✓
Bone fracture ✓      
Lower limb amputation ✓     ✓

Common adverse reactions, defined as an incidence rate of 5% or greater, are included in Table 2.5-8  Female genital mycotic infection is a common adverse reaction for all SGLT2i, occurring at an incidence rate of 5% or greater in pooled clinical studies as reported in the prescribing information for each drug.  Although UTI and increased urination are associated with all SGLT2i, the incidence rates do not meet the definition of common (ie, 5% or greater) for some of the agents.  Pooled clinical studies with ertugliflozin reported UTI at an incidence rate of 4% with the 5 mg dose and 4.1% with the 15 mg dose.8  Additionally, increased urination is only reported at an incidence rate of 5% or greater with canagliflozin per the prescribing information.5  Nasopharyngitis may occur with both dapagliflozin and ertugliflozin; however, a 5% or higher incidence rate only occurred with dapagliflozin.6,8

Table 2. Common adverse reactions of SGLT2i.a,5-8

  Invokana® (canagliflozin)5 Farxiga® (dapagliflozin)6 Jardiance® (empagliflozin)7 Steglatro™ (ertugliflozin)8
Female genital mycotic infection ✓ ✓ ✓ ✓
Urinary tract infection ✓ ✓ ✓  
Increased urination ✓      
Nasopharyngitis   ✓    
a5% or greater incidence

Infections

The SGLT2i agents may cause UTIs and fungal infections due to the increased level of glucose in the urine (ie, glucosuria).1,3,4  While UTIs are common among SGLT2i, rarely do they escalate to pyelonephritis or urosepsis.4  Providers should regularly monitor for signs and symptoms of UTI and treat if needed.  Another common adverse effect is genital mycotic infections, which occur more frequently in females than in males.1,3,4  The risk of developing a genital mycotic infection is higher in patients with a history of genital mycotic infections and uncircumcised males.4  Patients who develop genital mycotic infections while taking SGLT2i respond well to standard antifungal therapy, and cases are usually mild or moderate.  Urinary tract infections and mycotic infections can be prevented with adequate daily water intake and proper personal hygiene.1

Fournier’s gangrene (ie, necrotizing fasciitis of the perineum) is a rare fatal condition caused by bacterial infection around the genital region.1,4  Per the Food and Drug Administration (FDA), 55 cases were reported in patients receiving an SGLT2i from 2013 to 2019.  Careful assessment for necrotizing fasciitis should be taken in patients who present with fever, malaise, pain, tenderness, and/or swelling in the genital area.4-8  If Fournier’s gangrene is suspected, the SGLT2i should be discontinued, and the patient should be promptly hospitalized and treated with broad-spectrum antibiotics and surgical debridement, if needed.

Volume depletion

Glucosuria has an osmotic effect that causes intravascular volume contraction, resulting in volume depletion and related adverse events such as hypotension, syncope, and dehydration.3,4  Patients with renal impairment, elderly patients, patients with low systolic blood pressure, and patients on loop diuretics may be at an increased risk for volume depletion.5-8  The volume status should be assessed and corrected if needed prior to initiating an SGLT2i if one or more of these risk factors are present, and signs and symptoms of hypotension should be monitored during treatment.4-8

Volume depletion is thought to contribute to acute kidney injury.1,4  Kidney function should be monitored before and after initiating patients on an SGLT2i.  Dosing of the SGLT2i varies based on renal impairment; however, most of the SGLT2i drugs are not recommended or are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 30 mL/min/1.73m2.4-8

Electrolyte abnormalities are another potential complication of osmotic diuresis and volume depletion.9,10  Some of the SGLT2i have been associated with minor increases in serum potassium, phosphate, and magnesium levels, with incidences more commonly observed in those with reduced renal function.9-12  Canagliflozin has been associated with increases in serum potassium in patients with moderate renal impairment (ie, eGFR of 45 to 59 mL/min/1.73 m2), especially in patients with an elevated potassium level at baseline and in those taking concurrent medications that increase potassium.5,11  The SGLT2i may also increase phosphate reabsorption in the renal tubule.9  Data has shown serum phosphate elevations in patients with moderate renal impairment taking ertugliflozin, and meta-analyses have also found increases in serum phosphate concentrations with canagliflozin and dapagliflozin.8,11,12  Additionally, the meta-analysis by Tang and colleagues found that SGLT2i (canagliflozin, empagliflozin, dapagliflozin, and ipragliflozin [not available in the United States]) can elevate serum magnesium concentrations by 0.08 to 0.2 mEq/L in patients without chronic kidney disease.9,10,12

Ketoacidosis

Inhibiting SGLT2 increases urinary glucose clearance, leading to decreased plasma glucose, reduced insulin release, and increased glucagon.13  This mechanism results in a shift from glucose utilization to lipolysis and the production of ketone bodies, which may cause a rare and potentially life-threatening adverse event called diabetic ketoacidosis (DKA).13,14  Diabetic ketoacidosis is usually characterized by a high plasma glucose level; however, many cases of SGLT2i-associated ketoacidosis present atypically with normal or mildly increased plasma glucose levels (ie, plasma glucose < 250 mg/dL), known as euglycemic DKA.4,14  The normal or mildly elevated plasma glucose levels associated with euglycemic DKA oftentimes make it difficult for ketoacidosis to be recognized, leading to delayed treatment.  Diabetic ketoacidosis is more commonly associated with type 1 diabetes, and SGLT2i drugs are not recommended for use in this patient population.1,5-8

A meta-analysis found that SGLT2i were associated with an increased risk of DKA in those with type 2 diabetes as compared to either placebo or other antihyperglycemic medications (0.18% vs 0.09%, respectively; Peto odds ratio, 2.13; 95% CI, 1.38 to 3.27).14,15  There are several conditions and factors that may predispose or precipitate DKA (Table 3).5-8,14  Depending on the risk factor or condition, ketones should be monitored and/or the SGLT2i should be avoided or discontinued.14  If the patient has a planned surgery, the SGLT2i should be stopped for at least 3 days prior to surgery if taking canagliflozin, dapagliflozin, or empagliflozin, or at least 4 days prior if taking ertugliflozin.5-8,14,16

Table 3. Risk factors for the development of SGLT2i-associated DKA.a,5-8,14

  • Pregnancy
  • History of DKA
  • LADA
  • Alcohol abuse
  • Use of an insulin pump
  • Reduction in insulin dose
  • Reduced calorie intake
  • Volume depletion/dehydration
  • Acute illness
  • Surgery
  • Pancreatic insulin deficiency
  • Prolonged, strenuous exercise
  • Inability to check ketones
aNot an all-inclusive list
Abbreviations: DKA=diabetic ketoacidosis; LADA=late-onset autoimmune diabetes of adulthood

Patients should be counseled to routinely monitor ketones after starting an SGLT2i regardless of symptoms, particularly within the first few weeks after initiation.14  The FDA issued a warning for patients to immediately stop taking their SGLT2i and to promptly seek medical attention if they experience any symptoms of ketoacidosis including nausea, vomiting, abdominal pain, malaise, excessive thirst, and shortness of breath.14,16  An appropriate treatment for DKA consists of SGLT2i discontinuation, fluid and carbohydrate replacement, and insulin.1,4-8

Bone fractures

Phosphorus reabsorption, weight loss, and increases in parathyroid hormone are possible mechanisms contributing to the risk of bone fractures that may be associated with canagliflozin.2 Additionally, the SGLT2i agents’ volume depletion-related adverse effects (eg, hypotension and syncope) may increase the risk of falls, which provide another possible explanation for the higher incidence and risk for bone fractures observed with canagliflozin.1,3,4  In the CANVAS trial, canagliflozin-treated patients had a significantly higher rate of all fractures compared to the placebo group (15.4 vs 11.9 events per 1000 patient-years, respectively; hazard ratio [HR], 1.26; 95% CI, 1.04 to 1.52; p = 0.02) and a numerically higher rate of low-trauma fractures (11.6 vs 9.2 events per 1000 patient-years, respectively; HR, 1.23; 95% CI, 0.99 to 1.52; p = 0.06).17  However, this increased risk was not replicated in the CREDENCE trial (11.8 vs 12.1 fracture events per 1000 patient-years in the canagliflozin-treated group and the placebo group, respectively; HR, 0.98; 95% CI, 0.70 to 1.37).4,18  Bone fracture is listed as a warning and precaution in the prescribing information for canagliflozin, but not for dapagliflozin, empagliflozin, or ertugliflozin.5-8  However, all SGLT2i drugs could potentially predispose patients to volume-depleted hypotension and increase the risk of falls.1,3-8  

Lower limb amputations

Canagliflozin and ertugliflozin carry a warning and precaution for lower limb amputations.4,5,8 Canagliflozin was associated with a 2-fold increased risk of toe, foot, or leg amputation compared to placebo in the CANVAS trial (6.3 vs 3.4 events per 1000 patient-years, respectively; HR 1.97; 95% CI 1.41 to 2.75; p < 0.001).1,4,17  However, the risk of lower limb amputation was not found to be statistically significant in the CREDENCE trial (12.3 vs 11.2 events per 1000 patient-years in the canagliflozin group and the placebo group, respectively; HR, 1.11; 95% CI, 0.79 to 1.56).18  In 2017, the FDA issued a boxed warning for canagliflozin regarding this amputation risk; however, in August 2020, this boxed warning was removed.19  The risk of lower limb amputation has been downgraded to a warning and precaution in the prescribing information to reflect recent safety data suggesting that the risk may be lower than previously reported.  Ertugliflozin also has lower limb amputation listed as a warning and precaution in the prescribing information based on incidence rates of 0.2% with the 5 mg dose and 0.5% with the 15 mg dose in initial clinical trials; however, the manufacturer notes that a causal relationship has not been confirmed.8   In the VERTIS CV trial, higher rates of amputations were observed in those treated with ertugliflozin 5 mg (2%) and ertugliflozin 15 mg (2.1%) vs the placebo group (1.6%); however, this finding was not statistically significant.20  At this time, more data is needed to determine if lower limb amputation is a class effect.1,4 

A possible explanation for the risk of lower limb amputation includes volume depletion-associated peripheral ischemia, limiting blood supply to the extremities.1,4  Risk factors for lower limb amputations include prior history of amputation, neuropathy, and peripheral vascular disease.1,4,5,8  It is important to counsel the patient to perform routine preventive foot care and to monitor for the following while taking an SGLT2i: sores or ulcers in the lower limbs, new pain or tenderness, and signs and symptoms of infection.4,5,8  The patient should stop taking the SGLT2i if they notice these complications.

Summary

In summary, several adverse reactions and safety issues are unique to the SGLT2i drug class. These risks may be mitigated by preventive self-care, monitoring for the signs and symptoms of complications, and quick response to these complications when they occur.

References

  1. Garofalo C, Borrelli S, Liberti ME, et al. SGLT2 inhibitors: nephroprotective efficacy and side effects. Medicina (Kaunas). 2019;55(6). doi:10.3390/medicina55060268
  2. Triplett CL, Repas T, Alvarez C. Diabetes mellitus. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey ML, eds. Pharmacotherapy: A Pathophysiologic Approach. 10th ed. McGraw-Hill; 2020:chap 74. Accessed March 1, 2021. https://accesspharmacy.mhmedical.com/content.aspx?sectionid=146065891&bookid=1861#146065901.
  3. Halimi S, Vergès B. Adverse effects and safety of SGLT-2 inhibitors. Diabetes Metab. 2014;40(6 Suppl 1):S28-34. doi:10.1016/s1262-3636(14)72693-x.
  4. McGill JB, Subramanian S. Safety of sodium-glucose co-transporter 2 inhibitors. Am J Cardiol. 2019;124 Suppl 1:S45-S52. doi:10.1016/j.amjcard.2019.10.029.
  5. Prescribing information. Janssen Pharmaceuticals Inc; 2020. Accessed February 24, 2021. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3&type=pdf.
  6. Prescribing information. AstraZeneca Pharmaceuticals LP; 2020. Accessed February 24, 2021. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=72ad22ae-efe6-4cd6-a302-98aaee423d69&type=pdf.
  7. Prescribing information. Boehringer Ingelheim Pharmaceuticals Inc; 2020. Accessed February 24, 2021. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=faf3dd6a-9cd0-39c2-0d2e-232cb3f67565&type=pdf.
  8. Prescribing information. Merck Sharp & Dohme Corp; 2020. Accessed February 24, 2021. https://dailymed.nlm.nih.gov/dailymed/getFile.cfm?setid=e6f3e718-bb99-48f1-ab94-b9f0af05fed6&type=pdf.
  9. Cianciolo G, De Pascalis A, Capelli I, et al. Mineral and electrolyte disorders with SGLT2i therapy. JBMR Plus. 2019;3(11):e10242. doi: 10.1002/jbm4.10242.
  10. Filippatos TD, Tsimihodimos V, Liamis G, Elisaf MS. SGLT2 inhibitors-induced electrolyte abnormalities: an analysis of the associated mechanisms. Diabetes Metab Syndr. 2018;12(1):59-63. doi: 10.1016/j.dsx.2017.08.003.
  11. Weir MR, Kline I, Xie J, Edwards R, Usiskin K. Effect of canagliflozin on serum electrolytes in patients with type 2 diabetes in relation to estimated glomerular filtration rate (eGFR). Curr Med Res Opin. 2014;30(9):1759-1768. doi: 10.1185/03007995.2014.919907.
  12. Tang H, Zhang X, Zhang J, et al. Elevated serum magnesium associated with SGLT2 inhibitor use in type 2 diabetes patients: a meta-analysis of randomised controlled trials. 2016;59(12):2546-2551. doi: 10.1007/s00125-016-4101-6.
  13. Rosenstock J, Ferrannini E. Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors. Diabetes Care. 2015;38(9):1638-1642. doi:10.2337/dc15-1380.
  14. Musso G, Saba F, Cassader M, Gambino R. Diabetic ketoacidosis with SGLT2 inhibitors. BMJ. 2020;371:m4147. doi: 10.1136/bmj.m4147.
  15. Liu J, Li L, Li S, et al. Sodium-glucose co-transporter-2 inhibitors and the risk of diabetic ketoacidosis in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Diabetes Obes Metab. 2020;22(9):1619-1627. doi:10.1111/dom.14075.
  16. FDA revises labels of SGLT2 inhibitors for diabetes to include warnings about too much acid in the blood and serious urinary tract infections. U.S. Food and Drug Administration. Updated March 19, 2020. Accessed March 23, 2021. 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. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644-657. doi:10.1056/NEJMoa1611925.
  18. Perkovic V, Jardine MJ, Neal B, et al; CREDENCE Trial Investigators. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306. doi:10.1056/NEJMoa1811744.
  19. FDA removes Boxed Warning about risk of leg and foot amputations for the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). U.S. Food and Drug Administration. Updated September 2, 2020. Accessed March 1, 2021. https://www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed-warning-about-risk-leg-and-foot-amputations-diabetes-medicine-canagliflozin.
  20. Cannon CP, Pratley R, Dagogo-Jack S, et al; VERTIS CV Investigators. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383(15):1425-1435. doi: 10.1056/NEJMoa2004967.


Prepared by:
Khoa Le, PharmD
Clinical Pharmacist, Academic Detailer
University of Illinois Chicago College of Pharmacy

Kaitlin Miles, PharmD, BCPS
Clinical Pharmacist, Academic Detailer
University of Illinois Chicago College of Pharmacy

The information presented is current as of June 2021. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

Posted on Aug. 27, 2021

Last updated on April 18, 2022

Category: Diabetes