Review

Managing the side effects of sodium-glucose cotransporter-2 inhibitors

Nandan Kodur, BS, Betemariam Sharew, BA, M. Cecilia Lansang, MD, MPH and W. H. Wilson Tang, MD
Cleveland Clinic Journal of Medicine August 2025, 92 (8) 503-511; DOI: https://doi.org/10.3949/ccjm.92a.24071

ABSTRACT

Although sodium-glucose cotransporter-2 (SGLT2) inhibitors are widely used because of their exceptional cardiovascular and renal benefits, their side effects and corresponding management strategies have not been well characterized to date. The latest evidence suggests that class effects of SGLT2 inhibitors include volume depletion, genital fungal infections, and euglycemic diabetic ketoacidosis, while medication-specific side effects include urinary tract infections with dapagliflozin and potential increased risk of amputations with canagliflozin. Management strategies include close monitoring, adjusting medication dosages, and temporarily holding SGLT2 inhibitors when appropriate.

KEY POINTS

  • Class effects of SGLT2 inhibitors include volume depletion, genital fungal infections, and euglycemic diabetic ketoacidosis. Medication-specific side effects include urinary tract infections and a potential increased risk for amputations, which are associated with dapagliflozin and canagliflozin, respectively.

  • When SGLT2 inhibitors are combined with antihypertensive medications (especially diuretics) or glucose-lowering medications (especially insulin or insulin secretagogues), the dosages of these other medications may need to be lowered to prevent hypotension and hypoglycemia, respectively.

  • Managing side effects of SGLT2 inhibitors involves treating the specific side effect and temporarily discontinuing the medication when appropriate, with restarting of the medication only after careful consideration of the potential inciting trigger, likelihood of recurrence, and overall risk vs benefit.

Sodium-glucose cotransporter-2 (sglt2) inhibitors are glucose-lowering drugs that promote glucosuria by preventing renal glucose reabsorption in the proximal convoluted tubule.1 Over the past decade, multiple large randomized controlled trials have demonstrated the safety and remarkable life-saving benefits of SGLT2 inhibitors in both patients with and without diabetes. Indeed, because of the widespread cardiovascular and renal benefits of these medications, their indications have recently expanded to include not only diabetes but also heart failure and chronic kidney disease.1 Currently available SGLT2 inhibitors include empagliflozin, dapagliflozin, canagliflozin, sotagliflozin, and ertugliflozin.

Although the benefits of SGLT2 inhibitors are well characterized, their side effects and corresponding management strategies have been less well defined to date. Side effects ascribed to SGLT2 inhibitors include volume depletion, hypotension, acute kidney injury, genitourinary symptoms, euglycemic diabetic ketoacidosis, bone fractures, amputations, and hypoglycemia.2 However, recent evidence suggests that SGLT2 inhibitors may not in fact cause many of these side effects.

Here, we examine the latest evidence and conclude whether there is robust evidence to support each purported side effect of SGLT2 inhibitors, both when these medications are considered as a class and, when appropriate, as individual agents. For the side effects with robust evidence, we offer strategies for preventing and managing them.

VOLUME DEPLETION OR DEHYDRATION

Volume depletion is a common concern in patients on SGLT2 inhibitors, owing to natriuresis and concomitant water loss. Despite the potential risk of volume depletion or dehydration, there does not appear to be an increased risk of nephrolithiasis. On the contrary, recent findings suggest that treatment with an SGLT2 inhibitor may in fact be associated with decreased risk of kidney stones.3

Volume depletion or dehydration: Recommendations

Most cases of volume depletion are mild and can be prevented by taking proper precautions, such as by down-titrating diuretic medications as appropriate and counseling patients to maintain adequate hydration and electrolyte intake. Of note, patients with chronic heart failure who are on optimal guideline-directed medical therapy (which includes an SGLT2 inhibitor) and who have no congestive signs or symptoms along with no use of loop diuretics can be encouraged to maintain normal hydration (1.5–2.5 L of fluid intake per day), given recent evidence suggesting that fluid restriction may not be necessary or beneficial for many of these patients.4

Clinicians should also closely monitor serum osmolality and electrolyte levels in patients at high risk of severe volume depletion or dehydration due to physiologic or lifestyle factors (eg, pregnancy, vomiting, persistent diarrhea, gastroenteritis, fasting, low-carbohydrate or ketogenic diet). For patients who become severely dehydrated, it may be appropriate to temporarily withhold the SGLT2 inhibitor.

HYPOTENSION

Because SGLT2 inhibitors induce natriuresis and concomitant diuresis, there has been concern that they may precipitate hypotension in some patients. However, there are little to no data to support this concern.

A meta-analysis of 5 randomized controlled trials that included 10,050 patients with heart failure with reduced ejection fraction found that use of SGLT2 inhibitors was not associated with increased risk of volume depletion or hypotension.5 Indeed, an analysis of data from EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction) found that although empagliflozin slightly decreased blood pressure in patients with a baseline systolic blood pressure higher than 130 mm Hg, it did not increase the risk of symptomatic or asymptomatic hypotension compared with placebo.6

Although these findings should alleviate concerns regarding hypotension, it may nonetheless be appropriate to down-titrate antihypertensive medications as needed—particularly diuretics—when coadministered with SGLT2 inhibitors in patients at risk of hypotension.

ACUTE KIDNEY INJURY

Acute kidney injury has been raised as a potential concern with use of SGLT2 inhibitors, following reports in the US Food and Drug Administration Adverse Event Report System.7 This concern has been heightened by the observed initial dip in estimated glomerular filtration rate (eGFR) by roughly 3 to 5 mL/min/1.73 m2 when an SGLT2 inhibitor is started. Yet this initial decline in eGFR—which is due to the hemodynamic effects of SGLT2 inhibitors such as increased diuresis and renal tone—is transient and reversible, and thus should not cause concern about acute kidney injury.7 Indeed, recent findings suggest that SGLT2 inhibitors do not increase the risk of acute kidney injury and may in fact decrease the risk.7

A meta-analysis of 4 large randomized controlled trials in 38,723 patients with type 2 diabetes found that 3 different SGLT2 inhibitors—empagliflozin, canagliflozin, and dapagliflozin—reduced the risk of acute kidney injury by 25%.8 Similarly, a second meta-analysis of 30 clinical trials found that SGLT2 inhibitors reduced the risk of acute kidney injury by 25% and the risk of serious events due to acute kidney injury by 36%,9 and a third meta-analysis of more than 100 randomized controlled trials found a 41% reduction in the risk of acute kidney injury.10 These findings are corroborated by a meta-analysis of randomized controlled trials conducted in patients with heart failure with reduced ejection fraction.5 Hence, it appears that SGLT2 inhibitors do not increase the risk of acute kidney injury and, if anything, protect against it.

Acute kidney injury: Recommendations

Despite these promising findings, it is probably appropriate for clinicians to temporarily withhold SGLT2 inhibitors before high-risk procedures (eg, procedures involving contrast dye) or in patients with intrarenal acute kidney injury (eg, acute tubular necrosis), oliguric acute kidney injury, or hospitalization with acute kidney injury and intercurrent illness, as there is a lack of clinical data in these situations.7 There is also a lack of data supporting initiation of SGLT2 inhibitors in patients with an eGFR lower than 20 mL/min/1.73 m2, although an SGLT2 inhibitor can potentially be continued if the eGFR had been 20 mL/min/1.73 m2 or higher when the drug was first started but the eGFR has subsequently dropped to less than 20 mL/min/1.73 m2.11

Aside from these limited circumstances, clinicians can be assured that SGLT2 inhibitors are not likely to precipitate or exacerbate acute kidney injury. As such, when initiating an SGLT2 inhibitor there is often no need to immediately assess renal function by checking serum creatinine and eGFR levels, unless the patient has significant predisposing factors.

GENITOURINARY INFECTIONS

Genitourinary infections, which include genital fungal infections and urinary tract infections, are a notable concern with SGLT2 inhibitors and are thought to be due to glucosuria creating a breeding ground for bacteria.12

Although there have been reports that both types of genitourinary infections might be associated with SGLT2 inhibitors, recent studies implicate these drugs in genital fungal infections only but not in urinary tract infections. Indeed, meta-analyses of dozens of randomized controlled trials in patients with type 2 diabetes mellitus have found that SGLT2 inhibitors increase the risk of genital infections 3 to 5 times relative to placebo or active comparators, but do not increase the risk of urinary tract infections.10,13–15 Moreover, 2 large, propensity score–matched cohort studies found that SGLT2 inhibitors were associated with increased risk of genital infections compared with other second-line diabetes medications—specifically glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors—but were not associated with increased risk of severe or nonsevere urinary tract infections.16,17 However, while SGLT2 inhibitors as a class do not appear to increase the risk of urinary tract infections, dapagliflozin specifically does appear to increase risk.10,14,15

Overall, while urinary tract infections appear to be a medication-specific effect associated with dapagliflozin only, genital fungal infections appear to be a class effect of SGLT2 inhibitors.

Genitourinary infections: Recommendations

To decrease the risk of both genital fungal infections in patients on any SGLT2 inhibitor and of urinary tract infections in patients on dapagliflozin specifically, clinicians should counsel patients on proper genital hygiene (eg, washing the genital area thoroughly after urination), drinking adequate amounts of fluid to avoid urine stasis, and maintaining adequate glycemic control for those with diabetes (Table 1).18 Patients should also be counseled on the early signs of genitourinary infections, especially Fournier gangrene, a rare yet life-threatening necrotizing fasciitis of the genitals and perineum.

View this table:
TABLE 1

Preventing and treating genitourinary infections associated with use of sodium-glucose cotransporter-2 (SGLT2) inhibitors

For patients at high risk of genitourinary infections (eg, women, patients with diabetes), it may be appropriate to temporarily withhold an SGLT2 inhibitor at least a few days before scheduled procedures such as surgery or while a short-term indwelling Foley catheter is being used. Of note, prophylactic treatment with antibiotics or antifungal medications for preventing genitourinary infections is not routinely recommended, even in patients at high risk.18

If, despite precautions, patients develop a genital fungal infection or urinary tract infection, they should be treated with antifungal medications or antibiotics, respectively, and in most cases treatment with an SGLT2 inhibitor may be continued, given the favorable risk-benefit profile.18 That said, in cases of severe genitourinary infection it may be reasonable to temporarily withhold the SGLT2 inhibitor, with the medication being immediately restarted as soon as the infection has resolved.18 It should be noted that some patients may present with symptoms of a genitourinary infection without a confirmed diagnosis, which may stem from volume depletion that can be ameliorated with adequate hydration while maintaining treatment with an SGLT2 inhibitor.

SGLT2 inhibitors are not contraindicated in patients with recurrent genitourinary infections, and when considering whether to permanently discontinue these medications in such patients, clinicians should engage in shared decision-making with the patient to weigh the risks of recurrent infection against the life-saving benefits of these medications.

EUGLYCEMIC DIABETIC KETOACIDOSIS

Euglycemic diabetic ketoacidosis, which is characterized by volume depletion and increased anion gap metabolic acidosis, is a relatively rare yet life-threatening complication associated with use of SGLT2 inhibitors, typically in patients with diabetes.19,20 While the risk of this complication with use of SGLT2 inhibitors is higher in patients with type 1 diabetes, it also occurs in those with type 2 diabetes.19

SGLT2 inhibitors can induce euglycemic diabetic ketoacidosis as follows: glucosuria coupled with a precipitating factor (eg, fasting) results in a physiologic state of starvation along with a concomitant increase in the glucagon-to-insulin ratio, which in turn promotes ketogenesis and ketonemia. Glucosuria also results in diuresis and, in turn, volume depletion, which can impair renal function and thus exacerbate ketonemia.19

Notably, in contrast with the classic form of diabetic ketoacidosis, which presents with moderate to severe hyperglycemia (glucose ≥ 200 mg/dL), euglycemic diabetic ketoacidosis presents with mild hyperglycemia or even normoglycemia (glucose < 200 mg/dL) due to glucosuria. Of note, although use of SGLT2 inhibitors is more commonly associated with euglycemic diabetic ketoacidosis, it can also be associated with classic diabetic ketoacidosis.19

Clinical manifestations of euglycemic diabetic ketoacidosis are similar to those of classic diabetic ketoacidosis and include nonspecific symptoms such as dyspnea, fatigue, malaise, nausea, vomiting, and abdominal pain, as well as more specific signs such as Kussmaul breathing and fruity breath odor. Because of volume depletion and potential dehydration, euglycemic diabetic ketoacidosis can also present with hypotension, tachycardia, and decreased skin turgor, with more severe symptoms including altered mental status, hypovolemic shock, coma, and death. It is important to emphasize that patients with euglycemic diabetic ketoacidosis do not present with moderate or severe hyperglycemia and, therefore, may not present with characteristic symptoms of diabetic ketoacidosis such as polyuria or polydipsia.19

The diagnostic criteria for euglycemic diabetic ketoacidosis include ketonemia (beta-hydroxybutyrate level ≥ 3 mmol/L) with concomitant increased anion gap metabolic acidosis (pH < 7.3) or decreased serum bicarbonate levels (bicarbonate < 18 mmol/L), as well as absence of moderate or severe hyperglycemia (glucose < 200 mg/dL).19

Euglycemic diabetic ketoacidosis: Recommendations

The absence of moderate or severe hyperglycemia may make it difficult for clinicians to detect and diagnose euglycemic diabetic ketoacidosis, so all patients who are on an SGLT2 inhibitor and present with diabetic ketoacidosis–like symptoms—including patients without diabetes—should be screened for euglycemic diabetic ketoacidosis, even if their blood glucose levels are not significantly elevated. There should especially be high clinical suspicion in patients who have risk factors for ketoacidosis (eg, fasting, low-carbohydrate or ketogenic diet, excessive alcohol use, surgery, pregnancy, infection, trauma, major illness, persistent vomiting, gastroparesis, dehydration, and reduced dosage of insulin).21

An initial workup for suspected euglycemic diabetic ketoacidosis should assess levels of blood ketones, bicarbonate, and electrolytes, as well as venous blood gas and anion gap.21 Further testing should also be performed to rule out alternative causes of the patient’s condition (eg, infection).

If an SGLT2 inhibitor is the suspected cause of euglycemic diabetic ketoacidosis, it should be immediately discontinued.21 Next, euglycemic diabetic ketoacidosis should be treated similarly to classic diabetic ketoacidosis, except that a 5% or 10% dextrose solution should be coadministered with intravenous insulin to prevent insulin-induced hypoglycemia (Figure 1).19,21,22

Figure 1
Figure 1

Preventing and managing hypoglycemia and euglycemic diabetic ketoacidosis in patients taking a sodium-glucose cotransporter-2 (SGLT2) inhibitor.

Based on information from references 19, 21, and 22.

Once euglycemic diabetic ketoacidosis has resolved and the patient is ready for discharge, it may be appropriate to temporarily withhold or even permanently discontinue the SGLT2 inhibitor. Recent guidelines from the American Diabetes Association22 recommend that SGLT2 inhibitors should not be used in patients who have experienced an episode of diabetic ketoacidosis. That said, if the underlying risk factors have been adequately addressed, in select cases it may be appropriate for patients and clinicians to discuss restarting treatment, taking into account the potential inciting trigger as well as strategies to mitigate this trigger, likelihood of recurrence, patient’s ability to seek medical assistance promptly, and overall risk-benefit analysis.

To prevent episodes of euglycemic diabetic ketoacidosis, SGLT2 inhibitors should be temporarily discontinued in patients with acute risk factors for ketoacidosis (Figure 1). For example, because fasting increases the risk for ketoacidosis, SGLT2 inhibitors should be temporarily discontinued 3 to 4 days before any scheduled medical or surgical procedure that requires decreased food and liquid intake; in the case of emergent medical procedures, SGLT2 inhibitors should be discontinued immediately.21 This discontinuation should last for a few days following the procedure until food and liquid intake returns to normal. It should be noted, however, that recent evidence has challenged these recommendations, and it remains to be seen whether these recommendations might be amended.23

Temporary discontinuation of SGLT2 inhibitors is also recommended for patients whose plasma insulin levels are fluctuating significantly due to changes in insulin dosage.21 In this vein, a patient’s insulin dosage should not be rapidly lowered while they are on an SGLT2 inhibitor, as this can engender an imbalance in the glucagon-to-insulin ratio that might in turn trigger euglycemic diabetic ketoacidosis. Specifically, a patient’s insulin dosage should not be reduced by more than 10% to 20% of their total dosage at any given time, with the exception of special cases (eg, severe or recurrent hypoglycemia).21

While it may be appropriate to temporarily discontinue SGLT2 inhibitors in the aforementioned cases, with chronic risk factors for ketoacidosis (eg, low-carbohydrate or ketogenic diet, religious fasting such as during Ramadan), it may be more appropriate to continue the SGLT2 inhibitor and to mitigate the risk of euglycemic diabetic ketoacidosis by monitoring the patient closely.

BONE FRACTURES

Bone fractures have been proposed as a potential adverse effect of SGLT2 inhibitors, posited to be mediated by increased activation of fibroblast growth factor 23, which attenuates renal reabsorption of phosphate and synthesis of active vitamin D (1,25-dihydroxyvitamin D).22 Multiple studies provide evidence against this concern, however. A meta-analysis of 27 randomized controlled trials found that SGLT2 inhibitors did not increase the risk of bone fracture compared with placebo in patients with type 2 diabetes,24 which is corroborated by another meta-analysis of more than 100 randomized controlled trials.10 Supporting these findings, a propensity score–matched cohort study of 137,667 Medicare beneficiaries with type 2 diabetes found that SGLT2 inhibitors did not increase the risk of fracture relative to other diabetes medications, namely dipeptidyl peptidase 4 inhibitors and glucagon-like peptide-1 receptor agonists.25 Moreover, although there have been concerns that canagliflozin specifically might be associated with increased fracture risk, the CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) trial26 provides reassuring data that suggest otherwise. Hence, it appears that SGLT2 inhibitors as a class do not increase fracture risk.

AMPUTATIONS

Increased risk of amputation, particularly of the lower limb, has been reported as a rare adverse event associated with use of SGLT2 inhibitors in patients with diabetes, though this does not appear to be a class effect but rather seems to be specifically associated with use of canagliflozin.27–29

The CANVAS (Canagliflozin Cardiovascular Assessment Study) trial27 found that patients with diabetes treated with canagliflozin had roughly double the risk of amputation compared with patients treated with placebo, and a meta-analysis of 15 randomized controlled trials conducted in patients with diabetes concluded that canagliflozin—but no other SGLT2 inhibitor—was associated with slightly increased risk of amputation.28 This is a paradoxical finding given that SGLT2 inhibitors such as canagliflozin improve glycemic control and would therefore not be expected to increase the risk of amputation. Consistent with this line of reasoning, the CREDENCE trial26 found that canagliflozin did not increase the risk of amputation, although it should be noted that the trial investigators temporarily discontinued canagliflozin in patients with any active condition that made them susceptible to amputation. Supporting this null finding, a meta-analysis of 5 randomized controlled trials in 39,067 patients found that canagliflozin was not linked with increased risk of amputation.30

Given these contradictory findings regarding canagliflozin, it remains unclear whether this specific SGLT2 inhibitor might in fact increase the risk of amputation, or whether concerns have been overstated. While the US Food and Drug Administration acknowledges that canagliflozin may slightly increase the risk of amputation, the agency recently removed its boxed warning regarding amputation risk for this medication in response to the latest data from clinical trials, though this risk remains in the Warnings and Precautions section of the package insert.31 Thus, so long as clinicians are aware of this potential complication and regularly examine patients at risk for amputation, they should feel comfortable prescribing canagliflozin in addition to other SGLT2 inhibitors.

HYPOGLYCEMIA

Although hypoglycemia has been raised by some as a possible side effect of SGLT2 inhibitors, the risk is low when these medications are used as monotherapy, presumably because they do not induce insulin secretion.32 When used in combination with insulin or insulin secretagogues (ie, sulfonylureas and meglitinide analogues), however, the risk of hypoglycemia may be increased, potentially necessitating dosage adjustments of all glucose-lowering medications (Figure 1). To avoid the risk of euglycemic diabetic ketoacidosis, the dosage of insulin should be lowered gradually and not by more than 10% to 20% of the total dosage at any given time, except in special cases such as in patients who are experiencing severe or recurrent hypoglycemia.21

INCREASED KNOWLEDGE, INCREASED CONFIDENCE

SGLT2 inhibitors are commonly prescribed owing to their safety and exceptional cardiovascular and renal benefits across a spectrum of patient populations. Fortunately, knowledge of their side effects and corresponding management strategies have increased over the past few years.

The latest evidence indicates that class effects of SGLT2 inhibitors include volume depletion, genital fungal infections, and euglycemic diabetic ketoacidosis, while side effects associated with specific SGLT2 inhibitors include urinary tract infections with use of dapagliflozin and a potential increased risk of amputations with use of canagliflozin (Table 2).26,27,33–42 These side effects can be prevented and managed using the strategies outlined above, including close monitoring, adjusting the medication dosages as needed, and temporarily discontinuing SGLT2 inhibitors when appropriate, especially before medical procedures.

View this table:
TABLE 2

Side effects of sodium-glucose cotransporter-2 inhibitors in select randomized clinical trials

There is little to no evidence that SGLT2 inhibitors cause acute kidney injury or bone fractures. Also, there are little to no data to justify concerns regarding hypotension and hypoglycemia when SGLT2 inhibitors are used as monotherapy, though the dosage of diuretics and insulin or insulin secretagogues might need to be adjusted when these drugs are combined with SGLT2 inhibitors.

Overall, with increased knowledge of the side effects of SGLT2 inhibitors as well as their corresponding management strategies, clinicians can better educate patients and feel more confident prescribing these life-saving medications.

DISCLOSURES

Dr. Lansang has disclosed serving as a research principal investigator in investigator-initiated studies for Abbott and Dexcom and as a research principal investigator for Xeris. Dr. Tang has disclosed consulting for Alexion, Alleviant Medical, BioCardia, Boston Scientific, Bristol-Myers-Squibb, CardiaTec Biosciences, Cardiol Therapeutics, Genomics PLC, Intellia, Kiniksa Pharmaceuticals, Salubris Biotherapeutics, Sequana Medical, WhiteSwell, Zehna Therapeutics, and other activities from which remuneration is received or expected, including Board exam writing/approval committee for American Board of Internal Medicine, Editorship/Authorship for Belvoir Media Group, and Editorship/Authorship for Springer Nature. The other authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.

REFERENCES

  1. ↵
    1. Cowie MR,
    2. Fisher M
    . SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol 2020; 17(12):761–772. doi:10.1038/s41569-020-0406-8
    OpenUrlCrossRefPubMed
  2. ↵
    1. Mascolo A,
    2. Di Napoli R,
    3. Balzano N, et al
    . Safety profile of sodium glucose co-transporter 2 (SGLT2) inhibitors: a brief summary. Front Cardiovasc Med 2022; 9:1010693. doi:10.3389/fcvm.2022.1010693
    OpenUrlCrossRefPubMed
  3. ↵
    1. Paik JM,
    2. Tesfaye H,
    3. Curhan GC,
    4. Zakoul H,
    5. Wexler DJ,
    6. Patorno E
    . Sodium-glucose cotransporter 2 inhibitors and nephrolithiasis risk in patients with type 2 diabetes. JAMA Intern Med 2024; 184(3): 265–274. doi:10.1001/jamainternmed.2023.7660
    OpenUrlCrossRefPubMed
  4. ↵
    1. Mullens W,
    2. Damman K,
    3. Dhont S, et al
    . Dietary sodium and fluid intake in heart failure. A clinical consensus statement of the Heart Failure Association of the ESC. Eur J Heart Fail 2024; 26(4):730–741. doi:10.1002/ejhf.3244
    OpenUrlCrossRefPubMed
  5. ↵
    1. Vukadinovic D,
    2. Abdin A,
    3. Anker SD, et al
    . Side effects and treatment initiation barriers of sodium-glucose cotransporter 2 inhibitors in heart failure: a systematic review and meta-analysis [published correction appears in Eur J Heart Fail 2023; 25(3):444]. Eur J Heart Fail 2022; 24(9):1625–1632. doi:10.1002/ejhf.2584
    OpenUrlCrossRefPubMed
  6. ↵
    1. Böhm M,
    2. Anker SD,
    3. Butler J, et al
    . Empagliflozin improves cardiovascular and renal outcomes in heart failure irrespective of systolic blood pressure. J Am Coll Cardiol 2021; 78(13):1337–1348. doi:10.1016/j.jacc.2021.07.049
    OpenUrlCrossRefPubMed
  7. ↵
    1. Sridhar VS,
    2. Tuttle KR,
    3. Cherney DZI
    . We can finally stop worrying about SGLT2 inhibitors and acute kidney injury. Am J Kidney Dis 2020; 76(4):454–456. doi:10.1053/j.ajkd.2020.05.014
    OpenUrlCrossRefPubMed
  8. ↵
    1. Neuen BL,
    2. Young T,
    3. Heerspink HJL, et al
    . SGLT2 inhibitors for the prevention of kidney failure in patients with type 2 diabetes: a systematic review and meta-analysis [published correction appears in Lancet Diabetes Endocrinol 2019; 7(12):e23]. Lancet Diabetes Endocrinol 2019; 7(11):845–854. doi:10.1016/S2213-8587(19)30256-6
    OpenUrlCrossRefPubMed
  9. ↵
    1. Menne J,
    2. Dumann E,
    3. Haller H,
    4. Schmidt BMW
    . Acute kidney injury and adverse renal events in patients receiving SGLT2-inhibitors: a systematic review and meta-analysis. PLoS Med 2019; 16(12):e1002983. doi:10.1371/journal.pmed.1002983
    OpenUrlCrossRefPubMed
  10. ↵
    1. Donnan JR,
    2. Grandy CA,
    3. Chibrikov E, et al
    . Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a systematic review and meta-analysis. BMJ Open 2019; 9(1):e022577. doi:10.1136/bmjopen-2018-022577
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. de Boer IH,
    2. Khunti K,
    3. Sadusky T, et al
    . Diabetes management in chronic kidney disease: a consensus report by the American Diabetes Association (ADA) and Kidney Disease: Improving Global Outcomes (KDIGO). Kidney Int 2022; 102(5):974–989. doi:10.1016/j.kint.2022.08.012
    OpenUrlCrossRefPubMed
  12. ↵
    1. Wilding J
    . SGLT2 inhibitors and urinary tract infections. Nat Rev Endocrinol 2019; 15(12):687–688. doi:10.1038/s41574-019-0275-6
    OpenUrlCrossRefPubMed
  13. ↵
    1. Chesterman T,
    2. Thynne TR
    . Harms and benefits of sodium-glucose co-transporter 2 inhibitors. Aust Prescr 2020; 43(5):168–171. doi:10.18773/austprescr.2020.049
    OpenUrlCrossRefPubMed
  14. ↵
    1. Liu J,
    2. Li L,
    3. Li S, et al
    . Effects of SGLT2 inhibitors on UTIs and genital infections in type 2 diabetes mellitus: a systematic review and meta-analysis. Sci Rep 2017; 7(1):2824. doi:10.1038/s41598-017-02733-w
    OpenUrlCrossRefPubMed
  15. ↵
    1. Puckrin R,
    2. Saltiel MP,
    3. Reynier P,
    4. Azoulay L,
    5. Yu OHY,
    6. Filion KB
    . SGLT-2 inhibitors and the risk of infections: a systematic review and meta-analysis of randomized controlled trials. Acta Diabetol 2018; 55(5):503–514. doi:10.1007/s00592-018-1116-0
    OpenUrlCrossRefPubMed
  16. ↵
    1. Dave CV,
    2. Schneeweiss S,
    3. Patorno E
    . Comparative risk of genital infections associated with sodium-glucose co-transporter-2 inhibitors. Diabetes Obes Metab 2019; 21(2):434–438. doi:10.1111/dom.13531
    OpenUrlCrossRefPubMed
  17. ↵
    1. Dave CV,
    2. Schneeweiss S,
    3. Kim D,
    4. Fralick M,
    5. Tong A,
    6. Patorno E
    . Sodium-glucose cotransporter-2 inhibitors and the risk for severe urinary tract infections: a population-based cohort study. Ann Intern Med 2019; 171(4):248–256. doi:10.7326/M18-3136
    OpenUrlCrossRefPubMed
  18. ↵
    1. Kittipibul V,
    2. Cox ZL,
    3. Chesdachai S,
    4. Fiuzat M,
    5. Lindenfeld J,
    6. Mentz RJ
    . Genitourinary tract infections in patients taking SGLT2 inhibitors: JACC review topic of the week. J Am Coll Cardiol 2024; 83(16): 1568–1578. doi:10.1016/j.jacc.2024.01.040
    OpenUrlCrossRefPubMed
  19. ↵
    1. Umpierrez GE,
    2. Davis GM,
    3. ElSayed NA, et al
    . Hyperglycemic crises in adults with diabetes: a consensus report. Diabetes Care 2024; 47(8):1257–1275. doi:10.2337/dci24-0032
    OpenUrlCrossRefPubMed
  20. ↵
    1. Mehta AE,
    2. Zimmerman R
    . Classic diabetic ketoacidosis and the euglycemic variant: Something old, something new. Cleve Clin J Med 2025; 92(1):33–39. doi:10.3949/ccjm.92a.24075
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Danne T,
    2. Garg S,
    3. 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
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. American Diabetes Association Professional Practice Committee
    . 9. Pharmacologic approaches to glycemic treatment: standards of care in diabetes—2025. Diabetes Care 2025; 48(suppl 1):S181–S206. doi:10.2337/dc25-S009
    OpenUrlCrossRefPubMed
  23. ↵
    1. Dixit AA,
    2. Bateman BT,
    3. Hawn MT,
    4. Odden MC,
    5. Sun EC
    . Preoperative SGLT2 inhibitor use and postoperative diabetic ketoacidosis. JAMA Surg 2025; 160(4):423–430. doi:10.1001/jamasurg.2024.7082
    OpenUrlCrossRefPubMed
  24. ↵
    1. Li X,
    2. Li T,
    3. Cheng Y, et al
    . Effects of SGLT2 inhibitors on fractures and bone mineral density in type 2 diabetes: an updated meta-analysis. Diabetes Metab Res Rev 2019; 35(7):e3170. doi:10.1002/dmrr.3170
    OpenUrlCrossRefPubMed
  25. ↵
    1. Zhuo M,
    2. Hawley CE,
    3. Paik JM, et al
    . Association of sodium-glucose cotransporter-2 inhibitors with fracture risk in older adults with type 2 diabetes. JAMA Netw Open 2021; 4(10):e2130762. doi:10.1001/jamanetworkopen.2021.30762
    OpenUrlCrossRef
  26. ↵
    1. Perkovic V,
    2. Jardine MJ,
    3. Neal B, et al
    . Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med 2019; 380(24):2295–2306. doi:10.1056/NEJMoa1811744
    OpenUrlCrossRefPubMed
  27. ↵
    1. Neal B,
    2. Perkovic V,
    3. Mahaffey KW, et al
    . Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017; 377(7):644–657. doi:10.1056/NEJMoa1611925
    OpenUrlCrossRefPubMed
  28. ↵
    1. Lin C,
    2. Zhu X,
    3. Cai X, et al
    . SGLT2 inhibitors and lower limb complications: an updated meta-analysis [published correction appears in Cardiovasc Diabetol 2021; 20(1):119]. Cardiovasc Diabetol 2021; 20(1):91. doi:10.1186/s12933-021-01276-9
    OpenUrlCrossRefPubMed
  29. ↵
    1. Heyward J,
    2. Mansour O,
    3. Olson L,
    4. Singh S,
    5. Alexander GC
    . Association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and lower extremity amputation: a systematic review and meta-analysis. PLoS One 2020; 15(6):e0234065. doi:10.1371/journal.pone.0234065
    OpenUrlCrossRefPubMed
  30. ↵
    1. Miyashita S,
    2. Kuno T,
    3. Takagi H, et al
    . Risk of amputation associated with sodium-glucose co-transporter 2 inhibitors: a meta-analysis of five randomized controlled trials. Diabetes Res Clin Pract 2020; 163:108136. doi:10.1016/j.diabres.2020.108136
    OpenUrlCrossRefPubMed
  31. ↵
    1. Janssen Pharmaceuticals
    . Invokana (canagliflozin) package insert. www.accessdata.fda.gov/drugsatfda_docs/label/2024/204042s043lbl.pdf. Accessed July 18, 2025.
  32. ↵
    1. Vasilakou D,
    2. Karagiannis T,
    3. Athanasiadou E, et al
    . Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med 2013; 159(4):262–274. doi:10.7326/0003-4819-159-4-201308200-00007
    OpenUrlCrossRefPubMed
  33. ↵
    1. Zinman B,
    2. Wanner C,
    3. Lachin JM, et al
    . Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015; 373(22):2117–2128. doi:10.1056/NEJMoa1504720
    OpenUrlCrossRefPubMed
    1. Wiviott SD,
    2. Raz I,
    3. Bonaca MP, et al
    . Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019; 380(4):347–357. doi:10.1056/NEJMoa1812389
    OpenUrlCrossRefPubMed
    1. Cannon CP,
    2. Pratley R,
    3. Dagogo-Jack S, et al
    . Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med 2020;383(15):1425–1435. doi:10.1056/NEJMoa2004967
    OpenUrlCrossRefPubMed
    1. Bhatt DL,
    2. Szarek M,
    3. Pitt B, et al
    . Sotagliflozin in patients with diabetes and chronic kidney disease. N Engl J Med 2021; 384(2): 129–139. doi:10.1056/NEJMoa2030186
    OpenUrlCrossRefPubMed
    1. McMurray JJV,
    2. Solomon SD,
    3. Inzucchi SE, et al
    . Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381(21):1995–2008. doi:10.1056/NEJMoa1911303
    OpenUrlCrossRefPubMed
    1. Packer M,
    2. Anker SD,
    3. Butler J, et al
    . Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020; 383(15):1413–1424. doi:10.1056/NEJMoa2022190
    OpenUrlCrossRefPubMed
    1. Anker SD,
    2. Butler J,
    3. Filippatos G, et al
    . Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med 2021; 385(16):1451–1461. doi:10.1056/NEJMoa2107038
    OpenUrlCrossRefPubMed
    1. Bhatt DL,
    2. Szarek M,
    3. Steg PG, et al
    . Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2021; 384(2):117–128. doi:10.1056/NEJMoa2030183
    OpenUrlCrossRefPubMed
    1. Heerspink HJL,
    2. Stefánsson BV,
    3. Correa-Rotter R, et al
    . Dapagliflozin in patients with chronic kidney disease. N Engl J Med 2020; 383(15):1436–1446. doi:10.1056/NEJMoa2024816
    OpenUrlCrossRefPubMed
  42. ↵
    1. The EMPA-KIDNEY Collaborative Group,
    2. Herrington WG,
    3. Staplin N, et al
    . Empagliflozin in patients with chronic kidney disease. N Engl J Med 2023; 388(2):117–127. doi:10.1056/NEJMoa2204233
    OpenUrlCrossRefPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools

Jump to section

Subjects