Support compounds

SGLT2 Inhibitors (e.g., Canagliflozin)

Updated · 28 sources · Editorial policy

SGLT2 inhibitors are oral prescription drugs that make the kidneys pass glucose into the urine. The class includes canagliflozin (Invokana), dapagliflozin (Farxiga), empagliflozin (Jardiance) and ertugliflozin (Steglatro). They were first approved to lower blood sugar in type 2 diabetes, but large outcome trials showed that several of them also lower the risk of heart failure hospitalization and kidney disease progression, including in people without diabetes.

Because the glucose they flush out carries calories, these drugs cause modest weight loss, which is why they come up in fat-loss discussions. The weight loss in trials is a few kilograms, part of it is lean mass, and the class carries real risks: ketoacidosis that can occur at near-normal blood sugar, genital and urinary infections, and dehydration.

This page summarizes what the FDA labels, the major randomized trials and FDA safety reviews report. It is for education only and is not medical advice.

Property Detail
Drug class Sodium-glucose cotransporter 2 (SGLT2) inhibitors (“gliflozins”)
Main US brands Invokana (2013), Farxiga (2014), Jardiance (2014), Steglatro (2017)
Route Oral tablet, once daily
Labeled doses Canagliflozin 100–300 mg; dapagliflozin 5–10 mg; empagliflozin 10–25 mg; ertugliflozin 5–15 mg
Half-life (labels) Canagliflozin 10.6–13.1 h; others ≈12–17 h
Mechanism Blocks glucose reabsorption in the kidney, so ≈64–100 g of glucose per day is lost in urine
Boxed warning None on current labels (canagliflozin’s amputation boxed warning was removed in 2020)
US status Prescription only; not a controlled substance
WADA status Not named on the 2026 Prohibited List

What it is

SGLT2 is a transporter protein in the proximal tubule of the kidney. It reabsorbs most of the glucose that the kidneys filter out of the blood. Blocking it lowers the “renal threshold” for glucose, the blood sugar level above which glucose spills into the urine (Invokana label). In people with type 2 diabetes, canagliflozin 300 mg lowered that threshold from about 240 mg/dL to about 70–90 mg/dL.

The class traces back to phlorizin, a natural compound found in several fruit trees. It has been used in physiology research for over 150 years because it produces glucose in the urine by blocking sodium-glucose transporters in the kidney and gut (Ehrenkranz et al., Diabetes Metab Res Rev 2005). The modern gliflozins are more selective, orally usable relatives.

Canagliflozin, the agent this entry is named after, has the formula C₂₄H₂₅FO₅S and a molecular weight of 444.5 g/mol (PubChem).

Blocking SGLT2 also sends more sodium to the far end of the kidney tubule. The labels say this is believed to increase tubuloglomerular feedback (a signal that narrows the vessel feeding each filter unit) and lower pressure inside the kidney’s filters. This is the leading explanation for the kidney benefit, and it is why eGFR (estimated glomerular filtration rate, a measure of kidney filtering) dips slightly when the drug is started.

The approved agents compared

Agent (brand) First US approval Tablet strengths Labeled daily dose Main approved uses (current label)
Canagliflozin (Invokana) 2013 100, 300 mg 100 mg; up to 300 mg for glucose control Type 2 diabetes glucose control; lower risk of major cardiovascular events; lower risk of kidney failure in diabetic kidney disease with albuminuria
Dapagliflozin (Farxiga) 2014 5, 10 mg 5–10 mg for glucose control; 10 mg for other uses Type 2 diabetes; heart failure; chronic kidney disease; heart failure risk in type 2 diabetes
Empagliflozin (Jardiance) 2014 10, 25 mg 10 mg; up to 25 mg for glucose control Type 2 diabetes; heart failure; chronic kidney disease; cardiovascular death in type 2 diabetes with heart disease
Ertugliflozin (Steglatro) 2017 5, 15 mg 5 mg; up to 15 mg Type 2 diabetes glucose control only

Sources: the current FDA labels for Invokana, Farxiga, Jardiance and Steglatro. Two newer agents were approved in 2023: bexagliflozin (Brenzavvy) for type 2 diabetes, and sotagliflozin (Inpefa) for heart failure risk reduction.

All four labels state the drugs are not recommended for glucose control in type 1 diabetes, because they raise the risk of diabetic ketoacidosis.

Pharmacokinetics

All four drugs are absorbed quickly, last long enough for once-daily dosing, and are cleared mainly by glucuronidation (attachment of glucuronic acid by UGT enzymes) to inactive metabolites. None relies heavily on CYP450 liver enzymes.

Parameter Canagliflozin Dapagliflozin Empagliflozin Ertugliflozin
Time to peak 1–2 h ≈2 h (fasting) 1.5 h 1 h (fasting)
Oral bioavailability ≈65% 78% Not stated ≈100%
Terminal half-life 10.6 h (100 mg); 13.1 h (300 mg) ≈12.9 h 12.4 h 16.6 h
Main enzymes UGT1A9, UGT2B4 UGT1A9 UGT2B7, 1A3, 1A8, 1A9 UGT1A9, UGT2B7
Urinary glucose loss ≈100 g/day (100 or 300 mg) ≈70 g/day (5 or 10 mg) ≈64 g/day (10 mg); ≈78 g/day (25 mg) Not stated

All values are from the respective FDA labels. A few points matter in practice:

  • The effect outlasts the drug. For canagliflozin, dapagliflozin and empagliflozin, extra glucose in the urine returns toward baseline about 3 days after the last dose. The labels add that postmarketing reports describe ketoacidosis or glucose in the urine lasting more than 6 days, some up to 2 weeks, after stopping.
  • Kidney function sets the effect. Lower kidney filtering means less glucose is lost. With dapagliflozin, 24-hour urinary glucose loss was 42%, 80% and 90% lower in mild, moderate and severe kidney impairment than with normal kidney function. This is why the drugs are not recommended for glucose control below certain eGFR cut-offs.
  • Extra urine. Empagliflozin 25 mg raised 24-hour urine volume by 341 mL on day 1 and 135 mL on day 5.
  • Daily glucose loss in calories. About 100 g of glucose a day corresponds to roughly 400 kcal at 4 kcal per gram. As shown below, actual weight loss is much smaller than this would predict.

Approved medical use

Type 2 diabetes

All four drugs are approved as an add-on to diet and exercise to lower blood sugar in adults with type 2 diabetes. Canagliflozin, dapagliflozin and empagliflozin are also approved from age 10.

In the 26-week canagliflozin monotherapy trial (584 adults with type 2 diabetes), results versus placebo were (Invokana label):

Outcome Placebo Canagliflozin 100 mg Canagliflozin 300 mg
HbA1c change +0.14% −0.77% −1.03%
Reached HbA1c under 7% 21% 45% 62%
Fasting glucose change +8 mg/dL −27 mg/dL −35 mg/dL
Body weight change −0.6% −2.8% −3.9%
Systolic blood pressure vs placebo — −3.7 mmHg −5.4 mmHg

HbA1c is a blood test that reflects average blood sugar over about three months.

Heart failure and chronic kidney disease

Dapagliflozin and empagliflozin are approved for heart failure and chronic kidney disease whether or not the patient has diabetes. Canagliflozin’s kidney indication is limited to people with type 2 diabetes and diabetic kidney disease with albuminuria (protein in the urine) over 300 mg/day. Ertugliflozin is approved only for glucose control.

What the research shows

Cardiovascular outcome trials in type 2 diabetes

Four large placebo-controlled trials tested these drugs in people with type 2 diabetes and heart disease or high cardiovascular risk. “MACE” means major adverse cardiovascular events: cardiovascular death, nonfatal heart attack or nonfatal stroke.

Trial Drug n Follow-up MACE, hazard ratio (95% CI) Heart failure finding
EMPA-REG OUTCOME Empagliflozin 10 or 25 mg 7,020 Median 3.1 years 0.86 (0.74–0.99) Heart failure hospitalization 2.7% vs 4.1%
CANVAS Program Canagliflozin 10,142 Mean 188 weeks 0.86 (0.75–0.97) —
DECLARE-TIMI 58 Dapagliflozin 17,160 Median 4.2 years 0.93 (0.84–1.03), not significant Heart failure hospitalization HR 0.73 (0.61–0.88)
VERTIS CV Ertugliflozin 5 or 15 mg 8,246 Mean 3.5 years 0.97 (0.85–1.11), not significant CV death or heart failure hospitalization HR 0.88, not significant

Sources: Zinman et al., NEJM 2015; Neal et al., NEJM 2017; Wiviott et al., NEJM 2019; Cannon et al., NEJM 2020.

The results were not uniform across the class:

  • EMPA-REG OUTCOME found lower cardiovascular death (3.7% vs 5.9%) and lower death from any cause (5.7% vs 8.3%) with empagliflozin.
  • CANVAS found fewer cardiovascular events with canagliflozin, but about twice the rate of amputation: 6.3 vs 3.4 per 1,000 patient-years (HR 1.97, 95% CI 1.41–2.75), mostly of the toe or metatarsal.
  • DECLARE-TIMI 58 showed no effect on MACE or cardiovascular death, but fewer heart failure hospitalizations.
  • VERTIS CV met its safety goal (no increase in MACE) but showed no significant benefit.

Kidney disease

Trial Drug Population n Primary outcome, HR (95% CI)
CREDENCE Canagliflozin 100 mg Type 2 diabetes with albuminuric kidney disease 4,401 0.70 (0.59–0.82)
DAPA-CKD Dapagliflozin 10 mg Chronic kidney disease, with or without diabetes 4,304 0.61 (0.51–0.72)
EMPA-KIDNEY Empagliflozin 10 mg Chronic kidney disease, with or without diabetes 6,609 0.72 (0.64–0.82)

The primary outcomes were composites of kidney failure, a large sustained fall in eGFR, or death from kidney or cardiovascular causes (Perkovic et al., NEJM 2019; Heerspink et al., NEJM 2020; EMPA-KIDNEY Collaborative Group, NEJM 2023). CREDENCE and DAPA-CKD were both stopped early for benefit. In DAPA-CKD, 19 patients needed to be treated to prevent one primary event, and death from any cause fell from 6.8% to 4.7%.

Heart failure

Trial Drug Population n Primary outcome, HR (95% CI)
DAPA-HF Dapagliflozin 10 mg Ejection fraction 40% or less 4,744 0.74 (0.65–0.85)
EMPEROR-Reduced Empagliflozin 10 mg Ejection fraction 40% or less 3,730 0.75 (0.65–0.86)
EMPEROR-Preserved Empagliflozin 10 mg Ejection fraction over 40% 5,988 0.79 (0.69–0.90)

Ejection fraction is the share of blood the heart pumps out with each beat. In all three trials the benefit was similar in people with and without diabetes (McMurray et al., NEJM 2019; Packer et al., NEJM 2020; Anker et al., NEJM 2021). In EMPEROR-Preserved, the effect came mainly from fewer heart failure hospitalizations.

Weight and body composition

Weight loss is a consistent but modest effect.

  • People with type 2 diabetes. In a 24-week trial of 182 patients on metformin, dapagliflozin 10 mg lowered weight by 2.08 kg more than placebo. DXA scans (dual-energy X-ray absorptiometry) showed fat mass fell by 1.48 kg, so most of the loss was fat (Bolinder et al., JCEM 2012).
  • People without diabetes. In a 12-week trial of 376 overweight or obese adults without diabetes, weight fell by 2.2%, 2.9% and 2.7% with canagliflozin 50, 100 and 300 mg, versus 1.3% with placebo (Bays et al., Obesity 2014). The placebo-adjusted loss was therefore about 0.9–1.6% of body weight.
  • Why less than the calories lost. Using data from a 52-week canagliflozin trial in 153 patients, researchers calculated that people ate about 100 kcal/day more for every kilogram they lost. This appetite response, more than three times larger than the drop in energy expenditure, helps explain why weight loss levels off well below what the urinary calorie loss would predict (Polidori et al., Obesity 2016).

Not all the weight lost is fat. Two meta-analyses of randomized trials found a small loss of lean tissue:

Meta-analysis Trials Weight Fat mass Lean or muscle mass
Pan et al., PLoS One 2022 (type 2 diabetes) 18 (1,430 people) −2.73 kg −1.16 kg Lean mass −0.76 kg (95% CI −1.53 to 0.01); skeletal muscle −1.01 kg (95% CI −1.91 to −0.11)
Jobanputra et al., Diabetes Metab Res Rev 2026 (15 SGLT2 trials, mixed populations) 15 — — Lean mass −1.04 kg (95% CI −1.45 to −0.64)

The second review estimated that lean mass made up about 28% of the weight lost with SGLT2 inhibitors and GLP-1 drugs combined. Lean mass measured by DXA includes water, so part of this may be fluid. No controlled trials have tested SGLT2 inhibitors in resistance-trained people or alongside anabolic steroids.

Side effects and risks

Ketoacidosis, including at normal blood sugar

All four labels warn of diabetic ketoacidosis (DKA), a dangerous build-up of blood acids, and of fatal cases in type 2 diabetes. The labels list these triggers and risk factors (Invokana label):

  • insulin dose reduction or missed insulin doses;
  • reduced calorie intake or a ketogenic diet;
  • acute illness with fever, surgery, or volume depletion (dehydration);
  • alcohol abuse;
  • pancreatic disorders.

The key danger is that blood sugar can be near normal (for example, under 250 mg/dL), so the condition is easy to miss. A 2015 case series described 13 episodes of this “euglycemic” DKA or ketosis in nine people. The lack of high blood sugar delayed recognition by both patients and doctors (Peters et al., Diabetes Care 2015). In DECLARE-TIMI 58, DKA occurred in 0.3% on dapagliflozin vs 0.1% on placebo. The labels advise withholding the drug before surgery or prolonged fasting: at least 3 days for canagliflozin, dapagliflozin and empagliflozin, and at least 4 days for ertugliflozin.

Symptoms include nausea, vomiting, abdominal pain, malaise and shortness of breath. The ketogenic-diet and low-calorie triggers are directly relevant to anyone combining these drugs with aggressive dieting.

Genital and urinary infections, including Fournier’s gangrene

Sugar in the urine favors yeast and bacteria. In the canagliflozin label’s pooled placebo-controlled trials:

Infection Placebo Canagliflozin 100 mg Canagliflozin 300 mg
Female genital yeast infection 2.8% 10.6% 11.6%
Male genital yeast infection (balanitis) 0.7% 4.2% 3.8%

Rarely, the infection becomes Fournier’s gangrene, a necrotizing infection of the genitals and perineum. FDA reviewers found 55 cases with SGLT2 inhibitors between March 2013 and January 2019. All needed surgery, and 3 patients died (Bersoff-Matcha et al., Ann Intern Med 2019). All four labels now warn about it.

Dehydration, low blood pressure and kidney injury

The extra urine can cause volume depletion, low blood pressure on standing, and acute kidney injury, some cases needing dialysis. The labels name people with reduced kidney function, older adults and people on loop diuretics such as furosemide as higher risk. A small, reversible rise in serum creatinine in the first weeks is expected.

Lower limb amputation

In CANVAS and CANVAS-R, amputations were more frequent with canagliflozin (5.9 vs 2.8 and 7.5 vs 4.2 events per 1,000 patient-years). Most involved the toe or midfoot, but some were above or below the knee. FDA added a boxed warning to the Invokana label in July 2017 and removed it in August 2020, keeping the warning in the main label (FDA labels, 2017 and 2020). CREDENCE found no significant difference in amputations. The ertugliflozin label also lists amputation (4.7, 5.7 and 6.0 per 1,000 patient-years for placebo, 5 mg and 15 mg in VERTIS CV).

Hematocrit and red cells

These drugs raise hematocrit (the share of blood made up of red cells):

  • Empagliflozin: median hematocrit rose by 2.8% versus a 1.3% fall with placebo (Jardiance label).
  • Dapagliflozin 10 mg: +2.30% at week 24 versus −0.33% with placebo (Farxiga label).

This matters for anyone also taking testosterone, which raises hematocrit too (see testosterone cypionate). In a nationwide cohort of 53,971 US veterans with type 2 diabetes, men on both an SGLT2 inhibitor and testosterone had higher odds of hematocrit over 54% than those on an SGLT2 inhibitor alone (adjusted OR 3.80, 95% CI 2.27–6.11) or testosterone alone (adjusted OR 2.49, 95% CI 1.51–3.59) (Gosmanov et al., J Endocrinol Invest 2024). This was an observational study and cannot prove cause.

Other label findings

  • Low blood sugar is uncommon on its own but more likely when combined with insulin or sulfonylureas.
  • LDL cholesterol rose by 4.4 mg/dL (100 mg) and 8.2 mg/dL (300 mg) more than placebo with canagliflozin.
  • Bone fractures were more common with canagliflozin in CANVAS, starting as early as 12 weeks. Bone density at the hip fell by 0.9–1.2% more than placebo over 2 years.
  • Serious allergic reactions, including angioedema and anaphylaxis, are the only labeled contraindication.

Interactions

Interacting drug Effect Source
UGT inducers (rifampin, phenytoin, phenobarbital, ritonavir) Lower canagliflozin levels; rifampin cut exposure by about half Invokana label
Insulin or sulfonylureas Higher risk of low blood sugar All labels
Digoxin Canagliflozin raises digoxin exposure Invokana label
Lithium SGLT2 inhibitors may lower lithium levels Invokana label
Urine glucose and 1,5-AG tests Become unreliable for monitoring glucose All labels

In the US, all SGLT2 inhibitors are prescription drugs. None is listed as a controlled substance.

SGLT2 inhibitors are not named on the WADA 2026 Prohibited List. Section S5 bans diuretics and masking agents “and other substances with a similar chemical structure or similar biological effect(s)”. The list does not say whether these glucose-flushing drugs fall under that clause.

No trials have studied SGLT2 inhibitors for fat loss in lean or athletic people. The evidence for weight loss comes from people with diabetes or obesity and shows a loss of a few kilograms, partly lean mass.

Key takeaways

  • They flush glucose into the urine. Blocking SGLT2 in the kidney causes about 64–100 g of glucose a day to be lost in urine, depending on the drug and dose.
  • Proven organ benefits, not just sugar control. Dapagliflozin and empagliflozin lowered heart failure and kidney disease outcomes by roughly 20–40% in large trials, including in people without diabetes.
  • Weight loss is modest. Placebo-adjusted losses were about 2–3 kg in people with diabetes and under 2% of body weight in people without, with appetite partly compensating. In one meta-analysis, lean mass made up about 28% of the loss.
  • Ketoacidosis can hide behind normal blood sugar. Low-carbohydrate or ketogenic diets, calorie restriction, illness, dehydration and alcohol are labeled triggers.
  • Infections and dehydration are common risks. Genital yeast infections are several times more frequent than with placebo, and Fournier’s gangrene, though rare, can be fatal.
  • Hematocrit rises. Combining these drugs with testosterone was linked to higher odds of erythrocytosis in a large observational study.

Sources

  1. Janssen Pharmaceuticals. Invokana (canagliflozin) tablets, prescribing information, revised 06/2026. DailyMed.
  2. Janssen Pharmaceuticals. Invokana prescribing information, NDA 204042 supplement 026 (07/2017, boxed warning added) and supplement 034 (08/2020, boxed warning removed). FDA 2017; FDA 2020.
  3. AstraZeneca. Farxiga (dapagliflozin) tablets, prescribing information. DailyMed.
  4. Boehringer Ingelheim. Jardiance (empagliflozin) tablets, prescribing information. DailyMed.
  5. Merck Sharp & Dohme. Steglatro (ertugliflozin) tablets, prescribing information. DailyMed.
  6. TheracosBio. Brenzavvy (bexagliflozin) tablets, prescribing information. DailyMed.
  7. Lexicon Pharmaceuticals. Inpefa (sotagliflozin) tablets, prescribing information. DailyMed.
  8. National Center for Biotechnology Information. Canagliflozin, PubChem CID 24812758. PubChem.
  9. Ehrenkranz JR, Lewis NG, Kahn CR, Roth J. Phlorizin: a review. Diabetes Metab Res Rev. 2005;21(1):31–38. PubMed.
  10. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128. PubMed.
  11. 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. PubMed.
  12. 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. PubMed.
  13. Cannon CP, Pratley R, Dagogo-Jack S, et al. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N Engl J Med. 2020;383(15):1425–1435. PubMed.
  14. 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. PubMed.
  15. 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. PubMed.
  16. The EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, et al. Empagliflozin in patients with chronic kidney disease. N Engl J Med. 2023;388(2):117–127. PubMed.
  17. 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. PubMed.
  18. 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. PubMed.
  19. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451–1461. PubMed.
  20. Bolinder J, Ljunggren Ö, Kullberg J, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97(3):1020–1031. PubMed.
  21. Bays HE, Weinstein R, Law G, Canovatchel W. Canagliflozin: effects in overweight and obese subjects without diabetes mellitus. Obesity (Silver Spring). 2014;22(4):1042–1049. PubMed.
  22. Polidori D, Sanghvi A, Seeley RJ, Hall KD. How strongly does appetite counter weight loss? Quantification of the feedback control of human energy intake. Obesity (Silver Spring). 2016;24(11):2289–2295. PubMed.
  23. Pan R, Zhang Y, Wang R, et al. Effect of SGLT-2 inhibitors on body composition in patients with type 2 diabetes mellitus: a meta-analysis of randomized controlled trials. PLoS One. 2022;17(12):e0279889. PubMed.
  24. Jobanputra R, Sargeant JA, Plekhanova T, et al. The effects of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors on lean body mass in humans: a systematic review and meta-analysis of randomised controlled trials. Diabetes Metab Res Rev. 2026;42(5):e70194. PubMed.
  25. Peters AL, Buschur EO, Buse JB, et al. Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care. 2015;38(9):1687–1693. PubMed.
  26. Bersoff-Matcha SJ, Chamberlain C, Cao C, Kortepeter C, Chong WH. Fournier gangrene associated with sodium-glucose cotransporter-2 inhibitors: a review of spontaneous postmarketing cases. Ann Intern Med. 2019;170(11):764–769. PubMed.
  27. Gosmanov AR, Gemoets DE, Schumacher KA. Increased risk of erythrocytosis in men with type 2 diabetes treated with combined sodium-glucose cotransporter-2 inhibitor and testosterone replacement therapy. J Endocrinol Invest. 2024;47(10):2615–2621. PubMed.
  28. World Anti-Doping Agency. World Anti-Doping Code International Standard: Prohibited List 2026. WADA 2026 Prohibited List.