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Research · Medication

SGLT2 inhibitors

Meta-analyses of large trials found SGLT2 inhibitors cut hospitalization for heart failure by about a quarter and kidney disease progression by about a third, with or without diabetes. HbA1c fell about 0.7 points. Genital yeast infections rose about fivefold. Ketoacidosis roughly doubled but stayed uncommon. One canagliflozin trial program found more amputations.

Add to Bio HackChecked 2026-11-13
Status
Prescription drugs in the US. Empagliflozin, dapagliflozin and canagliflozin are FDA-approved to improve blood sugar control in type 2 diabetes from age 10. Empagliflozin and dapagliflozin are also approved for heart failure and for chronic kidney disease at risk of progression in adults. Canagliflozin is also approved to reduce major cardiovascular events in adults with type 2 diabetes and cardiovascular disease, and kidney and heart outcomes in diabetic kidney disease. None is approved for type 1 diabetes or weight loss.
Also called
empagliflozin, Jardiance, dapagliflozin, Farxiga, canagliflozin, Invokana, gliflozins, sodium-glucose cotransporter 2 inhibitors, SGLT2i, flozins
Taken for
type 2 diabetes, blood sugar, HbA1c, heart failure, chronic kidney disease, kidney protection, heart attack and stroke prevention, weight loss, blood pressure, gout, type 1 diabetes

Strong several reviews agree · Moderate one review or consistent trials · Limited one or a few small studies · Untested no study in people, listed with what it rests on

Shown to help8

Reported risks13

What people take it for, and what was found

Shown to help8

Strong

Heart failure hospitalization and cardiovascular death

Shown to cut cardiovascular death or heart failure hospitalization by about 23% in adults with heart failure, with or without diabetes.

The numbers and sources
Effect
Across five trials in heart failure, SGLT2 inhibitors lowered the composite of cardiovascular death or hospitalization for heart failure (HR 0.77, 95% CI 0.72 to 0.82), cardiovascular death (HR 0.87, 95% CI 0.79 to 0.95), first hospitalization for heart failure (HR 0.72, 95% CI 0.67 to 0.78) and death from any cause (HR 0.92, 95% CI 0.86 to 0.99). Effects were consistent across ejection fraction [1]. With dapagliflozin in reduced ejection fraction, worsening heart failure or cardiovascular death occurred in 16.3% against 21.2% on placebo over a median 18.2 months (HR 0.74, 95% CI 0.65 to 0.85) [2]. With empagliflozin in preserved ejection fraction, cardiovascular death or heart failure hospitalization occurred in 13.8% against 17.1% over a median 26.2 months (HR 0.79, 95% CI 0.69 to 0.90) [3]. Across 13 large placebo-controlled trials, the risk of cardiovascular death or heart failure hospitalization fell by 23% (RR 0.77, 95% CI 0.74 to 0.81), with similar effects in people with and without diabetes [4].
Population
21,947 participants in five heart failure trials [1]; 4,744 adults with heart failure and reduced ejection fraction [2]; 5,988 adults with heart failure and preserved ejection fraction [3]; 90,409 participants in 13 trials, 82.7% with diabetes [4].
Sources
[1], [2], [3], [4]
Caveats
The heart failure trials tested dapagliflozin, empagliflozin and sotagliflozin. Canagliflozin has no heart failure approval. In the preserved ejection fraction trial the effect was mainly on hospitalization [3]. Both single trials cited were funded by the manufacturers [2][3].
StrongCommon

Kidney disease progression

Shown to cut the risk of kidney disease progression by about 37% in adults with chronic kidney disease, heart failure or type 2 diabetes, with or without diabetes.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
Across 13 trials, allocation to an SGLT2 inhibitor lowered the risk of kidney disease progression by 37% (RR 0.63, 95% CI 0.58 to 0.69), with similar results in people with and without diabetes [4]. In 10 trials, progression occurred at 25.4 against 40.3 events per 1,000 patient-years (HR 0.62, 95% CI 0.57 to 0.68), including at an eGFR below 30 (HR 0.71, 95% CI 0.60 to 0.83), and kidney failure alone fell (HR 0.66, 95% CI 0.58 to 0.75) [5]. With dapagliflozin in chronic kidney disease, the primary kidney and cardiovascular outcome occurred in 9.2% against 14.5% on placebo over a median 2.4 years (HR 0.61, 95% CI 0.51 to 0.72, number needed to treat 19), and death from any cause in 4.7% against 6.8% [6]. With empagliflozin, kidney disease progression or cardiovascular death occurred in 13.1% against 16.9% over a median 2.0 years (HR 0.72, 95% CI 0.64 to 0.82) [7]. With canagliflozin in type 2 diabetes with kidney disease, the primary outcome occurred at 43.2 against 61.2 per 1,000 patient-years (HR 0.70, 95% CI 0.59 to 0.82), and end-stage kidney disease fell (HR 0.68, 95% CI 0.54 to 0.86) [8].
Population
90,409 participants in 13 trials [4]; 70,361 participants in 10 trials, mean age 64.8 [5]; 4,304 adults with chronic kidney disease [6]; 6,609 adults with chronic kidney disease [7]; 4,401 adults with type 2 diabetes and albuminuric kidney disease [8].
Sources
[4], [5], [6], [7], [8]
Caveats
The two meta-analyses come from the same consortium and share trials [4][5]. The band above is the number needed to treat of 19 in one dapagliflozin trial [6]. Two of the kidney trials were stopped early [6][8]. The trials did not enroll people on dialysis.
Strong

Heart attack, stroke and cardiovascular death in type 2 diabetes

Shown to cut major cardiovascular events by about 10% in adults with type 2 diabetes, with the benefit clearest in people with established cardiovascular disease.

The numbers and sources
Effect
Across three cardiovascular outcome trials, SGLT2 inhibitors lowered the composite of heart attack, stroke or cardiovascular death by 11% (HR 0.89, 95% CI 0.83 to 0.96). The benefit was seen in people with established cardiovascular disease (HR 0.86, 95% CI 0.80 to 0.93) and not in people without it (HR 1.00, 95% CI 0.87 to 1.16) [9]. Across six trials the estimate was similar (HR 0.90, 95% CI 0.85 to 0.95), and cardiovascular death fell (HR 0.85, 95% CI 0.78 to 0.93) with significant differences between trials [10]. With empagliflozin the composite occurred in 10.5% against 12.1% on placebo over a median 3.1 years (HR 0.86), cardiovascular death in 3.7% against 5.9% and death from any cause in 5.7% against 8.3%, with no significant difference in heart attack or stroke [11]. With dapagliflozin the composite occurred in 8.8% against 9.4% (HR 0.93, 95% CI 0.84 to 1.03) [12]. With canagliflozin it occurred at 26.9 against 31.5 per 1,000 patient-years (HR 0.86, 95% CI 0.75 to 0.97) [13].
Population
34,322 patients in three trials, 60.2% with established cardiovascular disease [9]; 46,969 patients in six trials, mean age 63.7 [10]; 7,020 adults with type 2 diabetes and cardiovascular disease [11]; 17,160 adults with type 2 diabetes [12]; adults with type 2 diabetes and raised cardiovascular risk, 65.6% with cardiovascular disease [13].
Sources
[9], [10], [11], [12], [13]
Caveats
The dapagliflozin trial did not find a lower rate of the composite [12]. The effect on cardiovascular death differed between drugs (I² 64.3%) [10]. One meta-analysis found the benefit only in people with established disease, and the other found no such difference [9][10].
Strong

Blood sugar in type 2 diabetes

Shown to lower HbA1c by about 0.66 points more than placebo in adults with type 2 diabetes, and about as much as other diabetes drugs.

The numbers and sources
Effect
Against placebo in 45 studies, SGLT2 inhibitors lowered HbA1c by 0.66 percentage points (95% CI 0.58 to 0.73). Against other diabetes drugs in 13 studies HbA1c was 0.06 points lower (95% CI 0.18 lower to 0.05 higher), and the risk of low blood sugar was similar [14]. In a network meta-analysis of trials of at least 24 weeks, canagliflozin, dapagliflozin and empagliflozin each lowered HbA1c and fasting glucose against placebo. Canagliflozin 300 mg lowered HbA1c by 0.2 points (95% CI 0.1 to 0.3) more than dapagliflozin 10 mg or empagliflozin 25 mg [15].
Population
11,232 participants in placebo-controlled studies and 5,175 in active-comparator studies [14]; 23,997 participants in 38 trials [15].
Sources
[14], [15]
Caveats
Most trials in the first review were rated at high risk of bias for missing data [14]. The glucose-lowering effect depends on kidney filtration and shrinks as kidney function falls.
Strong

Body weight

Shown to lower body weight by about 1.3 to 1.9 kg in trials, in adults with type 2 diabetes and in adults with overweight and no diabetes.

The numbers and sources
Effect
In adults with type 2 diabetes, body weight fell by 1.88 kg (95% CI 1.66 to 2.11) across 43 trials [16], and by 1.80 kg (95% CI 0.11 to 3.50) more than on other diabetes drugs [14]. In adults with overweight or obesity and no diabetes, weight fell by 2.32 kg on an SGLT2 inhibitor against 1.01 kg on placebo over 12 weeks or more, a difference of 1.31 kg. Waist circumference and fat mass did not change against placebo [17].
Population
22,528 patients with type 2 diabetes in 43 trials [16]; active-comparator studies in type 2 diabetes [14]; 750 adults without diabetes in 8 trials [17].
Sources
[16], [14], [17]
Caveats
Not an approved use. Heterogeneity was moderate in the largest analysis [16]. The trials in people without diabetes were small.
Strong

Blood pressure

Shown to lower systolic blood pressure by about 2.5 mm Hg and diastolic by about 1.5 mm Hg in adults with type 2 diabetes.

The numbers and sources
Effect
Across 43 trials in type 2 diabetes, systolic blood pressure fell by 2.46 mm Hg (95% CI 2.06 to 2.86) and diastolic by 1.46 mm Hg (95% CI 1.09 to 1.82) [16]. Against other diabetes drugs, systolic pressure fell by 4.45 mm Hg (95% CI 3.18 to 5.73) [14]. All three drugs lowered blood pressure against placebo in a network meta-analysis [15]. In adults without diabetes, blood pressure did not change against placebo [17].
Population
22,528 patients in 43 trials [16]; active-comparator studies [14]; 23,997 participants in 38 trials [15]; 750 adults without diabetes [17].
Sources
[16], [14], [15], [17]
Caveats
Not an approved use. Heterogeneity was moderate [16].
Moderate

Gout

Shown to lower gout events by about 45% against placebo in adults with type 2 diabetes or heart failure, in one meta-analysis of five trials.

The numbers and sources
Effect
Across five randomized trials with 1,052 gout-related events, SGLT2 inhibitors were associated with fewer gout outcomes than placebo (HR 0.55, 95% CI 0.45 to 0.67). The effect was smaller with empagliflozin (HR 0.68, 95% CI 0.57 to 0.81) than in the other trials (HR 0.46, 95% CI 0.39 to 0.55), and was not explained by how far uric acid fell [18].
Population
29,776 patients in five trials, 23,780 with type 2 diabetes [18].
Sources
[18]
Caveats
Not an approved use. Gout was not a primary outcome of the trials, and heterogeneity was moderate (I² 61%) [18].
Moderate

Type 1 diabetes, added to insulin

Shown to lower HbA1c by about 0.38 points when added to insulin in adults with type 1 diabetes, while about doubling the risk of ketoacidosis.

The numbers and sources
Effect
Added to insulin, SGLT2 inhibitors lowered HbA1c by 0.38 points, raised time in range by 8.6 percentage points, and lowered insulin use by 4.7 units a day and body weight by 2.5 kg. The risk of diabetic ketoacidosis rose (RR 2.19, 95% CI 1.16 to 4.17) [19]. The US labels state that the drugs are not for blood sugar control in type 1 diabetes and may raise the risk of ketoacidosis in these patients [20].
Population
Adults with type 1 diabetes in a meta-analysis of 90 studies of two drug classes [19].
Sources
[19], [20]
Caveats
Not an approved use in the US. The review pooled trials with other study designs. See the ketoacidosis block below.

Not shown to help1

Moderate

After a heart attack

Not shown to lower heart failure hospitalization or death after a heart attack in two trials of about 10,500 people.

The numbers and sources
Effect
In people at raised risk of heart failure after a heart attack, a first heart failure hospitalization or death from any cause occurred in 8.2% on empagliflozin and 9.1% on placebo over a median 17.9 months (HR 0.90, 95% CI 0.76 to 1.06). Heart failure hospitalization alone occurred in 3.6% against 4.7% (HR 0.77, 95% CI 0.60 to 0.98) and death in 5.2% against 5.5% [21]. In people with a heart attack and no diabetes or chronic heart failure, cardiovascular death or heart failure hospitalization occurred in 2.5% on dapagliflozin and 2.6% on placebo (HR 0.95, 95% CI 0.64 to 1.40) over about a year [22].
Population
6,522 patients after acute myocardial infarction [21]; 4,017 patients after acute myocardial infarction with impaired heart function and no diabetes [22].
Sources
[21], [22]
Caveats
Not an approved use. The dapagliflozin trial changed its primary analysis during the trial because few events occurred. Its composite of ranked outcomes favored dapagliflozin (win ratio 1.34, 95% CI 1.20 to 1.50), driven by weight and new diabetes [22].

Doses studied

The pooled blood sugar trials on the labels used empagliflozin 10 mg or 25 mg once daily, dapagliflozin 5 mg or 10 mg once daily and canagliflozin 100 mg or 300 mg once daily [20][23][24]. The network meta-analysis compared the same doses [15]. The dapagliflozin trial after heart attack used 10 mg once daily [22]. The canagliflozin kidney trial data on the label are for 100 mg, and the empagliflozin kidney trial data are for 10 mg [24][20].

The dapagliflozin label states that it is likely to be ineffective for blood sugar control at an eGFR below 45, because the effect depends on kidney filtration [23].

Risks

Reported risks9

ModerateVery common

Low blood sugar when taken with insulin or a sulfonylurea

Shown to raise low blood sugar events when added to a sulfonylurea or insulin, to 16.1% against 8.4% on placebo in one empagliflozin trial. Alone, rates matched placebo.

The numbers and sources
How common
Very common: more than 1 in 10 people.
Effect
In empagliflozin trials, a glucose of 70 mg/dL or below was recorded in 0.4% on empagliflozin alone and 0.4% on placebo. Added to metformin and a sulfonylurea it was 16.1% on 10 mg and 11.5% on 25 mg against 8.4% on placebo. Added to basal insulin it was 19.5% and 28.4% against 20.6%. In a trial in people aged 10 to 17, a glucose below 54 mg/dL occurred in 19.2% on empagliflozin against 7.5% on placebo [20]. In a network meta-analysis, canagliflozin raised the odds of hypoglycemia against placebo (ORs 1.4 to 1.6) [15]. In a review of trials against other diabetes drugs, the risk was similar [14].
Population
Adults with type 2 diabetes in 24-week and 18-week placebo-controlled trials, and 157 patients aged 10 to 17 [20]; 23,997 participants in 38 trials [15].
Sources
[20], [15], [14]
Caveats
The band above is for use together with a sulfonylurea or insulin. Severe events needing help were 0% to 1.3% across the adult trials [20].
StrongCommon

Genital yeast infections

Shown to raise genital yeast infections about fivefold, to about 4% to 6% of people against about 1% on placebo, and to about 11% of women on canagliflozin.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
Across trials, genital tract infections were more common on SGLT2 inhibitors than comparators (OR 5.06, 95% CI 3.44 to 7.45) [14], and all three drugs raised the odds by a similar amount (ORs 4 to 6 against placebo) [15]. In pooled empagliflozin trials, genital mycotic infections occurred in 4.1% on 10 mg and 3.7% on 25 mg against 0.9% on placebo. In women the rates were 5.4% and 6.4% against 1.5%, and in men 3.1% and 1.6% against 0.4% [20]. In pooled dapagliflozin trials the rates were 5.7% on 5 mg and 4.8% on 10 mg against 0.9% [23]. On canagliflozin, 10.6% and 11.6% of women had an infection against 2.8% on placebo, and 4.2% and 3.8% of men against 0.7% [24].
Population
Placebo and active-controlled trials in type 2 diabetes [14][15]; 1,976 adults on empagliflozin and 995 on placebo in five trials [20]; a 12-trial dapagliflozin pool [23]; four placebo-controlled canagliflozin trials [24].
Sources
[14], [15], [20], [23], [24]
Caveats
People with a past genital yeast infection had them far more often during the trials (23.1% to 25.0% on dapagliflozin against 10.0% on placebo) [23]. Under 1% stopped treatment over these infections [20][24].
ModerateCommon

Low blood pressure and fluid loss

Shown to cause fluid loss reactions such as low blood pressure and fainting in 2.3% to 3.4% on canagliflozin against 1.5% on comparators, more often with age over 75.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In eight pooled canagliflozin trials, at least one volume depletion reaction occurred in 2.3% on 100 mg and 3.4% on 300 mg against 1.5% on comparators. In people aged 75 and older the rates were 4.9% and 8.7% against 2.6%, and in people on a loop diuretic 3.2% and 8.8% against 4.7%. In the canagliflozin kidney trial, hypotension occurred in 2.8% against 1.5% on placebo [24]. In pooled empagliflozin trials, these reactions were reported by 0.5% on 10 mg and 0.3% on 25 mg against 0.3% on placebo, and the label states that diuretics taken with empagliflozin raised urine volume and may add to fluid loss [20]. In the dapagliflozin heart failure trial, volume depletion events did not differ from placebo [2].
Population
Adults in eight pooled canagliflozin trials and 2,201 on canagliflozin in the kidney trial [24]; 2,971 adults in five empagliflozin trials [20]; 4,744 adults with heart failure [2].
Sources
[24], [20], [2]
Caveats
Rates differed widely between drugs and trial pools, from no excess to about double.
ModerateCommon

Increased urination

Shown to cause more frequent urination in about 3% on empagliflozin against 1% on placebo in pooled trials.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In pooled empagliflozin trials, increased urination was reported by 3.4% on 10 mg and 3.2% on 25 mg against 1.0% on placebo, and thirst by 1.7% and 1.5% against 0%. In a 5-day study, daily urine volume rose by 341 mL on day 1 and 135 mL on day 5 [20].
Population
2,971 adults with type 2 diabetes in five trials [20].
Sources
[20]
Caveats
The figures are for empagliflozin.
ModerateCommon

Higher red blood cell concentration

Shown to raise hematocrit, with 2.7% to 3.5% of people moving above the reference range on empagliflozin against 0.6% on placebo.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In pooled empagliflozin trials, median hematocrit rose by 2.8% on either dose and fell by 1.3% on placebo. Among people who started in the reference range, 2.7% on 10 mg and 3.5% on 25 mg ended above it against 0.6% on placebo [20]. In pooled dapagliflozin trials, a hematocrit above 55% was recorded in 1.3% on 10 mg against 0.4% on placebo by week 24 [23].
Population
Adults with type 2 diabetes in pooled placebo-controlled trials [20][23].
Sources
[20], [23]
Caveats
A laboratory change. The labels do not report clinical events tied to it.
ModerateUncommon

Diabetic ketoacidosis

Shown to about double the risk of diabetic ketoacidosis in type 2 diabetes, to 0.3% against 0.1% on placebo in the largest trial.

The numbers and sources
How common
Uncommon: between 1 in 1,000 and 1 in 100 people.
Effect
Across 22 trials in type 2 diabetes, SGLT2 inhibitors raised the risk of diabetic ketoacidosis (RR 2.32, 95% CI 1.64 to 3.27). The rise was seen in chronic kidney disease trials (RR 2.70) and cardiovascular risk trials (RR 2.46) and was not significant in heart failure trials (RR 1.23, 95% CI 0.51 to 2.96) [26]. In the dapagliflozin cardiovascular trial, ketoacidosis occurred in 0.3% against 0.1% on placebo, 27 of 8,574 people against 12 of 8,569 [12][23]. In type 1 diabetes the risk about doubled (RR 2.19, 95% CI 1.16 to 4.17) [19]. The labels warn that blood glucose at presentation may be below 250 mg/dL, and report fatal cases after marketing [20][23].
Population
80,235 patients with type 2 diabetes in 22 trials [26]; 17,160 adults in one trial [12]; adults with type 1 diabetes [19].
Sources
[26], [12], [23], [19], [20]
Caveats
The rise was not seen in trials whose participants had an HbA1c of 7.9% or below (RR 1.05, 95% CI 0.49 to 2.26) [26].
LimitedHow often is not known

Fournier's gangrene

Case reports: FDA identified 55 cases of a necrotizing infection of the genital area in people on SGLT2 inhibitors over six years, with no rate.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
FDA staff identified 55 cases of Fournier gangrene in people taking SGLT2 inhibitors between March 2013 and January 2019, in 39 men and 16 women aged 33 to 87. All had surgical debridement, and three died. For comparison, FDA identified 19 cases with other diabetes drugs between 1984 and January 2019 [30]. The labels warn of necrotizing fasciitis of the perineum and describe it as rare and life-threatening [23].
Population
Spontaneous postmarketing reports to FDA [30].
Sources
[30], [23]
Caveats
The authors state that spontaneous reports cannot establish cause or incidence [30].
ModerateHow often is not known

LDL cholesterol rise

Shown to raise LDL cholesterol by a few percent in blood sugar trials, about 4.5% to 8.0% more than placebo on canagliflozin.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
In pooled canagliflozin trials, LDL cholesterol rose against placebo by 4.4 mg/dL (4.5%) on 100 mg and 8.2 mg/dL (8.0%) on 300 mg [24]. In empagliflozin trials it rose by 4.6% on 10 mg and 6.5% on 25 mg against 2.3% on placebo [20]. In dapagliflozin trials it rose by 2.9% on 10 mg against a fall of 1.0% on placebo at 24 weeks. After 4 years in the dapagliflozin cardiovascular trial, LDL cholesterol had fallen by 2.5 mg/dL on dapagliflozin and 4.4 mg/dL on placebo [23]. In a network meta-analysis, canagliflozin 300 mg raised LDL cholesterol by 0.13 to 0.15 mmol/L more than the other two drugs [15].
Population
Adults with type 2 diabetes in pooled placebo-controlled trials [24][20][23]; 23,997 participants in 38 trials [15].
Sources
[24], [20], [23], [15]
Caveats
Mean changes, with no count of people affected. The cardiovascular outcome trials above measured events in the same drugs [9][10].
LimitedHow often is not known

Lithium levels

The label warns that an SGLT2 inhibitor taken with lithium may lower lithium levels in the blood. It gives no rate.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The empagliflozin label states that use of an SGLT2 inhibitor with lithium may decrease serum lithium concentrations [20].
Population
A class statement in labeling, with no study counts [20].
Sources
[20]
Caveats
The label gives no numbers.

Mixed results4

ModerateCommon

Urinary tract infections

Mixed results: an early review found more urinary tract infections, while a 2026 trial-level meta-analysis found no significant rise in any or serious infections.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
An early meta-analysis found urinary tract infections more common on SGLT2 inhibitors (OR 1.42, 95% CI 1.06 to 1.90) [14]. A 2026 meta-analysis of outcome trials found a pooled RR of 1.14 for any urinary tract infection (95% CI 0.99 to 1.32) and 0.99 for serious or complicated infection (95% CI 0.78 to 1.27) [25]. In pooled empagliflozin trials, urinary tract infection was reported by 9.3% on 10 mg and 7.6% on 25 mg against 7.6% on placebo. The labels list urosepsis and kidney infection among postmarketing reports [20].
Population
Trials in type 2 diabetes [14]; 62,542 participants in 11 trials across type 2 diabetes, heart failure and chronic kidney disease [25]; 2,971 adults in five empagliflozin trials [20].
Sources
[14], [25], [20]
Caveats
Heterogeneity was substantial in the 2026 analysis (I² 76.0%) [25]. Among people aged 75 and over, rates were higher in every group including placebo [20].
ModerateCommon

Leg and foot amputation, a former FDA boxed warning on canagliflozin

Mixed results: one canagliflozin trial program found amputations in 3.3% against 1.5% on placebo, while a later canagliflozin trial and pooled trials of other drugs found no clear rise.

The numbers and sources
How common
Common: between 1 in 100 and 1 in 10 people.
Effect
In the CANVAS program, amputation occurred at 6.3 against 3.4 participants per 1,000 patient-years (HR 1.97, 95% CI 1.41 to 2.75), mostly at the toe or metatarsal [13]. On the label, 3.3% of people on canagliflozin and 1.5% on placebo had an amputation in CANVAS, and 1.5% against 0.9% in CANVAS-R [24]. FDA required a boxed warning in 2017 and removed it in 2020, stating that the risk, while still increased with canagliflozin, is lower than previously described [27]. In the canagliflozin kidney trial, amputation rates did not differ significantly (12.3 against 11.2 events per 1,000 patient-years) [8][24]. Pooling seven randomized trials of the class, the association was not significant with a random effects model (RR 1.28, 95% CI 0.93 to 1.76), was significant for canagliflozin alone (RR 1.59, 95% CI 1.26 to 2.01), and was not significant for dapagliflozin or empagliflozin [28]. A network meta-analysis found raised odds for the class (OR 1.2, 95% CI 1.1 to 1.3) and for canagliflozin (OR 1.6, 95% CI 1.1 to 2.4) [29]. Across four empagliflozin outcome trials the rate was 5.0 against 4.3 events per 1,000 patient-years (HR 1.05, 95% CI 0.81 to 1.36) [20].
Population
Adults with type 2 diabetes and raised cardiovascular risk followed an average of 5.7 years in CANVAS and 2.1 years in CANVAS-R [13][24]; 4,401 adults in the kidney trial [8]; 42,453 participants in seven trials with events [28]; 96,522 participants in 36 studies [29].
Sources
[13], [24], [27], [8], [28], [29], [20]
Caveats
The band above is the share with an amputation on canagliflozin in CANVAS. There is no boxed warning on the current labels. Heterogeneity between trials was substantial (I² 62%) [28].
ModerateHow often is not known

Early drop in kidney filtration and acute kidney injury

Mixed results: the labels report a small drop in eGFR in the first weeks and kidney injury reports after marketing, while pooled trials found 23% fewer acute kidney injuries.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
The empagliflozin label states that starting treatment raises serum creatinine and lowers eGFR within weeks, then stabilizes. In its cardiovascular trial the change generally did not exceed 0.1 mg/dL and 9.0 mL/min/1.73 m² at week 4, and reversed after stopping. Acute kidney injury is listed among postmarketing reports [20]. Across 13 placebo-controlled trials, allocation to an SGLT2 inhibitor lowered the risk of acute kidney injury by 23% (RR 0.77, 95% CI 0.70 to 0.84) [4]. In the dapagliflozin heart failure trial, kidney adverse events did not differ from placebo [2].
Population
Adults in empagliflozin trials [20]; 90,409 participants in 13 trials [4]; 4,744 adults with heart failure [2].
Sources
[20], [4], [2]
Caveats
The label gives no share of people for the early eGFR drop. Postmarketing reports have no denominator.
ModerateHow often is not known

Bone fractures

Mixed results: one canagliflozin trial found more fractures than placebo, while a later canagliflozin trial found no difference and a pooled analysis found a small rise with dapagliflozin.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
In the CANVAS trial, adjudicated fractures occurred at 1.59 and 1.79 events per 100 patient-years on canagliflozin 100 mg and 300 mg against 1.09 on placebo. The imbalance appeared within 26 weeks, and fractures were more often low trauma [24]. In the canagliflozin kidney trial, fracture rates did not differ significantly from placebo [8]. In a network meta-analysis of 66 studies, dapagliflozin was associated with fracture (OR 1.1, 95% CI 1.0 to 1.2) [29].
Population
Adults with type 2 diabetes and raised cardiovascular risk [24]; 4,401 adults with type 2 diabetes and kidney disease [8]; 102,862 participants in 66 studies [29].
Sources
[24], [8], [29]
Caveats
The sources give rates per patient-years, not the share of people.

Possible, not studied in people1

UntestedHow often is not known

Pregnancy

Not studied in people. Animal studies found reversible kidney changes in young rats exposed during the period matching the second and third trimesters.

No study in people. This rests on animal studies.

The numbers and sources
How common
How often is not known: the sources give no rate.
Effect
In juvenile rats, empagliflozin at about 13 times the maximum clinical dose caused increased kidney weights and dilated kidney tubules and pelvis, which were not seen after a 13-week recovery period. Doses given to rats and rabbits during the period matching the first trimester did not cause developmental harm at up to 48 and 128 times the clinical dose. On this basis the label advises against use in the second and third trimesters [20].
Population
Rats and rabbits [20].
Sources
[20]
Caveats
Animal doses were far above human doses, and no study in pregnant women was sourced.

Claims tested and not found

  1. That SGLT2 inhibitors prevent heart attack and stroke in people with diabetes and no cardiovascular disease. In people without established cardiovascular disease, major cardiovascular events did not differ from placebo (HR 1.00, 95% CI 0.87 to 1.16) [9].
  2. That starting one after a heart attack lowers death or heart failure hospitalization. Two trials found no significant difference from placebo in that outcome [21][22].
  3. That SGLT2 inhibitors raise serious urinary tract infections. Across 7 trials with 34,396 participants, serious or complicated urinary infection did not differ from placebo (RR 0.99, 95% CI 0.78 to 1.27) [25].
  4. That SGLT2 inhibitors damage the kidneys. Across 13 trials, acute kidney injury was 23% less frequent than on placebo (RR 0.77, 95% CI 0.70 to 0.84) [4].
  5. That the amputation finding applies to every drug in the class. Pooled randomized trials of dapagliflozin and of empagliflozin did not show a significantly raised risk [28], and across four empagliflozin outcome trials the hazard ratio was 1.05 (95% CI 0.81 to 1.36) [20].
  6. That SGLT2 inhibitors reduce body fat in people without diabetes. Across 8 trials, weight fell by 1.31 kg more than placebo, while fat mass and waist circumference did not change [17].

Sources

  1. Vaduganathan M, Docherty KF, Claggett BL, et al. SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials. The Lancet. 2022. https://doi.org/10.1016/S0140-6736(22)01429-5
  2. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. New England Journal of Medicine. 2019. https://doi.org/10.1056/NEJMoa1911303
  3. Anker SD, Butler J, Filippatos G, et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. New England Journal of Medicine. 2021. https://doi.org/10.1056/NEJMoa2107038
  4. 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. The Lancet. 2022. https://doi.org/10.1016/S0140-6736(22)02074-8
  5. Neuen BL, Fletcher RA, Anker SD, et al. SGLT2 Inhibitors and Kidney Outcomes by Glomerular Filtration Rate and Albuminuria: A Meta-Analysis. JAMA. 2026. https://doi.org/10.1001/jama.2025.20834
  6. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Chronic Kidney Disease. New England Journal of Medicine. 2020. https://doi.org/10.1056/NEJMoa2024816
  7. The EMPA-KIDNEY Collaborative Group, Herrington WG, Staplin N, et al. Empagliflozin in Patients with Chronic Kidney Disease. New England Journal of Medicine. 2023. https://doi.org/10.1056/NEJMoa2204233
  8. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. New England Journal of Medicine. 2019. https://doi.org/10.1056/NEJMoa1811744
  9. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. The Lancet. 2019. https://doi.org/10.1016/S0140-6736(18)32590-X
  10. 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 Cardiology. 2021. https://doi.org/10.1001/jamacardio.2020.4511
  11. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. New England Journal of Medicine. 2015. https://doi.org/10.1056/NEJMoa1504720
  12. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine. 2019. https://doi.org/10.1056/NEJMoa1812389
  13. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. New England Journal of Medicine. 2017. https://doi.org/10.1056/NEJMoa1611925
  14. Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Annals of Internal Medicine. 2013. https://doi.org/10.7326/0003-4819-159-4-201308200-00007
  15. Zaccardi F, Webb DR, Htike ZZ, et al. Efficacy and safety of sodium-glucose co-transporter-2 inhibitors in type 2 diabetes mellitus: systematic review and network meta-analysis. Diabetes, Obesity and Metabolism. 2016. https://doi.org/10.1111/dom.12670
  16. Mazidi M, Rezaie P, Gao HK, Kengne AP. Effect of Sodium-Glucose Cotransport-2 Inhibitors on Blood Pressure in People With Type 2 Diabetes Mellitus: A Systematic Review and Meta-Analysis of 43 Randomized Control Trials With 22 528 Patients. Journal of the American Heart Association. 2017. https://doi.org/10.1161/JAHA.116.004007
  17. Wong J, Chan KY, Lo K. Sodium-glucose co-transporter 2 inhibitors on weight change and cardiometabolic profiles in individuals with overweight or obesity and without diabetes: A meta-analysis. Obesity Reviews. 2021. https://doi.org/10.1111/obr.13336
  18. Banerjee M, Pal R, Maisnam I, et al. Serum uric acid lowering and effects of sodium-glucose cotransporter-2 inhibitors on gout: A meta-analysis and meta-regression of randomized controlled trials. Diabetes, Obesity and Metabolism. 2023. https://doi.org/10.1111/dom.15157
  19. Abdel-Rahman SM, Al-Shiab R, Shah E, et al. Efficacy and safety of GLP-1 receptor agonists and SGLT2 inhibitors as adjuncts to insulin in type 1 diabetes: Systematic review and meta-analysis. Diabetes, Obesity and Metabolism. 2026. https://doi.org/10.1111/dom.70506
  20. U.S. Food and Drug Administration. Jardiance (empagliflozin) tablets, prescribing information (Boehringer Ingelheim Pharmaceuticals). 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=faf3dd6a-9cd0-39c2-0d2e-232cb3f67565
  21. Butler J, Jones WS, Udell JA, et al. Empagliflozin after Acute Myocardial Infarction. New England Journal of Medicine. 2024. https://doi.org/10.1056/NEJMoa2314051
  22. James S, Erlinge D, Storey RF, et al. Dapagliflozin in Myocardial Infarction without Diabetes or Heart Failure. NEJM Evidence. 2024. https://doi.org/10.1056/EVIDoa2300286
  23. U.S. Food and Drug Administration. Farxiga (dapagliflozin) tablets, prescribing information (AstraZeneca Pharmaceuticals). 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=72ad22ae-efe6-4cd6-a302-98aaee423d69
  24. U.S. Food and Drug Administration. Invokana (canagliflozin) tablets, prescribing information (Janssen Pharmaceuticals). 2026. DailyMed. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b9057d3b-b104-4f09-8a61-c61ef9d4a3f3
  25. Matteucci A, Di Fusco SA, Bonanni M, et al. Are SGLT2 inhibitors really associated with increased urinary tract infection risk? A trial-level meta-analysis across type 2 diabetes, heart failure, and chronic kidney disease. DARU Journal of Pharmaceutical Sciences. 2026. https://doi.org/10.1007/s40199-026-00637-7
  26. Wang Y, Qin Y, Zhang J, et al. Sodium-Glucose Cotransporter-2 Inhibitors and Diabetic-Ketoacidosis in T2DM Patients: An Updated Meta-Analysis and a Mendelian Randomization Analysis. Clinical Pharmacology & Therapeutics. 2025. https://doi.org/10.1002/cpt.3615
  27. U.S. Food and Drug Administration. FDA removes Boxed Warning about risk of leg and foot amputations for the diabetes medicine canagliflozin (Invokana, Invokamet, Invokamet XR). Drug Safety Communication. 2020. https://www.fda.gov/drugs/drug-safety-and-availability/fda-removes-boxed-warning-about-risk-leg-and-foot-amputations-diabetes-medicine-canagliflozin
  28. Heyward J, Mansour O, Olson L, et al. Association between sodium-glucose cotransporter 2 (SGLT2) inhibitors and lower extremity amputation: A systematic review and meta-analysis. PLOS ONE. 2020. https://doi.org/10.1371/journal.pone.0234065
  29. Sridharan K, Sivaramakrishnan G. Risk of limb amputation and bone fractures with sodium glucose cotransporter-2 inhibitors: a network meta-analysis and meta-regression. Expert Opinion on Drug Safety. 2025. https://doi.org/10.1080/14740338.2024.2377755
  30. Bersoff-Matcha SJ, Chamberlain C, Cao C, et al. Fournier Gangrene Associated With Sodium-Glucose Cotransporter-2 Inhibitors: A Review of Spontaneous Postmarketing Cases. Annals of Internal Medicine. 2019. https://doi.org/10.7326/M19-0085

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