INTRODUCTION — Current treatments for type 2 diabetes have centered on increasing insulin availability (either through direct insulin administration or through agents that promote insulin secretion), improving sensitivity to insulin, delaying the delivery and absorption of carbohydrate from the gastrointestinal tract, or increasing urinary glucose excretion. Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce blood glucose by increasing urinary glucose excretion.

This topic will review the mechanism of action and therapeutic utility of SGLT2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus. The initial management of hyperglycemia in adults with type 2 diabetes, the factors involved in the selection of medications for the management of persistent hyperglycemia, and the use of SGLT2 inhibitors for the treatment of diabetic nephropathy and the management of heart failure are presented separately. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus" and "Management of persistent hyperglycemia in type 2 diabetes mellitus" and "Treatment of diabetic kidney disease" and "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults", section on 'Approach to secondary therapy'.)

MECHANISM OF ACTION — The SGLT2 is expressed in the proximal tubule and mediates reabsorption of approximately 90 percent of the filtered glucose load. SGLT2 inhibitors promote the renal excretion of glucose and thereby modestly lower elevated blood glucose levels in patients with type 2 diabetes. The ability to lower blood glucose and glycated hemoglobin (A1C) levels is limited by the filtered load of glucose and the osmotic diuresis that is caused by this therapy. Moreover, although the currently developed SGLT2 inhibitors almost completely block proximal tubular glucose reabsorption, the measured inhibition is less than 50 percent based on urine glucose excretion.

SGLT2 inhibitors only lower plasma glucose levels by blocking reabsorption of filtered glucose, which falls as plasma levels fall. Thus, they do not usually cause hypoglycemia in the absence of therapies that otherwise cause hypoglycemia. SGLT2 inhibitors modestly decrease blood pressure and weight [1].

SUGGESTED APPROACH TO THE USE OF SGLT2 INHIBITORS

Candidates — SGLT2 inhibitors are not considered as initial therapy for the majority of patients with type 2 diabetes. Initial therapy in most patients with type 2 diabetes should begin with diet, weight reduction, exercise, and metformin (in the absence of contraindications). (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)

In patients with cardiorenal comorbidities, many SGLT2 inhibitors have demonstrated benefit for cardiorenal outcomes (see 'Cardiovascular effects' below and 'Microvascular outcomes' below). However, SGLT2 inhibitors are associated with only modest improvement in glycemia, are costly, and long-term safety data on the effects of prolonged glucosuria are lacking. In addition, there are insufficient data on cardiovascular outcomes in individuals with diabetes but without overt cardiorenal disease. All of these factors must be recognized when considering combination therapy for monotherapy failure. (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach'.)

SGLT2 inhibitors play a role in the following settings (the specific drugs listed have been demonstrated to have significant beneficial effects in placebo-controlled clinical trials) [2-6]:

●In patients with overt atherosclerotic cardiovascular disease (CVD) not reaching glycemic goals with metformin and lifestyle modifications (empagliflozin, canagliflozin, and dapagliflozin, but not ertugliflozin)

●In patients with heart failure not reaching glycemic goals with metformin and lifestyle modifications (empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin)

●In patients with urine albumin-to-creatinine ratio >300 mg/g and estimated glomerular filtration rate [eGFR] <90 mL/min/1.73 m² (canagliflozin, dapagliflozin)

●As a third-line agent in patients not meeting glycemic goals on two oral agents (eg, metformin and sulfonylurea) if for some reason combination metformin and insulin is not a therapeutic option

●As a third-line agent in patients not meeting glycemic goals on metformin and insulin therapy, in whom glucagon-like peptide-1 (GLP-1) receptor agonists are contraindicated and increasing insulin dosing would lead to weight gain

●As a second agent in patients with inadequate glycemic control on metformin who are unwilling or unable to consider injection therapy and in whom weight gain and risk of hypoglycemia are a significant issue

Regardless of the initial response to therapy, the natural history of most patients with type 2 diabetes is for blood glucose concentrations to rise gradually with time. Thus, most patients require additional therapy (add a second oral or injectable agent, including insulin, or switch to insulin). The long-term benefits and risks of using one combination over another are unknown. There is a paucity of high-quality, head-to-head drug comparison trials and trials with important clinical endpoints, such as effects on microvascular and macrovascular complications and mortality [7]. The choice of therapy should be individualized based upon patient characteristics, preferences, and costs (table 1). (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Our approach'.)

Contraindications and precautions — SGLT2 inhibitors should not be used for the treatment of hyperglycemia in patients with:

●Type 1 diabetes

●Type 2 diabetes and estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m² (ertugliflozin) or <45 mL/min/1.73 m² (dapagliflozin, empagliflozin), or <30 mL/min/1.73 m² (canagliflozin)

●Prior diabetic ketoacidosis (DKA)

SGLT2 inhibitors have less glycemic benefit in patients with more severe kidney disease at initiation, and for the treatment of hyperglycemia, SGLT2 inhibitors are not recommended for initiation in patients with eGFR thresholds as described immediately above, and all SGLT2 inhibitors should be stopped with eGFR <30 mL/min/1.73 m². For the treatment of kidney disease, however, SGLT2 inhibitors have established renal benefits in patients with eGFR ≥30 mL/min/1.73m². (See "Treatment of diabetic kidney disease".)

We avoid use of SGLT2 inhibitors in patients with the following conditions because of increased risk while using these agents:

●Frequent bacterial urinary tract infections or genitourinary yeast infections. (See 'Genitourinary tract' below.)

●Low bone mineral density and high risk for fracture and falls. (See 'Bone fracture' below.)

●Foot ulceration (eg, neuropathy, foot deformity, vascular disease, and/or history of previous foot ulceration). (See 'Amputations' below.)

●Factors predisposing to DKA (eg, ketosis-prone type 2 diabetes, pancreatic insufficiency, drug or alcohol addiction) (See 'Diabetic ketoacidosis' below.)

Since the SGLT2 inhibitors can cause a mild degree of dehydration, they should be used with caution in conjunction with other medications that predispose to acute renal injury (nonsteroidal anti-inflammatory drugs [NSAIDs], angiotensin-converting enzyme [ACE] inhibitors/angiotensin II receptor blockers [ARBs], diuretics) and comorbidities that might predispose to acute renal injury (hypovolemia, heart failure, liver injury). (See 'Dosing' below and 'Acute kidney injury' below.)

Choice of therapy — There are many different medications for patients who fail initial therapy with lifestyle intervention and metformin. The factors involved in the selection of a particular class of medication for combination therapy is reviewed in detail separately (see "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Monotherapy failure'). When a decision has been made to use an SGLT2 inhibitor, canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin are available options.

●When a decision has been made to use an SGLT2 inhibitor in a patient with type 2 diabetes and a prior history of atherosclerotic CVD, we suggest empagliflozin, rather than another SGLT2 inhibitor. This suggestion is based on the results of the empagliflozin and cardiovascular outcomes study [4]. Although canagliflozin also showed cardiovascular benefits, there was an increase in the risk of lower limb amputations and fractures in canagliflozin-treated patients that was not observed in trials of empagliflozin or dapagliflozin. (See 'Cardiovascular effects' below and 'Amputations' below.)

●In patients with type 2 diabetes and heart failure or kidney disease, all SGLT2 inhibitors have shown salutary effects; choice of agent is primarily dictated by provider preference, insurance formulary restrictions, drug-specific labeling regarding use, with varying degrees of renal function and cost. (See 'Cardiovascular effects' below and 'Microvascular outcomes' below and 'Contraindications and precautions' above.)

●In patients without cardiorenal disease, choice of SGLT2 inhibitor is often dictated by cost and insurer formulary preference, as the published trials have not revealed any substantial differences with regard to A1C lowering, weight reduction, or risk for mycotic infections (see 'Clinical outcomes' below).

There are no trials directly comparing the individual SGLT2 inhibitors. In network meta-analyses, placebo-corrected A1C reductions for monotherapy and dual therapy ranged from approximately 0.6 to 0.9 and 0.3 to 0.6 percentage points, respectively [8,9]. Canagliflozin 300 mg reduced A1C to a slightly greater extent than dapagliflozin 10 mg or empagliflozin 25 mg (mean difference -0.2 percentage points) [8,9].

Pretreatment evaluation — Prior to starting an SGLT2 inhibitor, volume status and renal function (serum creatinine with eGFR) should be assessed. Hypovolemia should be corrected prior to initiating an SGLT2 inhibitor. Liver function should be assessed prior to initiation of canagliflozin or dapagliflozin. Patients at risk for falls and fracture may benefit from assessment of bone density. (See "Falls in older persons: Risk factors and patient evaluation", section on 'Risk factors' and "Osteoporotic fracture risk assessment", section on 'Assessment of fracture risk'.)

To reduce the risk of hypoglycemia, patients using insulin or insulin secretagogues (sulfonylureas, glinides) may require a dose reduction with initiation of SGLT2 inhibitors.

Dosing — SGLT2 inhibitors have less glycemic benefit in patients with more severe kidney disease at initiation, and for the treatment of hyperglycemia, SGLT2 inhibitors are not recommended for initiation in patients with eGFR <30 mL/min/1.73 m² (canagliflozin), <45 mL/min/1.73 m² (dapagliflozin, empagliflozin), or <60 mL/min/1.73 m² (ertugliflozin).

After initial therapy, the decision to escalate the dose (typically after 4 to 12 weeks) should be based on tolerance, adverse effects, and glycemic assessment (home glucose monitoring and/or A1C).

●Canagliflozin – Canagliflozin is taken orally before the first meal of the day [10,11]. The initial dose is 100 mg once daily, and it can be increased to 300 mg daily to achieve glycemic goals. In patients with moderate renal impairment (eGFR 45 to 59 mL/min/1.73 m²), the dose should not exceed 100 mg daily. Canagliflozin should not be given to patients with severe hepatic impairment. No dose adjustment is needed in patients with mild or moderate hepatic impairment [10,12].

●Dapagliflozin – Dapagliflozin (10 mg once daily) can be taken any time of day with or without food. It is not recommended for use in patients with active bladder cancer [13,14]. For patients with severely reduced liver function, a starting dose of 5 mg is recommended. There is limited experience in patients with severe hepatic impairment.

●Empagliflozin – Empagliflozin is taken orally once daily in the morning with or without food [15]. The initial dose is 10 mg daily, and it can be increased to 25 mg once daily to achieve glycemic goals. In patients taking empagliflozin who have a persistent fall in eGFR below 45 mL/min/1.73 m², it should be discontinued. Empagliflozin may be used in patients with hepatic impairment.

●Ertugliflozin – Ertugliflozin is taken once daily in the morning with or without food [16]. The initial dose is 5 mg once daily and may be increased to a maximum dose of 15 mg once daily to achieve glycemic goals. In patients taking ertugliflozin who have a persistent fall in eGFR below 60 mL/min/1.73 m², it should be discontinued.

Monitoring — In addition to glycemic indices (A1C, fasting blood sugar), renal function and volume status (blood pressure) should be monitored during SGLT2 treatment.

●Renal function

eGFR >60 mL/min/1.73 m² – We measure serum creatinine after three months and, if stable, then annually or as clinically indicated.

eGFR between 45 and 60 mL/min/1.73 m² – We measure serum creatinine every three months or as clinically indicated.

●Glycemic indices

In patients taking insulin or insulin secretagogues, SGLT2 inhibitors can increase the risk of hypoglycemia.

For patients taking insulin or insulin secretagogues, we ask them to monitor fasting and pre-meal fingerstick glucose for the first few weeks following initiation or dose escalation of SGLT2 inhibitors. Insulin dosing should be decreased by 10 to 20 percent and insulin secretagogue dosing by 50 percent if blood glucoses <80 mg/dL are measured.

We measure A1C initially every three months until glycemic goals are achieved. We obtain A1C at least twice yearly in patients meeting glycemic goals but continue to assess more frequently (quarterly) in patients whose therapy has changed or who are not meeting goals.

Patients taking SGLT2 inhibitors should be monitored for signs and symptoms of genitourinary tract infections and foot ulceration. (See 'Genitourinary tract' below and 'Amputations' below.)

CLINICAL OUTCOMES

Glycemic efficacy — SGLT2 inhibitors are relatively weak glucose-lowering agents, with mean reductions in A1C compared with placebo ranging between 0.4 to 1.1 percent depending on baseline level of hyperglycemia. They have been studied as monotherapy and in combination with metformin, sulfonylureas, pioglitazone, sitagliptin, and insulin [1,17-24]. Dapagliflozin, canagliflozin, and empagliflozin are available in Europe and the United States [14,25,26] and ertugliflozin in the United States [27]. Other SGLT2 inhibitors are in development.

In meta-analyses of clinical trials comparing SGLT2 inhibitors with placebo or active comparators (metformin, sulfonylurea, dipeptidyl peptidase-4 [DPP-4] inhibitors, insulin), SGLT2 inhibitors compared with placebo reduced A1C by approximately 0.5 to 0.7 percentage points (mean difference versus active comparators -0.06 to -0.13 percent) [17,28-30].

As examples:

●In a 52-week, double-blind trial, 814 patients with type 2 diabetes and inadequate glycemic control with metformin (mean A1C 7.7 percent) were randomly assigned to dapagliflozin or glipizide [31]. The mean reduction in A1C was similar in both groups (-0.52 percentage points). Dapagliflozin reduced weight (-3.2 versus +1.2 kg with glipizide) and produced fewer severe (requiring assistance) hypoglycemia episodes (0 versus 0.7 percent with glipizide).

●In another trial, 808 patients with type 2 diabetes mellitus and inadequate glycemic control with insulin and up to two oral agents were randomly assigned to dapagliflozin (2.5, 5, or 10 mg once daily) or placebo [32]. After 24 weeks, A1C decreased by 0.79 to 0.96 percentage points with dapagliflozin compared with 0.39 percentage points with placebo (mean difference -0.40 to -0.57 percent in the 2.5 to 10 mg groups). Daily insulin dose decreased by 0.63 to 1.95 units with dapagliflozin and increased by 5.65 units with placebo. Dapagliflozin reduced weight (-0.92 to -1.61 versus +0.43 kg with placebo). The rate of hypoglycemic episodes was higher in the dapagliflozin group (56.6 versus 51.8 percent).

●In a 52-week, double-blind trial, 755 patients with type 2 diabetes and inadequate glycemic control with metformin plus a sulfonylurea (mean A1C 8.1 percent) were randomly assigned to canagliflozin (300 mg daily) or sitagliptin (100 mg daily) [33]. The mean reduction in A1C from baseline was significantly better with canagliflozin than sitagliptin (least squares mean change -1.03 and -0.66 percent, respectively). Canagliflozin reduced weight (-2.5 versus 0.3 percent change from baseline) and systolic blood pressure (-5.1 versus 0.99 mmHg, respectively) compared with sitagliptin. Although the overall incidence of adverse events was similar for the two drugs, the frequency of genital fungal infections was almost sixfold higher with canagliflozin. The overall results of this study must be viewed cautiously as almost 40 percent of the subjects did not complete the year-long study.

●In a 52-week, double-blind trial, 1452 patients with type 2 diabetes and inadequate glycemic control with metformin (mean A1C 7.8 percent) were randomly assigned to glimepiride (titrated based upon blood glucose, median dose 5.6 mg daily) or canagliflozin (100 or 300 mg daily) [34]. The mean reduction in A1C from baseline was similar in the glimepiride and lower-dose canagliflozin groups (-0.81 and -0.82 percentage points, respectively) and better by 0.1 A1C percentage point in the higher-dose canagliflozin group (-0.93 percentage points). The proportion of patients achieving an A1C <7 or <6.5 percent was similar among groups (approximately 56 and 31 percent of patients, respectively). Canagliflozin reduced weight (-4.2 to -4.4 kg compared with +0.8 kg with glimepiride) and was associated with less frequent severe hypoglycemia (<1 compared with 3 percent) but with more frequent genital yeast infections (in women, 11 to 14 percent versus 2 percent with glimepiride).

●In a 52-week trial, patients with type 2 diabetes and inadequate glycemic control on multidose insulin and metformin (mean A1C 8.3 percent) were randomly assigned to empagliflozin (10 or 25 mg once daily) or placebo [19]. The reduction in A1C was greater with empagliflozin (-1.18, -1.21, and -0.81 for empagliflozin 10 mg, empagliflozin 25 mg, and placebo, respectively). Compared with placebo, empagliflozin reduced insulin doses by 9 to 11 units per day and weight by 2.4 kg.

●In a 52-week, double-blind trial, 1326 patients with type 2 diabetes and inadequate glycemic control with metformin (mean A1C 7.8 percent) were randomly assigned to ertugliflozin (5 or 15 mg daily) or glimepiride (titrated based upon blood glucose, median dose 3 mg daily) [22]. The mean reduction in A1C from baseline with ertugliflozin 15 mg daily was noninferior to glimepiride (-0.6 and -0.7 percentage points, respectively). Ertugliflozin reduced weight (-3.4 kg compared with +0.9 kg with glimepiride) and was associated with less frequent severe hypoglycemia (<0.2 compared with 2.3 percent) but with more frequent genital yeast infections (in women, 10 versus 1.4 percent with glimepiride).

Cardiovascular effects

●Atherosclerotic cardiovascular disease (CVD) – Empagliflozin and canagliflozin have been shown to decrease atherosclerotic cardiovascular morbidity and mortality in patients with type 2 diabetes and overt CVD [4,5]. In the primary analysis, dapagliflozin did not appear to reduce atherosclerotic cardiovascular morbidity or cardiovascular mortality [3]; however, it decreased cardiovascular outcomes in a subanalysis of the primary trial [35]. The cardiovascular trials to date have been carried out in very high-risk populations to increase the hazard rate for major CVD events and complete the studies in a relatively brief period of time. Of note, compared with the empagliflozin and canagliflozin trials, the dapagliflozin trial had a lower fraction of participants with established CVD and a greater proportion of patients with multiple risk factors for CVD (multiple risk factors in 60 percent compared with 0 and 34 percent in the empagliflozin and canagliflozin trials, respectively). This difference in patient population may explain, in part, the differences in atherosclerotic CVD outcomes. However, the ertugliflozin cardiovascular trial only included patients with established CVD and did not show superior benefit in the composite outcome (cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) [36].

●Heart failure – In patients with type 2 diabetes and heart failure, all SGLT2 inhibitors have shown salutary effects.

In meta-analyses of the three major CVD outcome trials (empagliflozin, canagliflozin, dapagliflozin), SGLT2 inhibitors compared with placebo reduced the risk of major adverse cardiovascular events (86.9 versus 99.6 events per 1000 patient-years, hazard ratio [HR] 0.89, 95% CI 0.83-0.96) and a composite outcome of CV death or hospitalization for heart failure (48.2 versus 65.6 events per 1000 patient-years, HR 0.77, 95% CI 0.71-0.84) [37,38]. The clinical benefit of the SGLT2 inhibitors in reducing the risk of major cardiovascular events (myocardial infarction, stroke, cardiovascular death) was limited to those patients with established atherosclerotic CVD, with no benefit in those with multiple risk factors for CVD [37,38]. In contrast to the findings for major adverse cardiovascular events, the meta-analyses showed a reduction in hospitalization for heart failure with use of SGLT2 inhibitors regardless of the presence of established atherosclerotic CVD or heart failure at baseline.

In a subsequent meta-analysis of five trials comparing an SGLT2 inhibitor (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, sotagliflozin) with placebo in people with diabetes and established CVD, SGLT2 inhibitors reduced the risk of cardiovascular mortality (72 versus 86 per 1000 persons; odds ratio [OR] 0.82, 95% CI 0.70-0.95) and heart failure hospitalizations (78 versus 116 per 1000 persons, OR 0.65, 95% CI 0.59-0.71) [39]. SGLT2 inhibitors did not reduce the risk of fatal or nonfatal myocardial infarction (54 versus 56 per 1000 persons; OR 0.97, 95% CI 0.84-1.12) or stroke (34 versus 31 per 1000 persons; OR 1.12, 95% CI 0.92-1.36).

Until large, prospective, randomized trials are conducted, it is unknown whether empagliflozin, canagliflozin, or other SGLT2 inhibitors will have similar CVD effects in the majority of persons with type 2 diabetes who do not have overt CVD.

The individual trials are reviewed below.

●Empagliflozin – In a trial designed specifically to evaluate cardiovascular morbidity and mortality in patients with type 2 diabetes and established CVD, 7028 patients with type 2 diabetes (mean A1C approximately 8 percent) and CVD were randomly assigned to empagliflozin (10 or 25 mg) or placebo once daily [4]. The majority of patients were taking metformin, antihypertensives, and lipid-lowering agents (equally distributed in both groups) to control blood glucose, blood pressure, and cholesterol, respectively. Approximately 48 percent of patients in each group were taking insulin.

After three years, the primary outcome (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) occurred in fewer patients assigned to empagliflozin than to placebo (10.5 versus 12.1 percent; HR pooled analysis 0.86, 95% CI 0.74-0.99). The findings were driven by a significant reduction in risk of death from cardiovascular causes (3.7 versus 5.9 percent with placebo; HR 0.62, 95% CI 0.49-0.77). There was no significant difference in the occurrence of the individual components of nonfatal myocardial infarction (4.5 versus 5.2 percent with placebo) or nonfatal stroke (3.2 versus 2.6 percent). Findings were similar in the individual empagliflozin dose groups.

The rate of hospitalization for heart failure was lower in the empagliflozin group (2.7 versus 4.1 percent in the placebo group). Compared with patients taking placebo, patients taking empagliflozin had lower A1C levels (mean 7.8 versus 8.2 percent) and reductions in weight, waist circumference, systolic and diastolic blood pressure (with no increase in heart rate), and uric acid. There were small increases in low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol in patients taking empagliflozin.

In patients with heart failure with reduced ejection fraction (HFrEF), with or without diabetes, empagliflozin has been shown to reduce cardiovascular mortality and worsening heart failure [40]. Empagliflozin in the treatment of HFrEF is reviewed separately. (See "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults", section on 'Approach to secondary therapy' and "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults", section on 'Empagliflozin'.)

●Canagliflozin – In two trials designed to assess the effects of canagliflozin on cardiovascular, renal, and safety outcomes in patients with type 2 diabetes and high cardiovascular risk, 10,142 patients (mean A1C 8.2 percent) were randomly assigned to canagliflozin or placebo [5]. The majority of patients were taking metformin, antihypertensives, and lipid-lowering agents (equally distributed in both groups) to manage blood glucose, blood pressure, and cholesterol, respectively. Approximately 50 percent of patients in each group were taking insulin.

After a mean follow-up of 3.6 years, the primary outcome, a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, occurred in fewer patients in the canagliflozin group (26.9 versus 31.5 patients per 1000 patient-years, HR 0.86, 95% CI 0.75-0.97). The reductions in the occurrence of the individual components of the composite outcome in those randomized to canagliflozin (11.6 versus 12.8, 9.7 versus 11.6, and 7.1 versus 8.4 patients per 1000 patient-years, respectively) were not statistically significant. The rate of hospitalization for heart failure was lower in the canagliflozin group (5.5 versus 8.7 patients per 1000 patient-years in the placebo group, HR 0.67, 95% CI 0.52-0.87).

Compared with patients taking placebo, patients taking canagliflozin had lower A1C levels (mean difference -0.58 percent) and reductions in weight and systolic and diastolic blood pressure.

In a subsequent trial designed to primarily evaluate renal outcomes in patients with type 2 diabetes and nephropathy (mean eGFR 56.2 mL/min/1.73 m², median urinary albumin-to-creatinine ratio 927 [mg/g]), there were similar reductions in cardiovascular events [6].

Renal outcomes and the increased risk of amputations in the canagliflozin group are reviewed below. (See 'Microvascular outcomes' below and 'Amputations' below.)

●Dapagliflozin – In a trial designed to assess the effects of dapagliflozin on cardiovascular and renal outcomes, 17,160 patients with type 2 diabetes (mean A1C approximately 8.3 percent) who had or were at risk for CVD were randomly assigned to dapagliflozin (10 mg) or placebo once daily [3]. The majority of patients were taking metformin, antihypertensives, and lipid-lowering agents (equally distributed in both groups) to manage blood glucose, blood pressure, and cholesterol, respectively. Approximately 40 percent of patients in each group were taking insulin.

After a median follow-up of 4.2 years, the first primary outcome (a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal ischemic stroke) occurred in 8.8 and 9.4 percent of patients taking dapagliflozin and placebo, respectively (HR 0.93, 95% CI 0.84-1.03). There was a significant reduction in the second primary outcome (a composite of cardiovascular death or hospitalization for heart failure), primarily driven by a significant reduction in hospitalization for heart failure (6.2 versus 8.5 percent with placebo, HR 0.73, 95% CI 0.61-0.88). There was no difference between the two groups in death from any cause (6.2 versus 6.6 percent in the placebo group, HR 0.93, 95% CI 0.82-1.04).

The dapagliflozin trial included enough participants with established cardiovascular disease or multiple risk factors at baseline, randomized to dapagliflozin or placebo, to perform subanalyses within the two groups and compare them [35]. Dapagliflozin reduced the two co-primary cardiovascular outcomes in the participants with a prior myocardial infarction (15.2 versus 17.8 percent [HR 0.84, 95% CI 0.72-0.99]), but not in those without prior myocardial infarction (7.1 versus 7.1 percent [HR 1.00, 95% CI 0.88-1.13]). In a subsequent exploratory analysis, dapagliflozin also reduced the incidence of atrial fibrillation/atrial flutter adverse events [41].

In patients with or without diabetes, dapagliflozin has been shown to reduce all-cause mortality and worsening heart failure in adults with heart failure with reduced ejection fraction (HFrEF) with New York Heart Association functional class II, III, or IV [42]. Dapagliflozin in the treatment of HFrEF is reviewed separately. (See "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults", section on 'Approach to secondary therapy'.)

●Ertugliflozin – In a trial designed to evaluate lack of inferiority on composite cardiovascular outcomes, 8246 individuals with type 2 diabetes (mean A1C 8.2 percent) and prevalent CVD were randomly assigned to ertugliflozin (5 or 15 mg) or placebo once daily [36]. The majority of participants were taking metformin (76 percent), and approximately 47 percent of patients were taking insulin. After a mean follow-up of 3.5 years, ertugliflozin treatment did not meet superiority to placebo in the primary composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke (11.9 percent in each group [HR 0.97, 95% CI 0.85-1.11]). There was a significant reduction in hospitalization for heart failure (2.5 versus 3.6 percent with placebo [HR 0.7, 95% CI 0.54-0.90]).

The findings from these studies need to be kept in perspective. The large relative cardiovascular benefit of empagliflozin and canagliflozin, while impressive, was in a very high-risk population with established CVD at baseline. Moreover, the absolute risk reduction is approximately 10 to 15 cases per 1000 patient-years, and the benefit in patients taking canagliflozin, in particular, must be balanced with the increased risk of amputations. The difference in glycemia between the treatment groups was minimal, suggesting that extra-glycemic effects of the drugs were responsible for the CVD outcome. The salutary impact of SGLT2 inhibitors on heart failure outcomes seems to be a class effect.

Microvascular outcomes — There are a growing number of trials evaluating microvascular outcomes in patients taking SGLT2 inhibitors. In a meta-analysis of the three major CVD outcome trials, empagliflozin, canagliflozin, and dapagliflozin reduced progression of diabetic kidney disease, with a similar effect observed in patients with established atherosclerotic CVD or multiple risk factors for CVD [37]. (See "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy'.)

Although the benefit was present across all estimated glomerular filtration rates (eGFRs) studied, there appeared to be less benefit in those with more severe kidney disease at initiation. SGLT2 inhibitors are not recommended for initiation in patients with eGFR <30 or <45 mL/min/1.73 m² and should be stopped with eGFR <30 mL/min/1.73 m², with some differences in each medication depending on the labeling. (See 'Contraindications and precautions' above.)

The mechanism behind the reduction in incident or worsening nephropathy with SGLT2 inhibitors is likely multifactorial but is thought to be largely related to a direct renovascular effect. The relatively brief duration of the studies and modest improvement in glycemia compared with placebo make glucose lowering an unlikely explanation for the reductions in relatively late-stage nephropathy.

There have been reports of acute kidney injury, some requiring hospitalization and dialysis, in patients taking canagliflozin or dapagliflozin. (See 'Adverse effects' below.)

●Empagliflozin – In the empagliflozin trial described above, which was designed specifically to evaluate cardiovascular morbidity and mortality in patients with type 2 diabetes and established CVD, microvascular disease was a prespecified secondary outcome [4]. The composite microvascular endpoint (the initiation of retinal photocoagulation, vitreous hemorrhage, diabetes-related blindness, or incident or worsening nephropathy) occurred in fewer patients in the empagliflozin group (14 versus 20.5 percent).

The reduction was driven entirely by a reduction in incident or worsening nephropathy (defined as progression to macroalbuminuria, doubling of the serum creatinine level, initiation of renal replacement therapy, or death from renal disease), which occurred in 12.7 and 18.8 percent of patients in the empagliflozin and placebo groups, respectively (HR 0.61, 95% CI 0.53-0.70) [43]. There were significant reductions in each component of the outcome, except for death from renal disease. There were three deaths from renal disease in the empagliflozin group (0.1 percent) and none in the placebo group.

●Canagliflozin – In the canagliflozin trial (described above) assessing cardiovascular, renal, and safety outcomes in patients with type 2 diabetes and high cardiovascular risk, progression of albuminuria (a secondary endpoint) occurred less frequently in the canagliflozin group (89.4 versus 128.7 participants per 1000 patient-years in the placebo group, HR 0.73, 95% CI 0.67-0.79) [5].

In a post hoc exploratory analysis of a composite outcome of sustained 40 percent reduction in estimated glomerular filtration rate (eGFR), the need for renal replacement therapy, or death from renal causes occurred less frequently in the canagliflozin than placebo group (5.5 versus 9.0 patients per 1000 patient-years, HR 0.60, 95% CI 0.47-0.77) [5].

In a subsequent trial specifically designed to evaluate renal outcomes, 4401 patients with type 2 diabetes and hyperalbuminuria (mean eGFR 56.2 mL/min/1.73 m², median urinary albumin-to-creatinine ratio 927 [mg/g]) were randomly assigned to canagliflozin (100 mg daily) or placebo [6]. The majority of patients were taking insulin and/or metformin, with approximately 30 percent taking a sulfonylurea. All patients were receiving an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker. The trial was stopped early for benefit after a median follow-up of 2.6 years. The primary outcome (a composite of end-stage kidney disease [ESKD], doubling of serum creatinine, or death from renal or cardiovascular causes) occurred in a smaller proportion of patients taking canagliflozin (43.2 versus 61.2 events per 1000 patient-years, HR 0.70, 95% CI 0.59-0.82). The effect size was similar across components of the primary outcome, except for renal death, which occurred in few patients (two versus five renal deaths with placebo). The renal protective effect was most pronounced in those with an eGFR between 45 to 60 mL/min/1.73 m² at study onset but was seen with eGFR as low as 30 mL/min/1.73 m².

●Dapagliflozin – In the dapagliflozin trial described above assessing cardiovascular and renal outcomes in patients with type 2 diabetes who had or were at risk for CVD, there was a reduction in the renal outcome (a composite of a sustained decrease of 40 percent or more in eGFR to <60 mL/min, new end-stage kidney disease, or death from renal or cardiovascular causes), which occurred in 4.3 and 5.6 percent of the patients in the dapagliflozin and placebo groups, respectively (HR 0.76, 95% CI 0.67-0.87) [3].

In a subsequent trial designed to assess renal outcomes, 4304 individuals with eGFR 25 to 75 mL/min/1.73 m² and urine albumin-to-creatinine ratio 200 to 5000 mg/g (median, 950 mg/g) were randomly assigned to dapagliflozin (10 mg once daily) or placebo [2]. After a median follow-up of 2.4 years, the composite primary outcome (sustained decline in eGFR of ≥50 percent, ESKD, or death from renal or cardiovascular causes) occurred in fewer patients in the dapagliflozin group (9.2 versus 14.5 percent, HR 0.61, 95% CI 0.51-0.72). The benefit was similar across components of the primary outcome, except for renal death, which occurred in few patients (two versus six renal deaths with placebo).

●Ertugliflozin – In the ertugliflozin trial described above assessing cardiovascular outcomes in patients with type 2 diabetes and prevalent CVD, there was a nonsignificant reduction in the composite renal endpoint of death from renal causes, renal replacement therapy, or doubling of the serum creatinine level (3.2 versus 3.9 percent [HR 0.81, 95% CI 0.63-1.04]) [36]. Although not statistically significant, the trend is similar to other drugs in the class despite stricter prespecified renal endpoints.

All-cause mortality — SGLT2 inhibitors appear to reduce overall mortality in people with diabetes and established CVD. In a meta-analysis of five trials comparing an SGLT2 inhibitor (canagliflozin, dapagliflozin, empagliflozin, ertugliflozin, sotagliflozin) with placebo in people with diabetes and CVD, SGLT2 inhibitors reduced the risk of all-cause mortality (96 versus 113 per 1000 persons; OR 0.84, 95% CI 0.74-0.96) [39].

Weight loss — SGLT2 inhibitors decrease weight [1,44]. The weight loss appears to be sustained over time. In a meta-analysis of longer-term trials (one to two years), comparing SGLT2 inhibitors with placebo, there was a significant reduction in weight with SGLT2 inhibitors (mean difference at two years -2.99 kg, 95% CI -3.64 to -2.34) [30].

ADVERSE EFFECTS

Genitourinary tract

●Infection – In clinical trials, side effects of SGLT2 inhibitors include an approximate two- to fourfold increased incidence of vulvovaginal candidiasis, reported in up to 10 to 15 percent of women [22,45,46]. Similarly, in meta-analyses of trials, there was a higher rate of vulvovaginal candidal infections (eg, 9.5 versus 2.6 percent in the control groups) [1,17,47]. SGLT2 inhibitors increase the rate of urinary tract infections (8.8 versus 6.1 percent) [1,17]. In addition, the US Food and Drug Administration (FDA) has received reports of potentially fatal:

•Urosepsis and pyelonephritis [48]

•Necrotizing fasciitis of the perineum (Fournier's gangrene) [49-51]

●Bladder cancer – In clinical trials, there were 10 cases of bladder cancers diagnosed among dapagliflozin users, five of which occurred in the first six months of dapagliflozin, a much shorter time interval than would be expected if dapagliflozin promoted tumorigenesis. However, these findings have prompted the FDA to recommend postmarketing surveillance studies [14,52]. There are no long-term safety data with regard to the effects of chronic glucosuria on the urinary tract.

Hypotension — SGLT2 inhibitors cause an osmotic diuresis and intravascular volume contraction. In older patients or in patients taking diuretics, angiotensin-converting enzyme (ACE) inhibitors, or angiotensin receptor blockers (ARBs), SGLT2 inhibitors may cause symptomatic hypotension [53,54].

Acute kidney injury — There have been postmarketing reports of acute kidney injury (some requiring hospitalization and dialysis) in patients taking canagliflozin or dapagliflozin [55,56]. Among 101 cases of possible SGLT2-associated acute kidney injury reported to the FDA, approximately one-half occurred within one month of initiating the drug, and most patients improved after the drug was discontinued. Some patients with acute kidney injury may have been volume depleted, hypotensive, or taking other medications that could affect the kidneys. It is unclear whether any of the patients in these reports had preexisting chronic kidney disease.

In a subsequent analysis of SGLT2 users and nonusers in two different cohorts, the risk of acute kidney injury was not increased with SGLT2 inhibitor use [57]. Furthermore, in trials that were designed to evaluate cardiovascular morbidity and mortality in patients with type 2 diabetes and established cardiovascular disease (CVD), SGLT2 inhibitors reduced the incidence of worsening nephropathy, suggesting a renal protective effect. (See 'Microvascular outcomes' above.)

Nevertheless, renal function should be assessed prior to initiation of SGLT2 inhibitors and monitored during treatment. They should be used with caution in patients with comorbidities that might predispose to acute renal injury (eg, heart failure, hypovolemia) and in conjunction with other medications that predispose to acute renal injury (nonsteroidal anti-inflammatory drugs [NSAIDs], ACE inhibitors/ARBs, diuretics). Dose adjustments and more frequent monitoring are required when estimated glomerular filtration rate (eGFR) is 45 to 60 mL/min. (See 'Dosing' above and 'Contraindications and precautions' above.)

Bone fracture — In some [58,59], but not all [6,60,61], studies, the incidence of fractures was higher in patients taking canagliflozin. As an example, in one analysis, there were 1.4 and 1.5 bone fractures per 100 patient-years exposure to canagliflozin 100 mg and 300 mg, respectively, compared with 1.1 per 100 patient-years in the comparator (placebo or active) group [58,59]. Low trauma fractures have been reported as early as 12 weeks after starting the drug.

A possible mechanism, particularly for fractures occurring in older individuals after only 12 weeks of therapy, is orthostatic hypotension resulting in postural dizziness and falls. SGLT2 inhibitors may also adversely affect bone density. Bone density studies were performed as part of a two-year, placebo-controlled trial of canagliflozin in 716 older patients. Patients in the canagliflozin compared with control group had progressively greater loss of bone density over time at the total hip (placebo-corrected declines of 0.9 and 1.2 percent for canagliflozin 100 and 300 mg, respectively) and spine (placebo-corrected declines of 0.3 and 0.7 percent, respectively) [58,62,63].

Although fractures have been reported to occur more frequently only in patients taking canagliflozin, based on putative mechanisms, other SGLT2 inhibitors may also reduce bone mass and increase bone fractures. A meta-analysis of trials evaluating safety outcomes did not show an increased risk of fracture with dapagliflozin or empagliflozin [64]. The increase in fracture with canagliflozin was not significant (odds ratio [OR] 1.15, 95% CI 0.71-1.88).

Diabetic ketoacidosis — SGLT2 inhibitors appear to increase the risk of DKA [65]. As an example, in a population-based cohort study from Canada and the United Kingdom (more than 350,000 patients and 500 DKA events), SGLT2 inhibitors (empagliflozin, dapagliflozin, canagliflozin) compared with dipeptidyl peptidase 4 (DPP-4) inhibitors were associated with an increased risk of DKA (incidence 2.03 versus 0.75 per 1000 person-years [HR 2.85, 95% CI 1.99-4.08]) [66]. Among the three SGLT2 inhibitors, canagliflozin was associated with the highest risk (HR 3.58 compared with 1.86 and 2.52 for dapagliflozin and empagliflozin, respectively). In several studies, "euglycemic" (usually meaning plasma glucose <250 mg/dL) DKA has been reported in patients with type 2 diabetes [67-70]. In these individuals, the absence of substantial hyperglycemia delays recognition of the problem by both the patients and the clinicians. Serum ketones should be obtained in any patient with nausea, vomiting, or malaise while taking SGLT2 inhibitors, and SGLT2 inhibitors should be discontinued if acidosis is confirmed [71]. (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis" and "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment".)

The risk of SGLT2 inhibitors with regard to DKA has been uniformly demonstrated in placebo-controlled trials in type 1 diabetes. The increased risk for DKA occurred in these studies even though participants at high risk for DKA were excluded at baseline and substantial efforts to mitigate this risk were included, to no avail. Off-label use in type 1 diabetes is therefore discouraged [72].

Amputations — Compared with some oral and injectable diabetes agents, SGLT2 inhibitors, particularly canagliflozin, are associated with an increased risk of amputation [70,73,74].

●In two randomized trials evaluating canagliflozin versus placebo in patients with type 2 diabetes and established CVD (or at increased CVD risk) [5,75,76], there was an approximately twofold increased risk of lower limb amputations (predominantly toe and midfoot) in patients taking canagliflozin (amputation incidence 5.9 and 2.8 per 1000 patient-years for patients taking canagliflozin and placebo, respectively, in the first trial, and 7.5 and 4.2 per 1000 patient-years, respectively, in the second trial) [77]. Patients were followed for a mean 5.7 and 2.1 years, respectively. Patients with a history of prior amputation, peripheral vascular disease, and neuropathy were at highest risk for amputation.

●In a pharmacovigilance study of over eight million case safety reports, 79 lower-limb amputations associated with the use of SGLT2 inhibitors were reported since 2013. An increased risk of lower-limb amputations was reported with both canagliflozin (proportional reporting ratio [PRR] 7.09, 95% CI 5.25-9.57) and empagliflozin (PRR 4.96, 95% CI 2.89-8.50), although the absolute number of lower-limb amputations reported was quite low (56 and 14, respectively) [78]. There was a significant increased risk of toe amputations with canagliflozin, empagliflozin, and dapagliflozin (PRRs 8.91, 6.86, and 2.62, respectively).

In a post hoc analysis of the empagliflozin cardiovascular trial, however, there was no increased risk of lower limb amputation [79]. Similarly, in the renal outcomes trial, canagliflozin was not associated with an increased risk of lower extremity amputation (or fracture) [6]. However, the study was terminated early due to benefit, and due to the findings in prior canagliflozin trials, the protocol was amended to employ a risk mitigation strategy in which a foot exam was performed at every study visit and the study medication was stopped if risk factors for amputation were present. (See 'Microvascular outcomes' above.)

SGLT2 inhibitors should not be prescribed to patients at risk for foot amputation, including neuropathy (loss of protective sensation), foot deformity, vascular disease, and history of previous foot ulceration. Patients taking SGLT2 inhibitors should be monitored for signs and symptoms of foot ulceration. (See "Evaluation of the diabetic foot".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Diabetes mellitus in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Type 2 diabetes (The Basics)" and "Patient education: Treatment for type 2 diabetes (The Basics)")

●Beyond the Basics topics (see "Patient education: Type 2 diabetes: Overview (Beyond the Basics)" and "Patient education: Type 2 diabetes: Treatment (Beyond the Basics)" and "Patient education: Blood glucose monitoring in diabetes (Beyond the Basics)" and "Patient education: Preventing complications from diabetes (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●The sodium-glucose co-transporter 2 (SGLT2) is expressed in the proximal tubule and mediates reabsorption of approximately 90 percent of the filtered glucose load. SGLT2 inhibitors promote the renal excretion of glucose and thereby modestly lower elevated blood glucose levels in patients with type 2 diabetes. They do not usually cause hypoglycemia in the absence of therapies that otherwise cause hypoglycemia. SGLT2 inhibitors decrease blood pressure and weight. (See 'Mechanism of action' above and 'Glycemic efficacy' above and 'Weight loss' above.)

●SGLT2 inhibitors are not considered as initial therapy for the majority of patients with type 2 diabetes. (See 'Candidates' above.)

The treatment of patients with type 2 diabetes mellitus includes education, with emphasis on lifestyle changes including diet, exercise, and weight reduction when appropriate. In the absence of contraindications, metformin is usually the initial pharmacologic therapy for most patients with type 2 diabetes. Initial management is discussed elsewhere. (See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)

●The therapeutic options for patients who fail initial therapy with lifestyle intervention and metformin are to add a second oral or injectable agent, including insulin, or to switch to insulin. The choice of therapy should be individualized based upon patient characteristics, preferences, and costs. Options include insulin, sulfonylureas, glucagon-like peptide-1 (GLP-1) agonists, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, SGLT2 inhibitors, glinides, and alpha-glucosidase inhibitors. All of these medications have advantages and disadvantages (table 1). (See "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Monotherapy failure'.)

●When a decision has been made to use an SGLT2 inhibitor in a patient with type 2 diabetes and atherosclerotic CVD, we suggest empagliflozin, rather than another SGLT2 inhibitor (Grade 2B). This is based on the results of the empagliflozin and cardiovascular outcomes trial. Although canagliflozin also showed cardiovascular benefits, there was an increase in the risk of lower limb amputations and fractures in canagliflozin-treated patients that was not observed in trials of empagliflozin (or dapagliflozin). In the primary analysis, dapagliflozin did not appear to reduce atherosclerotic cardiovascular morbidity or cardiovascular mortality; however, it decreased cardiovascular outcomes in a subanalysis of the primary trial.

●In patients with type 2 diabetes and heart failure, all SGLT2 inhibitors have shown salutary effects; choice of agent is primarily dictated by provider preference, insurance formulary restrictions, and cost. In patients without CVD, choice of SGLT2 inhibitor is also often dictated by cost and insurer formulary preference. (See 'Choice of therapy' above and 'Cardiovascular effects' above and 'Microvascular outcomes' above.)

SGLT2 inhibitors for the treatment of diabetic kidney disease and heart failure with reduced ejection fraction are reviewed separately. (See "Treatment of diabetic kidney disease", section on 'Type 2 diabetes: Treat with additional kidney-protective therapy' and "Secondary pharmacologic therapy in heart failure with reduced ejection fraction (HFrEF) in adults", section on 'SGLT2 inhibitor'.)

●SGLT2 inhibitors in general may also have a role as a third agent in those who cannot or will not take insulin, when full doses of metformin and a sulfonylurea have not produced satisfactory metabolic control, or in patients in whom risk of hypoglycemia is high (frail, older adults) or in whom avoidance of weight gain is a priority. However, long-term safety has not been established. (See 'Candidates' above and "Management of persistent hyperglycemia in type 2 diabetes mellitus", section on 'Dual agent failure'.)

●We avoid use of SGLT2 inhibitors in patients with frequent bacterial urinary tract infections or genitourinary yeast infections, low bone density and high risk for falls and fractures, foot ulceration, and factors predisposing to diabetic ketoacidosis (DKA; eg, pancreatic insufficiency, drug or alcohol abuse disorder) because of increased risk while using these agents. (See 'Contraindications and precautions' above.)

●Volume status and renal function (serum creatinine with estimation of glomerular filtration rate [eGFR]) should be assessed prior to starting an SGLT2 inhibitor and periodically thereafter. Patients taking SGLT2 inhibitors should be monitored for signs and symptoms of genitourinary tract infections and foot ulceration. (See 'Pretreatment evaluation' above and 'Monitoring' above.)

●The most common side effects of SGLT2 inhibitors are vulvovaginal candidal infections and hypotension. Acute kidney injury, urinary tract infections, necrotizing fasciitis of the perineum, euglycemic diabetic ketoacidosis, increased risk of lower extremity amputation, and bone fractures have also been reported. (See 'Adverse effects' above.)