Ertugliflozin (Steglatro)
Brand names: Steglatro (monotherapy), Steglujan (with sitagliptin), Segluromet (with metformin)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Type 2 diabetes mellitus — glycemic control | Adults (≥18 years) | Monotherapy or combination | FDA Approved |
Ertugliflozin is approved as an adjunct to dietary modification and physical activity for improving blood glucose control in adults with type 2 diabetes. It can be used alone or combined with other glucose-lowering agents including metformin, sitagliptin, sulfonylureas, and insulin. Fixed-dose combination products are available with sitagliptin (Steglujan) and with metformin (Segluromet). The drug is explicitly not recommended for glycemic control in type 1 diabetes due to the elevated risk of ketoacidosis in this population.
Weight management adjunct in type 2 diabetes: While not an approved indication, ertugliflozin produces consistent weight loss of 2–3 kg in clinical trials, which may be a secondary benefit in overweight patients with type 2 diabetes. Evidence quality: Moderate (consistent findings across phase 3 RCTs as secondary endpoint).
Blood pressure reduction in type 2 diabetes: Ertugliflozin produces modest systolic blood pressure reductions of 3–5 mmHg in clinical trials. Some clinicians consider this benefit when choosing among glucose-lowering agents. Evidence quality: Moderate (secondary endpoint data from pooled trials).
Dosing
Adult Dosing by Clinical Scenario
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| T2DM — monotherapy (diet/exercise insufficient) | 5 mg once daily | 5–15 mg once daily | 15 mg/day | Take in the morning, with or without food Uptitrate if tolerated and additional control needed |
| T2DM — add-on to metformin | 5 mg once daily | 5–15 mg once daily | 15 mg/day | Continue metformin at current dose HbA1c reduction ~0.5–0.7% added to metformin |
| T2DM — add-on to metformin + sitagliptin | 5 mg once daily | 5–15 mg once daily | 15 mg/day | Triple oral combination Or use Steglujan (ertugliflozin/sitagliptin fixed-dose) |
| T2DM — add-on to insulin (± metformin) | 5 mg once daily | 5–15 mg once daily | 15 mg/day | Consider reducing insulin dose to lower hypoglycemia risk Monitor blood glucose closely during initiation |
| T2DM — add-on to sulfonylurea (± metformin) | 5 mg once daily | 5–15 mg once daily | 15 mg/day | Consider reducing SU dose to mitigate hypoglycemia Hypoglycemia rates rise substantially when combined with SU/insulin |
| T2DM with ASCVD (cardiovascular risk reduction setting) | 5 mg once daily | 5–15 mg once daily | 15 mg/day | VERTIS CV demonstrated non-inferiority for MACE but did not show superiority Other SGLT2 inhibitors may be preferred when CV benefit is the primary treatment goal |
Renal and Hepatic Dose Adjustments
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| eGFR ≥45 mL/min/1.73 m² | 5 mg once daily | 5–15 mg once daily | 15 mg/day | No dose adjustment needed |
| eGFR <45 mL/min/1.73 m² | Not recommended | Insufficient glycemic efficacy demonstrated in this population A study in eGFR 30–60 failed to show benefit over placebo | ||
| Mild or moderate hepatic impairment | 5 mg once daily | 5–15 mg once daily | 15 mg/day | No dose adjustment required |
| Severe hepatic impairment | Not recommended | Not studied in severe hepatic impairment (Child-Pugh C) | ||
Withhold ertugliflozin for at least 4 days before elective surgery or procedures that involve prolonged fasting. This is critical to reduce the risk of perioperative ketoacidosis, which can present with euglycemic blood glucose levels. Resume therapy only after the patient is clinically stable and tolerating oral intake. Urinary glucose excretion persists for approximately 4 days after discontinuation, though postmarketing reports have documented glucosuria and ketoacidosis lasting over 6 days and up to 2 weeks in some cases.
Pharmacology
Mechanism of Action
Ertugliflozin selectively blocks the sodium-glucose co-transporter 2 (SGLT2) protein located in the proximal renal tubule. SGLT2 is the primary transporter responsible for reclaiming approximately 90% of the filtered glucose load from the glomerular filtrate back into the systemic circulation. By inhibiting this transporter, ertugliflozin lowers the renal threshold for glucose reabsorption, resulting in increased urinary glucose excretion (glycosuria) and a reduction in circulating blood glucose. This insulin-independent mechanism produces dose-proportional increases in daily urinary glucose output, with both the 5 mg and 15 mg doses achieving near-maximal glycosuric effect. Secondary pharmacodynamic effects include mild osmotic diuresis (increased urinary volume), modest blood pressure reduction, and caloric loss through excreted glucose contributing to weight loss.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Tmax ~1 h (fasted); bioavailability ~100%; high-fat meal reduces Cmax by 29% but does not alter AUC | Rapid onset of action; can be taken with or without food without dose adjustment |
| Distribution | Vd 85.5 L; protein binding 93.6% (concentration-independent); blood-to-plasma ratio 0.66 | Moderate tissue distribution; protein binding unchanged in renal or hepatic impairment |
| Metabolism | Primary: UGT1A9 and UGT2B7 O-glucuronidation to two inactive glucuronides; CYP-mediated oxidation accounts for only ~12% | Minimal CYP450 involvement translates to a very low drug interaction potential; does not inhibit or induce major CYP isoenzymes |
| Elimination | t½ 16.6 h; clearance 11.2 L/h; excretion: 50.2% urine, 40.9% feces; only 1.5% excreted unchanged in urine | Supports once-daily dosing; steady state reached in 4–6 days; accumulation 10–40% with multiple dosing |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Female genital mycotic infections | 9.1–12.2% | Dose-related (vs 3.0% placebo); includes vulvovaginal candidiasis, vulvitis, and vulvovaginitis; topical antifungals usually sufficient |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Male genital mycotic infections | 3.7–4.2% | Includes balanitis and balanoposthitis (vs 0.4% placebo); higher in uncircumcised males; phimosis reported in 0.5% requiring circumcision in some |
| Urinary tract infections | 4.0–4.1% | Similar to placebo (3.9%) in short-term trials; in VERTIS CV: 12.0–12.2% vs 10.2% placebo over ~3.5 years |
| Headache | 2.9–3.5% | Versus 2.3% placebo; typically mild and transient |
| Vaginal pruritus | 2.4–2.8% | Versus 0.4% placebo; may accompany genital mycotic infections |
| Increased urination | 2.4–2.7% | Includes pollakiuria, urgency, polyuria, nocturia (vs 1.0% placebo); expected pharmacological effect from osmotic diuresis |
| Thirst / dry mouth | 1.4–2.7% | Versus 0.6% placebo; advise adequate hydration |
| Nasopharyngitis | 2.0–2.5% | Similar to placebo (2.3%); unlikely drug-related |
| Back pain | 1.7–2.5% | Similar to placebo (2.3%); unlikely drug-related |
| Weight decrease | 1.2–2.4% | Mean 2–3 kg weight loss in trials; typically considered a beneficial effect rather than adverse |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Diabetic ketoacidosis | ~0.1% | Variable; may be precipitated by illness, surgery, or fasting | Discontinue immediately; hospitalize; treat ketoacidosis per protocol; can present with euglycemic glucose levels (<250 mg/dL) |
| Lower limb amputation | 0.2–0.5% | Months to years; VERTIS CV: 5.7–6.0 events/1000 patient-years vs 4.7 placebo | Discontinue if infections, ulcers, or new pain/tenderness of lower limbs develop; counsel on preventive foot care |
| Acute kidney injury | Rare | Early treatment; often with concurrent volume depletion | Correct volume depletion; assess renal function; withhold if acute decline occurs; postmarketing cases have required hospitalization and dialysis |
| Necrotizing fasciitis of perineum (Fournier’s gangrene) | Very rare | Any time during treatment | Discontinue immediately; urgent surgical debridement and broad-spectrum antibiotics; SGLT2 class-wide postmarketing signal |
| Serious urinary tract infections (urosepsis, pyelonephritis) | 0.4–0.9% | Any time during treatment | Hospitalize if indicated; treat with appropriate antibiotics; consider discontinuation in severe or recurrent cases |
| Angioedema | Very rare (postmarketing) | Any time during treatment | Discontinue permanently; emergency management if airway compromise; contraindicated on rechallenge |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Female genital mycotic infections | 0.6% | Versus 0% placebo (pooled 26-week trials) |
| Male genital mycotic infections | 0.2% | Versus 0% placebo (pooled 26-week trials) |
Genital mycotic infections are the most clinically significant common adverse effect of ertugliflozin, driven by increased urinary glucose creating a favorable environment for Candida species. They are more prevalent in females and in uncircumcised males. Most cases are mild to moderate and respond to standard topical antifungal treatment. Patients with a prior history of genital fungal infections are at the greatest risk and should be counselled proactively. Discontinuation is rarely necessary, and recurrence can often be managed by maintaining perineal hygiene and prompt treatment at symptom onset.
LDL-cholesterol: Dose-related increases of 2.6% (5 mg) to 5.4% (15 mg) relative to placebo at 26 weeks. Hemoglobin: Mean increase of ~0.47 g/dL (likely related to hemoconcentration from diuresis). Serum phosphate: Mean increases of 6.8–8.5% at 26 weeks. Serum creatinine: Small initial increases within weeks of initiation that stabilize; this hemodynamic effect reverses on discontinuation and does not represent structural kidney damage.
Drug Interactions
Ertugliflozin has an inherently low drug interaction profile. It is primarily metabolized by UGT1A9 and UGT2B7 glucuronidation with minimal CYP450 involvement (~12%). It does not inhibit or induce any major CYP isoenzyme or UGT enzyme at therapeutic concentrations. In vivo studies confirm no clinically meaningful pharmacokinetic changes when co-administered with metformin, glimepiride, sitagliptin, or simvastatin. Ertugliflozin is a substrate of P-gp and BCRP transporters but does not inhibit major drug transporters.
Urine glucose tests: Will be positive during treatment and for several days after discontinuation (not useful for glycemic monitoring). 1,5-anhydroglucitol (1,5-AG) assays: Results are unreliable in patients receiving any SGLT2 inhibitor; use HbA1c or fructosamine instead.
Monitoring
-
Renal Function
Baseline, then as clinically indicated
Routine Assess eGFR before initiation; do not initiate if eGFR <45 mL/min/1.73 m². Expect a small, transient rise in serum creatinine within weeks of starting (hemodynamic effect, not structural damage). Monitor more frequently in patients with eGFR 45–60 or with risk factors for acute kidney injury. -
HbA1c
Baseline, then every 3–6 months
Routine Standard glycemic monitoring. Consider uptitration from 5 mg to 15 mg if HbA1c target not achieved after 3 months and drug is tolerated. Do not use 1,5-AG assays for glycemic monitoring. -
Volume Status
Before initiation, then ongoing
Routine Correct volume depletion before starting ertugliflozin. Monitor for signs of hypotension (dizziness, lightheadedness) especially in elderly, patients on diuretics, or those with eGFR <60. Ensure adequate hydration. -
Blood Glucose
Increased frequency at initiation
Trigger-based Particularly important when combined with insulin or sulfonylureas due to increased hypoglycemia risk. Monitor capillary glucose more frequently during the first weeks. -
Foot Examination
Baseline, then at each visit
Routine Assess for infections, ulcers, new pain, or signs of peripheral vascular disease. Amputation risk was numerically higher with ertugliflozin in the VERTIS CV trial. Discontinue if active foot complications develop. -
Genital Infections
Each visit; patient self-monitoring
Trigger-based Ask about symptoms of vulvovaginal candidiasis or balanitis at follow-up visits. Counsel patients on perineal hygiene and prompt reporting of symptoms. Treat with topical antifungals; escalate if recurrent. -
Ketones
When clinically indicated
Trigger-based Consider monitoring urine or blood ketones during acute illness, perioperative period, reduced caloric intake, or if patient develops nausea, vomiting, abdominal pain, or malaise. DKA may present with near-normal glucose. -
Lipid Panel
Baseline, then annually
Routine Dose-related LDL-C increases of 2.6–5.4% relative to placebo. May warrant statin therapy adjustment in patients near LDL treatment thresholds.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to ertugliflozin or any excipient in the formulation (angioedema has been reported postmarketing)
- Dialysis or end-stage renal disease — drug will not provide glycemic benefit and exposes patient to unnecessary risk
Relative Contraindications (Specialist Input Recommended)
- Type 1 diabetes mellitus — markedly increased risk of life-threatening DKA; ertugliflozin is explicitly not indicated for type 1 diabetes
- eGFR <45 mL/min/1.73 m² — insufficient glycemic efficacy demonstrated; use not recommended
- Severe hepatic impairment (Child-Pugh C) — not studied; use not recommended
- Active or recurrent diabetic foot ulcers, peripheral arterial disease, or prior amputation — numerically higher amputation rates seen in VERTIS CV; document risk-benefit discussion
- History of recurrent genital mycotic infections — high likelihood of exacerbation; weigh benefit vs quality-of-life impact
- Pregnancy (2nd and 3rd trimester) — animal data show adverse renal developmental effects at exposures corresponding to late pregnancy; transition to insulin-based therapy
Use with Caution
- Volume depletion or hypotension risk — correct dehydration before initiation; monitor elderly and those on diuretics or with low systolic blood pressure
- Elderly patients (≥65 years) — higher incidence of volume depletion-related adverse effects (2.2–2.6% vs 1.1% with comparator)
- Patients on insulin or sulfonylureas — increased hypoglycemia risk; consider dose reduction of the insulin secretagogue at initiation
- Patients with pancreatic disorders — increased risk factor for ketoacidosis; counsel on DKA symptoms and ketone monitoring
- Planned surgery — withhold at least 4 days preoperatively; resume when stable and tolerating oral intake
All SGLT2 inhibitors, including ertugliflozin, carry FDA warnings for ketoacidosis (including euglycemic presentations in type 2 diabetes, and fatal cases reported postmarketing), risk of lower limb amputation (predominantly toe and forefoot), and necrotizing fasciitis of the perineum (Fournier’s gangrene, a rare but life-threatening necrotizing infection requiring emergent surgery). Clinicians should educate all patients on warning signs of these conditions and ensure prompt evaluation if symptoms develop. The December 2024 labeling update added guidance on temporary withholding before surgery and addressed the lithium interaction for the first time.
Patient Counselling
Purpose of Therapy
Ertugliflozin works by blocking the kidneys from reabsorbing sugar back into the bloodstream, causing excess glucose to be excreted in the urine. This lowers blood sugar independently of insulin. It is used alongside diet and exercise and may be combined with other diabetes medications. It is taken once daily in the morning and can be taken with or without food.
How to Take
Take one tablet each morning. If a dose is missed, take it as soon as remembered; do not double the next dose. Store at room temperature and protect from moisture. Urine glucose tests will be positive while on this medication — this is expected and not a cause for concern.
Sources
- Steglatro (ertugliflozin) tablets, for oral use. Full Prescribing Information. Revised December 2024. Merck Sharp & Dohme LLC. FDA Label Primary source for all dosing, indications, contraindications, adverse reaction incidence rates, pharmacokinetic parameters, and drug interaction data in this monograph.
- Steglatro (ertugliflozin) tablets. Summary of Product Characteristics. European Medicines Agency. EMA European regulatory summary; approved March 2018 for type 2 diabetes in the EU.
- Steglujan (ertugliflozin and sitagliptin) tablets. Full Prescribing Information. Revised December 2024. Merck Sharp & Dohme LLC. FDA Label Fixed-dose combination product labeling; contains additional sitagliptin-specific safety data relevant to combination prescribing.
- 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. doi:10.1056/NEJMoa2004967 VERTIS CV trial (N=8,246): established cardiovascular non-inferiority for MACE (HR 0.97, 95.6% CI 0.85–1.11) but did not demonstrate superiority on key secondary endpoints.
- Cosentino F, Cannon CP, Cherney DZI, et al. Efficacy of ertugliflozin on heart failure-related events in patients with type 2 diabetes mellitus and established atherosclerotic cardiovascular disease: results of the VERTIS CV trial. Circulation. 2020;142(23):2205–2215. doi:10.1161/CIRCULATIONAHA.120.050255 Prespecified secondary analysis showing 30% reduction in first heart failure hospitalization (HR 0.70), consistent with SGLT2 class effect.
- Cannon CP, McGuire DK, Pratley R, et al. Design and baseline characteristics of the VERTIS-CV trial. Am Heart J. 2018;206:11–23. doi:10.1016/j.ahj.2018.08.016 Design paper for the pivotal CVOT; details baseline population, statistical methodology, and primary/secondary endpoint hierarchy.
- Pratley RE, Cannon CP, Cherney DZI, et al. Cardiorenal outcomes, kidney function, and other safety outcomes with ertugliflozin in older adults with type 2 diabetes (VERTIS CV). Lancet Healthy Longev. 2023;4(4):e143–e154. doi:10.1016/S2666-7568(23)00032-6 Secondary analysis in >4,000 adults ≥65 years showing consistent benefit-risk profile across age subgroups.
- American Diabetes Association Professional Practice Committee. Standards of Care in Diabetes — 2025. Diabetes Care. 2025;48(Suppl 1). doi:10.2337/dc25-SINT Positions SGLT2 inhibitors as preferred agents in T2DM patients with established ASCVD, heart failure, or CKD; notes distinction between agents with proven superiority vs non-inferiority for cardiovascular outcomes.
- 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 Cardiol. 2021;6(2):148–158. doi:10.1001/jamacardio.2020.4511 Meta-analysis of SGLT2 inhibitor CVOTs including VERTIS CV; quantifies consistent HF hospitalization reduction across the class.
- Cinti F, Moffa S, Impronta F, et al. Spotlight on ertugliflozin and its potential in the treatment of type 2 diabetes: evidence to date. Drug Des Devel Ther. 2017;11:2905–2919. doi:10.2147/DDDT.S114932 Comprehensive review of ertugliflozin pharmacology, selectivity for SGLT2 over SGLT1, and early clinical trial data prior to approval.
- Markham A. Ertugliflozin: first global approval. Drugs. 2018;78(4):513–519. doi:10.1007/s40265-018-0878-6 Drug approval summary covering chemical structure, selectivity profile, and pivotal registration trial results.
- Hussey EK, Kapur A, O’Connor-Semmes R, et al. Safety, pharmacokinetics, and pharmacodynamics of ertugliflozin (PF-04971729) in healthy subjects. Clin Pharmacol Drug Dev. 2017;6(5):519–528. doi:10.1002/cpdd.378 Phase 1 data establishing PK parameters including dose-proportional exposure, 100% bioavailability, and urinary glucose excretion dose-response.
- Sahasrabudhe V, Terra SG, Engell RT, et al. Effect of renal impairment on the pharmacokinetics of ertugliflozin. Clin Pharmacol Drug Dev. 2017;6(4):381–390. doi:10.1002/cpdd.311 Characterizes the 1.6–1.7-fold increase in AUC across mild, moderate, and severe renal impairment, deemed not clinically meaningful; confirms declining urinary glucose excretion with worsening kidney function.
- Aronson R, Frias J, Goldman A, et al. Safety of ertugliflozin in patients with type 2 diabetes mellitus: pooled analysis of seven phase 3 randomized controlled trials. Diabetes Ther. 2020;11(6):1347–1367. doi:10.1007/s13300-020-00803-3 Comprehensive pooled safety analysis across 4,849 patients and up to 104 weeks; source for adverse event incidence rates and discontinuation data.