Glyxambi (Empagliflozin/Linagliptin) – Clinical Guidance
Indications
Glyxambi is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes when treatment with both empagliflozin and linagliptin is appropriate. 1 The fixed-dose combination is available as 10 mg empagliflozin/5 mg linagliptin or 25 mg empagliflozin/5 mg linagliptin tablets. 1
When to Use Glyxambi
- Patients inadequately controlled on metformin monotherapy who require dual therapy with complementary mechanisms—empagliflozin blocks renal glucose reabsorption while linagliptin increases incretin activity to stimulate insulin secretion and reduce glucagon. 1, 2
- Patients requiring both cardiovascular/renal protection (from empagliflozin) and additional glycemic control (from linagliptin) without the weight gain or hypoglycemia risk of sulfonylureas or insulin. 3, 2
- Patients with pill-burden concerns where a single-tablet formulation improves adherence compared to taking empagliflozin and linagliptin separately. 4, 5
When NOT to Use Glyxambi
- Patients with established heart failure—SGLT2 inhibitors are preferred as monotherapy or with metformin, but thiazolidinediones (which share fluid-retention mechanisms with some combination therapies) are contraindicated in heart failure; prioritize empagliflozin alone or with metformin. 6
- Patients requiring maximum cardiovascular mortality reduction—use empagliflozin 25 mg alone (which has proven mortality benefit in EMPA-REG OUTCOME) rather than the fixed combination, as DPP-4 inhibitors lack cardiovascular mortality benefit. 6
- Patients with eGFR <45 mL/min/1.73 m²—empagliflozin's glucose-lowering efficacy diminishes below this threshold, though cardiovascular/renal benefits persist; linagliptin requires no renal dose adjustment but the combination becomes less effective for glycemic control. 7
Dosing Regimen
Starting Dose
- Begin with 10 mg empagliflozin/5 mg linagliptin once daily in the morning, taken with or without food. 1
Dose Escalation
- If additional glycemic control is needed after 4–12 weeks, increase to 25 mg empagliflozin/5 mg linagliptin once daily. 1 The linagliptin dose remains fixed at 5 mg; only the empagliflozin component is titrated.
Special Populations
- No dose adjustment required for renal impairment (eGFR ≥30 mL/min/1.73 m²), though glycemic efficacy of empagliflozin decreases when eGFR <45 mL/min/1.73 m². 7
- No dose adjustment required for hepatic impairment for either component. 4
- Elderly patients (≥65 years) may have increased risk of volume depletion with empagliflozin; monitor closely and consider starting with the lower dose. 7
Contraindications
Absolute Contraindications
- Severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease requiring dialysis—empagliflozin is contraindicated. 7
- History of serious hypersensitivity reaction to empagliflozin, linagliptin, or any excipient (e.g., angioedema, anaphylaxis). 1
- Diabetic ketoacidosis—insulin is required; SGLT2 inhibitors can precipitate or worsen ketoacidosis. 7
Relative Contraindications (Use with Extreme Caution)
- Active urinary tract infection or recurrent genital mycotic infections—empagliflozin increases risk of genitourinary infections. 7
- Volume depletion or hypotension—empagliflozin causes osmotic diuresis; correct volume status before initiating. 7
- History of pancreatitis—DPP-4 inhibitors have been associated with pancreatitis, though causality is not definitively established; monitor closely. 7
Precautions and Monitoring
Before Initiating Therapy
- Assess renal function (eGFR) to confirm eGFR ≥30 mL/min/1.73 m² and establish baseline. 7
- Evaluate volume status—correct dehydration or hypotension before starting empagliflozin. 7
- Screen for active genitourinary infections and treat before initiating. 7
- Review concomitant medications—reduce insulin or sulfonylurea doses by 20–50% to prevent hypoglycemia when adding Glyxambi. 7
Ongoing Monitoring
- Renal function every 3–6 months in patients with eGFR 45–60 mL/min/1.73 m², and annually in those with normal function. 7
- Signs of volume depletion (dizziness, orthostatic hypotension, syncope)—especially in elderly patients, those on diuretics, or with eGFR 30–60 mL/min/1.73 m². 7
- Symptoms of ketoacidosis (nausea, vomiting, abdominal pain, dyspnea, confusion)—even if blood glucose is <250 mg/dL (euglycemic DKA). 7
- Genital mycotic infections (pruritus, discharge, dysuria)—more common in women and uncircumcised men. 7
- Urinary tract infections (dysuria, frequency, urgency, fever)—treat promptly and consider discontinuing empagliflozin if pyelonephritis or urosepsis develops. 7
- Foot care and lower-limb complications—SGLT2 inhibitors may increase risk of lower-limb amputation in patients with peripheral vascular disease; inspect feet regularly. 7
Situations Requiring Temporary Discontinuation
- Before major surgery or prolonged fasting—stop empagliflozin 3 days prior to reduce ketoacidosis risk. 7
- During acute illness with reduced oral intake (e.g., gastroenteritis, influenza)—hold empagliflozin until patient resumes normal eating/drinking. 7
- If ketoacidosis is suspected—discontinue immediately and initiate insulin therapy. 7
Adverse Effects
Common (≥5% incidence)
- Urinary tract infections (9–10% with empagliflozin vs. 5% placebo)—more frequent in women; treat with standard antibiotics. 3
- Genital mycotic infections (6–7% with empagliflozin vs. 2% placebo)—topical antifungals are usually effective; infections rarely require drug discontinuation. 3
- Increased urination (polyuria)—due to osmotic diuresis from empagliflozin; typically resolves within 2–4 weeks. 1
- Nasopharyngitis (5–6% with linagliptin)—upper respiratory symptoms; self-limited. 3
Serious but Rare (<1% incidence)
- Ketoacidosis (including euglycemic DKA)—can occur even with blood glucose <250 mg/dL; risk factors include insulin deficiency, reduced caloric intake, surgery, alcohol abuse. 7
- Acute kidney injury—usually related to volume depletion; more common in elderly patients or those with baseline renal impairment. 7
- Fournier's gangrene (necrotizing fasciitis of the perineum)—rare but life-threatening; presents with genital/perineal pain, erythema, fever; requires immediate surgical debridement and broad-spectrum antibiotics. 7
- Hypotension/orthostatic hypotension—due to volume depletion from osmotic diuresis; risk increased with loop diuretics, elderly age, or eGFR 30–60 mL/min/1.73 m². 7
- Pancreatitis—persistent severe abdominal pain (with or without vomiting); discontinue Glyxambi if suspected. 7
- Severe hypersensitivity reactions (angioedema, anaphylaxis)—discontinue immediately and do not rechallenge. 1
Hypoglycemia Risk
- Minimal intrinsic hypoglycemia risk when Glyxambi is used alone or with metformin—the glucose-dependent mechanisms of both empagliflozin and linagliptin confer low hypoglycemia potential. 3, 2
- Increased hypoglycemia risk when combined with insulin or sulfonylureas—reduce insulin dose by ~20% and sulfonylurea dose by ~50% when adding Glyxambi. 7
Patient Counseling Points
Administration Instructions
- Take once daily in the morning with or without food; swallow tablet whole (do not split, crush, or chew). 1
- If a dose is missed, take it as soon as remembered on the same day; do not double the next dose. 1
Expected Benefits
- Improved blood sugar control with HbA1c reductions of 0.6–0.8% when added to metformin (greater than either agent alone). 3, 5
- Modest weight loss of 2–3 kg due to empagliflozin's caloric loss through urinary glucose excretion. 1, 3
- Blood pressure reduction of 3–5 mmHg systolic due to empagliflozin's diuretic effect. 1
- Cardiovascular and renal protection from empagliflozin (reduced risk of CV death, heart failure hospitalization, and kidney disease progression). 7, 6
Warning Signs Requiring Immediate Medical Attention
- Symptoms of ketoacidosis: nausea, vomiting, abdominal pain, unusual fatigue, difficulty breathing, confusion—even if blood sugar is not very high. 7
- Severe genital or perineal pain, redness, swelling, or fever—possible Fournier's gangrene. 7
- Persistent severe abdominal pain (with or without vomiting)—possible pancreatitis. 7
- Signs of severe allergic reaction: rash, hives, swelling of face/lips/tongue, difficulty breathing. 1
Lifestyle Modifications
- Maintain adequate hydration (8–10 glasses of water daily) to reduce risk of volume depletion and urinary tract infections. 7
- Practice good genital hygiene to minimize risk of mycotic infections; women should wipe front-to-back. 7
- Inspect feet daily for cuts, blisters, or sores—especially if you have neuropathy or peripheral vascular disease. 7
- Avoid prolonged fasting or very-low-carbohydrate diets while on empagliflozin, as these increase ketoacidosis risk. 7
Drug Interactions
- Diuretics (furosemide, hydrochlorothiazide)—may increase risk of dehydration and hypotension; monitor volume status closely. 7
- Insulin or sulfonylureas—your doctor will reduce these doses to prevent low blood sugar when starting Glyxambi. 7
- Rifampin (antibiotic)—may reduce linagliptin levels; consider increasing Glyxambi dose or using alternative antibiotic. 4
Alternative Second-Line Therapies
When Glyxambi Is Not Appropriate
If cardiovascular disease is present:
- Empagliflozin 25 mg alone (without linagliptin) is preferred—proven 38% reduction in cardiovascular death in EMPA-REG OUTCOME trial. 6
- GLP-1 receptor agonists (semaglutide, liraglutide, dulaglutide)—provide 20–26% reduction in major adverse cardiovascular events and promote greater weight loss (5–7 kg) than Glyxambi. 7, 6
If heart failure is present:
- SGLT2 inhibitors alone (empagliflozin, dapagliflozin, canagliflozin)—reduce heart failure hospitalization by 30–35%; avoid adding DPP-4 inhibitors, which lack heart failure benefit. 7, 6
If chronic kidney disease (eGFR 20–60 mL/min/1.73 m²) is present:
- SGLT2 inhibitors alone—slow CKD progression and reduce albuminuria; linagliptin adds minimal benefit in this setting. 7, 6
- GLP-1 receptor agonists—reduce albuminuria and slow eGFR decline; preferred if eGFR <30 mL/min/1.73 m² (where SGLT2 inhibitors lose glycemic efficacy). 7
If maximum weight loss is the priority:
- GLP-1 receptor agonists (especially semaglutide 2.4 mg or tirzepatide)—produce 10–20% weight loss vs. 2–3% with Glyxambi. 7, 6
If cost is a barrier:
- Metformin + generic sulfonylurea (glipizide, glimepiride)—much less expensive but higher hypoglycemia risk and no cardiovascular/renal protection. 7
- Metformin + pioglitazone—generic thiazolidinedione; avoid in heart failure due to fluid retention. 6
Monitoring Recommendations
Baseline (Before Starting Glyxambi)
- HbA1c to establish glycemic control target. 7
- Fasting plasma glucose to guide dose titration. 7
- Comprehensive metabolic panel (eGFR, electrolytes, liver enzymes). 7
- Urinalysis to rule out active urinary tract infection. 7
- Blood pressure (sitting and standing) to assess for orthostatic hypotension. 7
- Body weight to track weight changes. 1
Follow-Up Monitoring Schedule
At 4 weeks:
- Fasting glucose to assess early glycemic response. 7
- Blood pressure (sitting and standing) to detect volume depletion. 7
- Symptoms of genitourinary infections (dysuria, pruritus, discharge). 7
At 3 months:
- HbA1c to determine if dose escalation (to 25 mg empagliflozin/5 mg linagliptin) is needed. 7
- eGFR and electrolytes to monitor renal function. 7
- Body weight to quantify weight loss. 1
Every 6 months (once stable):
- HbA1c to confirm sustained glycemic control. 7
- eGFR to detect any decline in renal function. 7
- Lipid panel (empagliflozin modestly increases LDL-C by 2–5 mg/dL). 7
Annually:
- Comprehensive foot examination to screen for neuropathy, ulcers, or vascular insufficiency. 7
- Urinary albumin-to-creatinine ratio to assess for diabetic nephropathy progression. 7
Common Pitfalls to Avoid
- Do not use Glyxambi as initial monotherapy—it is indicated only when both empagliflozin and linagliptin are appropriate, typically after metformin failure. 1
- Do not continue full-dose insulin or sulfonylureas when adding Glyxambi—reduce insulin by ~20% and sulfonylureas by ~50% to prevent hypoglycemia. 7
- Do not ignore volume depletion symptoms (dizziness, orthostatic hypotension)—especially in elderly patients or those on loop diuretics; hold Glyxambi and rehydrate. 7
- Do not dismiss mild genital symptoms—early treatment of mycotic infections prevents progression and improves adherence. 7
- Do not overlook euglycemic DKA—ketoacidosis can occur even with blood glucose <250 mg/dL; check ketones if patient has nausea, vomiting, or abdominal pain. 7
- Do not combine Glyxambi with other DPP-4 inhibitors (sitagliptin, saxagliptin, alogliptin)—no additional benefit and increased adverse event risk. 7
- Do not use Glyxambi in patients with eGFR <30 mL/min/1.73 m²—empagliflozin is contraindicated; switch to GLP-1 receptor agonist or insulin. 7