Adult: Available preparations:
Ertugliflozin 5 mg and sitagliptin 100 mg tab
Ertugliflozin 15 mg and sitagliptin 100 mg tab
As an adjunct to diet and exercise to improve glycaemic control: Initially, 5 mg ertugliflozin/100 mg sitagliptin once daily, taken in the morning. Dose may be increased up to Max 15 mg ertugliflozin/100 mg sitagliptin once daily if further glycaemic control is needed. Patients already taking ertugliflozin: Maintain current ertugliflozin dose with sitagliptin 100 mg once daily. Correct volume depletion prior to treatment initiation, if present.
eGFR 45-<60 mL/min/1.73 m2: Not recommended; eGFR <45 mL/min/1.73 m2 and patients with ESRD or undergoing dialysis: Contraindicated.
Severe (Child-Pugh class C): Not recommended.
Renal impairment (eGFR <45 mL/min/1.73 m2); patients with ESRD or undergoing dialysis.
Patient with volume depletion, CV disease; history of genital mycotic infections, pancreatitis, hypotension, or angioedema with other DPP-4 inhibitor; risk factors predisposing to ketoacidosis (e.g. pancreatic insulin deficiency, caloric restriction, alcohol abuse, acute febrile illness, dehydration, pancreatic surgery) or amputation (e.g. peripheral vascular disease, diabetic foot ulcers, neuropathy, prior amputation); risk factors for acute kidney injury (e.g. hypovolaemia, chronic renal insufficiency, CHF); undergoing surgery, including bariatric procedures. Uncircumcised males. Temporarily discontinue therapy ≥4 days before surgery or any event that may precipitate ketoacidosis. Not indicated for use in patients with type 1 diabetes mellitus or diabetic ketoacidosis. Renal (eGFR 45-<60 mL/min/1.73 m2) and severe hepatic impairment. Elderly. Pregnancy and lactation.
Significant: Bone fractures, severe arthralgia, bullous pemphigoid, genital mycotic infections (e.g. candidal balanitis, balanoposthitis, vulvovaginitis, vulvovaginal candidiasis), symptomatic hypotension, volume depletion, lower limb amputation (mainly of the toe), acute renal injury or failure, impaired renal function (e.g. decreased eGFR, increased serum creatinine), serious UTIs (e.g. pyelonephritis, urosepsis), increased LDL-cholesterol (LDL-C), heart failure, hypoglycaemia. Gastrointestinal disorders: Constipation, vomiting, stomatitis, diarrhoea. Investigations: Increased Hb, BUN, hepatic enzymes; serum lipid changes, decreased weight. Metabolism and nutrition disorders: Thirst. Musculoskeletal and connective tissue disorders: Back pain, myalgia, rhabdomyolysis, pain in extremity. Nervous system disorders: Headache, dizziness. Renal and urinary disorders: Increased urination. Reproductive system and breast disorders: Vulvovaginal pruritus. Respiratory, thoracic and mediastinal disorders: Upper respiratory tract infection, nasopharyngitis. Skin and subcutaneous tissue disorders: Pruritus. Potentially Fatal: Acute pancreatitis including haemorrhagic or necrotising pancreatitis, serious hypersensitivity reactions (e.g. anaphylaxis, angioedema, Stevens-Johnson syndrome). Rarely, diabetic ketoacidosis, necrotising fasciitis of the perineum (Fournier’s gangrene).
Patient Counseling Information
This drug may cause dizziness and somnolence, if affected, do not drive or operate machinery. This drug may also increase your risk of lower limb amputations; it is important to adhere to your routine preventive foot care.
Monitor blood glucose, HbA1c (at least twice yearly in patients with stable glycaemic control; quarterly in patients not meeting treatment goals), renal function (at baseline and periodically during therapy), volume status (e.g. blood pressure, electrolytes, haematocrit); LDL-C. Assess for signs or symptoms of acute pancreatitis, heart failure, genital mycotic infections, UTIs, hypersensitivity reactions; sores, ulcers, or infection of the lower limb and feet. Confirm signs of ketoacidosis by directly measuring blood ketones and arterial pH.
Ertugliflozin: Increased risk of hypoglycaemia when combined with insulin or insulin secretagogues (e.g. sulfonylurea). May increase the risk of hypotension and dehydration with diuretics.
Sitagliptin may cause a slight increase in plasma digoxin concentrations.
Ertugliflozin: May cause positive test result for glucosuria. May interfere with glycaemic control monitoring using 1,5-anhydroglucitol (1,5-AG) assay.
Description: Ertugliflozin is a potent, selective, and reversible inhibitor of sodium-glucose co-transporter 2 (SGLT2), the main transporter responsible for filtered glucose reabsorption in the renal proximal convoluted tubules. Inhibition of SGLT2 reduces the renal reabsorption of filtered glucose and lowers the renal threshold for glucose, thereby increasing urinary glucose excretion and reducing plasma glucose levels.
Sitagliptin inhibits the dipeptidyl peptidase-4 (DPP-4) enzyme resulting in prolonged active incretin levels. Incretin hormones, including glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), regulate glucose homeostasis by increasing insulin synthesis and release from pancreatic β-cells and lowering glucagon secretion from pancreatic α-cells. Reduced glucagon secretion leads to decreased hepatic glucose production. Pharmacokinetics: Absorption: Ertugliflozin: Bioavailability: Approx 100%. Time to peak plasma concentration: Approx 1 hour.
Sitagliptin: Rapidly absorbed from the gastrointestinal tract. Bioavailability: Approx 87%. Time to peak plasma concentration: Approx 1-4 hours. Distribution: Ertugliflozin: Volume of distribution: 86 L. Plasma protein binding: Approx 94%.
Sitagliptin: Volume of distribution: Approx 198 L. Plasma protein binding: 38%. Metabolism: Ertugliflozin: Extensively metabolised primarily by uridine diphosphate glucuronosyltransferases (UGT)1A9 and UGT2B7 via O-glucuronidation into 2 inactive metabolites; undergoes minimal metabolism by CYP450 isoenzyme.
Sitagliptin: Undergoes minimal metabolism, mainly by CYP3A4 isoenzyme and to a lesser extent by CYP2C8 isoenzyme. Excretion: Ertugliflozin: Via urine (approx 50%; 1.5% as unchanged drug); faeces (approx 41%; approx 34% as unchanged drug). Elimination half-life: Approx 17 hours.
Sitagliptin: Via urine (approx 79% as unchanged drug; 16% as metabolites) and faeces (13%). Terminal half-life: Approx 12 hours.