Ertugliflozin and Sitagliptin - Indication, Dosage, and Pharmacological Aspects

Overview:

A combination tablet containing Ertugliflozin and Sitagliptin was created to treat type 2 diabetes. Several studies have been conducted to test if this combination tablet works the same as taking the individual components separately. These studies showed that the combination tablet is as effective and safe as taking the individual components. This also means that the benefits and side effects of Ertugliflozin and Sitagliptin when taken together are the same, whether taken separately as two tablets or when taken as a single combined tablet. The combination drug received the FDA (Food and Drug Administration) approval in 2017.

Drug Group:

Ertugliflozin is a member of the SGLT2 (sodium-glucose co-transporter 2) inhibitor class of medications. It works by causing the kidneys to excrete additional glucose as urine, which lowers blood sugar.

A class of drugs called DPP-4 (dipeptidyl peptidase-4 (DPP-4) ) inhibitors includes Sitagliptin. With diet and exercise, this oral medication helps control blood sugar levels, which is helpful in the management of type 2 diabetes.

Available Doses and Dosage Forms:

• Ertugliflozin and Sitagliptin 5 mg/100 mg (milligram) tablets have 5 mg of Ertugliflozin and 100 mg of Sitagliptin, are beige, almond-shaped, and have "554" imprinted on one side.

• Ertugliflozin and Sitagliptin 15 mg/100 mg tablets have 15 mg of Ertugliflozin and 100 mg of Sitagliptin, are brown, almond-shaped, and have "555" imprinted on one side.

For Patients:

What Is Type 2 Diabetes Mellitus?

Type 2 diabetes occurs when the body has trouble regulating and using sugar (glucose) as its main source of energy. This leads to high levels of sugar in the blood over time.

What Is Ertugliflozin and Sitagliptin?

Ertugliflozin and Sitagliptinare used together with diet and exercise to help lower blood sugar levels in adults who have type 2 diabetes. However, it is not intended for people with type 1 diabetes or those experiencing diabetic ketoacidosis, a condition that involves high levels of ketones in the blood or urine. It is important to note that Ertugliflozin and Sitagliptin’s safety and effectiveness have not been established in children under 18.

What Is the Dosage of Ertugliflozin and Sitagliptin?

Ertugliflozin and Sitagliptin tablets come in 5 mg/100 mg and 15 mg/100 mg strengths for adults with type 2 diabetes. The starting dose is one tablet daily, which can be increased if needed. Adjustments may be necessary for kidney and liver issues. This medication is not for type 1 diabetes and has not been studied in patients with pancreatitis (inflammation of the pancreas) history.

How Is Ertugliflozin and Sitagliptin Administered?

• Take Ertugliflozin and Sitagliptin exactly as prescribed by the doctor.

• Swallow Ertugliflozin and Sitagliptin with water once every morning, either with or without food.

• The doctor may adjust the dose if necessary.

• If the person forgets a dose, take it as soon as they remember. If it is almost time for the next dose, skip the missed one and take the next dose at the regular time. Do not take two doses at once.

• The doctor might recommend taking Ertugliflozin and Sitagliptin alongside other diabetes medications, but this could increase the risk of low blood sugar. Be aware of the symptoms and discuss any concerns with the doctor.

• Stick to the prescribed diet and exercise routine while taking Ertugliflozin and Sitagliptin.

• Monitor the blood sugar levels as directed by the doctor.

• The doctor will regularly check the diabetes status with blood tests, including blood sugar levels and HbA1c.

• Talk to the doctor about managing low or high blood sugar and other diabetes-related complications.

• The kidney function will be monitored through blood tests before and during Ertugliflozin and Sitagliptin treatment.

• Notify the doctor if a person experiences stress like fever, injury, infection, or surgery, as it may affect the diabetes treatment.

• Ertugliflozin and Sitagliptin might cause sugar to appear in the urine during a urine test.

• If a person accidentally takes excessive dosage of Ertugliflozin and Sitagliptin, contact the doctor or go to the nearest hospital emergency room.

What Are the Side Effects of Ertugliflozin and Sitagliptin?

• Inflammation of the pancreas.

• Ketoacidosis is a serious condition where the body produces high levels of blood acids called ketones.

• Lower limb amputation is the surgical removal of a limb, typically a leg.

• Sudden loss of kidney function.

• Loss of fluids in the body.

• Severe infections in the urinary tract and kidneys.

• The inability of the heart to pump enough blood to meet the body's needs.

• Low blood sugar levels when taking certain diabetes medications.

• Severe infection of the tissue around the genitals and anus.

• Fungal infections in the genital area.

• Severe allergic reactions.

• Severe and disabling joint pain.

• Rare skin conditions characterized by large blisters.

Overdose:

• If someone takes too much Ertugliflozin and Sitagliptin, contact the poison control center right away. Follow standard supportive measures based on the patient's condition.

• For an overdose of Ertugliflozin, there is no information on whether it can be removed by hemodialysis.

• In case of an overdose of Sitagliptin, it is advisable to remove any unabsorbed material from the stomach, monitor the patient's condition, including obtaining an electrocardiogram, and provide supportive therapy as needed.

• Sitagliptin can be removed from the body to some extent through hemodialysis, where about 13.5 percent of the dose is removed over a three to four-hour session. Prolonged hemodialysis may be considered if necessary. It is uncertain if Sitagliptin can be removed by peritoneal dialysis.

Storage:

Ertugliflozin and Sitagliptin tablets come in two strengths: 5 mg of Ertugliflozin combined with 100 mg of Sitagliptin, are beige colored, almond-shaped tablets with "554" on one side, available in bottles of 30 tablets, 90 tablets, and bulk bottles of 500 tablets. 15 mg of Ertugliflozin combined with 100 mg of Sitagliptin are brown colored, almond-shaped tablets with "555" on one side, available in bottles of 30 tablets, 90 tablets, and bulk bottles of 500 tablets. These tablets should be stored at room temperature between 20 °C (Celsius) to 25 °C (68 °F (Fahrenheit) to 77 °F), with excursions permitted between 15 °C to 30 °C (59 °F to 86 °F). They should be protected from moisture and stored in a dry place.

For Doctors:

Indication:

Ertugliflozin and Sitagliptin are prescribed alongside dietary and exercise measures to enhance glycemic regulation in adult patients diagnosed with type 2 diabetes mellitus.

Dose:

• The tablets containing Ertugliflozin and Sitagliptin in the ratio of 5 mg/100 mg consist of 5 mg of Ertugliflozin and 100 mg of Sitagliptin.

• The tablets containing Ertugliflozin and Sitagliptin in the ratio of 15 mg/100 mg comprise 15 mg of Ertugliflozin and 100 mg of Sitagliptin.

Dosing Considerations:

• Start with one pill of Ertugliflozin and Sitagliptin each morning, containing five milligrams of Ertugliflozin and 100 mg of Sitagliptin.

• Take the pill with or without food.

• The person can continue with the same dose if they are already taking Ertugliflozin.

• If more blood sugar control is needed, the doctor may increase the dose to one pill containing 15 mg of Ertugliflozin and 100 mg of Sitagliptin daily, as long as the patient tolerates it.

• Avoid using Ertugliflozin and Sitagliptin if the kidney function is below a certain level (eGFR (estimated glomerular filtration rate) less than 45 mL/min/1.73 m2), or if the person has severe kidney impairment (eGFR <30 mL/min/1.73 m2), end-stage renal disease (ESRD), or are on dialysis.

What Are the Pharmacological Aspects of Ertugliflozin and Sitagliptin?

1. Pharmacodynamics:

• Ertugliflozin: For urinary glucose excretion and volume, Ertugliflozin increases glucose excretion in urine, dose-dependently, in both healthy individuals and those with type 2 diabetes. This effect persists with multiple doses, leading to increased urinary volume. For cardiac electrophysiology, in a study of 42 healthy subjects, even at 6.7 times the recommended dose, Ertugliflozin did not significantly prolong the QTc interval, indicating no clinically relevant cardiac effects.

• Sitagliptin: Generally, Sitagliptin inhibits the DPP-4 enzyme (dipeptidyl peptidase) for 24 hours in patients with type 2 diabetes, increasing active GLP-1 (gastric inhibitory polypeptide) and GIP (glucagon‐like peptide) hormones, lowering glucagon, and enhancing insulin response to glucose, thus improving glucose control. For the blood glucose effect, Sitagliptin alone raises active GLP-1 levels, while Metformin, synergistically increases active GLP-1. Its impact on glycemic control's clinical significance remains uncertain. For cardiac electrophysiology, studies in healthy subjects and patients with diabetes showed no meaningful QTc interval changes with Sitagliptin, even at doses exceeding the recommended amount, suggesting minimal cardiac effects.

2. Mechanism of Action: Ertugliflozin and Sitagliptin are medications used to treat type 2 diabetes. It contains two different drugs that work together to help control blood sugar levels: Ertugliflozin and Sitagliptin. Ertugliflozin works by blocking a specific transporter in the kidneys that normally helps reabsorb glucose (sugar) back into the bloodstream. By blocking this transporter, Ertugliflozin helps the kidneys excrete more glucose in the urine, thereby reducing blood sugar levels. Sitagliptin works differently. It is a type of drug called a DPP-4 inhibitor. It helps control blood sugar levels by preventing the breakdown of certain hormones in the body called incretins. These hormones help regulate insulin release and blood sugar levels after meals. By preventing their breakdown, Sitagliptin helps increase insulin production and decrease glucose production by the liver, ultimately lowering blood sugar levels. Together, these two drugs, Ertugliflozin and Sitagliptin, work in different ways to help improve blood sugar control in people with type 2 diabetes.

3. Pharmacokinetics:

• Ertugliflozin: After daily doses of 5 mg or 15 mg, steady-state levels in plasma are reached in four to 6 days. There is no significant buildup of Ertugliflozin in the body with repeated doses. Food does not significantly affect how the body absorbs or processes Ertugliflozin. Ertugliflozin is mainly cleared from the body through metabolism and is excreted in feces and urine.

• Sitagliptin: After taking a 100 mg dose, Sitagliptin levels in the blood peak within one to four hours. The body absorbs Sitagliptin quickly, and its levels increase with higher doses. Food does not affect how the body absorbs or processes Sitagliptin. Sitagliptin is mainly cleared from the body through urine. People with kidney or liver problems may have slightly different levels of Sitagliptin in their bodies, but these differences are not clinically significant.

Clinical Studies: Due to differences in how clinical trials are conducted, the rates of adverse reactions observed in trials of one drug cannot be directly compared to those of another drug or reflect real-world rates. The safety of combining Ertugliflozin and Sitagliptin was studied in 990 patients with type 2 diabetes over 26 weeks in three trials. Adverse reactions observed were similar to those seen with ertugliflozin alone in a pool of placebo-controlled trials involving 1,029 patients over 26 weeks. Adverse reactions were more common with Ertugliflozin than with placebo and were experienced by at least two percent of patients taking either Ertugliflozin 5 mg or 15 mg.

What Are the Contraindications of Ertugliflozin and Sitagliptin?

• Ertugliflozin and Sitagliptin are not suitable for patients with type 1 diabetes mellitus due to the potential increased risk of diabetic ketoacidosis.

• Ertugliflozin and Sitagliptin’s safety has not been evaluated in patients with a history of pancreatitis, and it is uncertain whether such patients are at higher risk of developing pancreatitis while using Ertugliflozin and Sitagliptin.

• Patients with severe renal impairment (glomerular filtration rate < 30 mL/min/1.73 m² (milliliter per minute per meter square)), end-stage renal disease (ESRD), or undergoing dialysis should exercise caution when using Ertugliflozin and Sitagliptin.

• Hypersensitivity reactions, including anaphylaxis or angioedema, may occur in individuals with a known hypersensitivity to Sitagliptin, ertugliflozin, or any excipient present in Ertugliflozin and Sitagliptin.

What Are the Drug Interactions of Ertugliflozin and Sitagliptin?

When taken together, Ertugliflozin and Sitagliptin do not significantly affect each other's levels in the body. Ertugliflozin is unlikely to interfere with other medications, and no dosage adjustments are needed when taking it with common drugs. Sitagliptin is also unlikely to cause interactions with other drugs, and it does not bind tightly to plasma proteins, reducing the likelihood of drug interactions based on protein binding. The effectiveness of Sitagliptin is not significantly altered when taken with other medications commonly used to treat various conditions. Overall, both ertugliflozin and Sitagliptin are well-tolerated and have predictable pharmacokinetics, meaning the body processes them in consistent ways. They do not have significant interactions with other drugs commonly used by patients.

Warnings and Precautions:

• Pancreatitis: Close monitoring for pancreatitis symptoms is essential, and the medication should be stopped if suspected.

• Ketoacidosis: Patients may develop ketoacidosis, especially those with type 1 diabetes. Severe metabolic acidosis should prompt evaluation for ketoacidosis.

• Lower Limb Amputation: Long-term use is associated with an increased risk of lower limb amputations, particularly in patients with certain risk factors.

• Acute Renal Failure: Worsening renal function, including acute renal failure, may occur, especially in patients with pre-existing renal issues.

• Volume Depletion: Intravascular volume contraction can lead to symptomatic hypotension or acute changes in creatinine levels.

• Urosepsis and Pyelonephritis: Serious urinary tract infections may occur, necessitating hospitalization.

• Heart Failure: Some patients may experience heart failure.

• Hypoglycemia: Combining with insulin or insulin secretagogues increases the risk of hypoglycemia.

• Necrotizing Fasciitis: Rare cases of Fournier’s Gangrene have been reported, requiring immediate evaluation and discontinuation of the medication.

• Genital Mycotic Infections: Ertugliflozin increases the risk of genital fungal infections.

• Hypersensitivity Reactions: Serious hypersensitivity reactions, including anaphylaxis, have been reported.

• Severe Arthralgia: Some patients experience severe joint pain, which may necessitate discontinuation of the medication.

• Bullous Pemphigoid: DPP-4 inhibitors have been associated with bullous pemphigoid, a serious skin condition.

Specific Considerations:

1. Pregnancy: Avoid Ertugliflozin and Sitagliptin during the second and third trimesters due to potential adverse effects on fetal kidneys. Limited data on their use during pregnancy.

2. Lactation: Unknown effects on breastfed infants. Risk to human kidney development based on animal studies.

3. Pediatric Use: Safety and effectiveness is not established in patients under 18.

4. Geriatric Use: No dosage adjustment based on age, but elderly patients may need more frequent renal function assessments.

5. Renal Impairment: Contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m2), ESRD, or dialysis. No adjustment is needed for eGFR ≥45 mL/min/1.73 m2.