What is the recommended use and dosing of Terzepatide (GIP/GLP-1 receptor agonist) for patients with type 2 diabetes and obesity?

Tirzepatide for Type 2 Diabetes and Obesity Management

Recommended Use

Tirzepatide is a dual GIP/GLP-1 receptor agonist indicated for adults with type 2 diabetes as an adjunct to diet and exercise, and for weight reduction in adults with obesity or overweight with weight-related comorbidities, including treatment of moderate to severe obstructive sleep apnea in adults with obesity. 1

The American Diabetes Association recommends that a GLP-1 receptor agonist, including a dual GIP and GLP-1 RA (tirzepatide), is preferred to insulin for glycemic management in adults with type 2 diabetes due to greater glycemic effectiveness and beneficial effects on weight and hypoglycemia risk 2.

Clinical Positioning

For Type 2 Diabetes with Cardiovascular Disease

• In patients with type 2 diabetes and established atherosclerotic cardiovascular disease (prior MI, ischemic stroke, unstable angina with ECG changes, myocardial ischemia on imaging, or revascularization), GLP-1 receptor agonists have the greatest level of evidence for MACE benefit 2
• Treatment decisions should be made independently of baseline HbA1c or individualized HbA1c target 2

For Type 2 Diabetes with High Cardiovascular Risk

• GLP-1 receptor agonists can be considered in patients aged ≥55 years with coronary, carotid, or lower extremity artery stenosis >50%, left ventricular hypertrophy, eGFR <60 mL/min/1.73 m², or albuminuria 2

For Type 2 Diabetes with Obesity

• When choosing glucose-lowering medications for people with type 2 diabetes and overweight or obesity, prioritize medications with beneficial effect on weight 2
• The preferred pharmacotherapy should be a GLP-1 receptor agonist or dual GIP and GLP-1 receptor agonist with greater weight loss efficacy (specifically semaglutide or tirzepatide), especially considering their added weight-independent benefits 2

For Type 2 Diabetes with Chronic Kidney Disease

• In adults with type 2 diabetes and advanced CKD (eGFR <30 mL/min/1.73 m²), a GLP-1 RA is preferred for glycemic management due to lower risk of hypoglycemia and for cardiovascular event reduction 2

Dosing Protocol

Initiation and Titration

• Start at 2.5 mg subcutaneously once weekly for 4 weeks (this is for treatment initiation only and is not a maintenance dose) 1
• After 4 weeks, increase to 5 mg subcutaneously once weekly 1
• Increase in 2.5 mg increments after at least 4 weeks on the current dose to reduce gastrointestinal adverse reactions 1

Maintenance Dosing

• For weight reduction and long-term maintenance: 5 mg, 10 mg, or 15 mg subcutaneously once weekly 1
• For obstructive sleep apnea: 10 mg or 15 mg subcutaneously once weekly 1
• Maximum dosage: 15 mg subcutaneously once weekly 1
• Consider treatment response and tolerability when selecting the maintenance dosage 1

Administration Details

• Administer once weekly at any time of day, with or without meals 1
• Inject subcutaneously in the abdomen, thigh, or upper arm, rotating injection sites with each dose 1
• Solution should appear clear and colorless to slightly yellow 1

Missed Dose Management

• If a dose is missed, administer as soon as possible within 4 days (96 hours) after the missed dose 1
• If more than 4 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day 1
• The day of weekly administration can be changed if at least 3 days (72 hours) separate the two doses 1

Clinical Efficacy

Glycemic Control

• Tirzepatide reduces HbA1c by 1.87% to 2.59% (20 to 28 mmol/mol) across the SURPASS clinical trial program 3
• In SURPASS-2, tirzepatide demonstrated greater HbA1c reduction than semaglutide 1 mg 3, 4
• A substantial proportion of patients (23.0% to 62.4%) achieved HbA1c <5.7% (normoglycemia range) 4

Weight Loss

• Tirzepatide produces weight loss of 5.4 to 12.9 kg in patients with type 2 diabetes 3, 5
• In the SURMOUNT-1 trial (patients without diabetes), tirzepatide resulted in 16.5% to 22.4% body weight reduction over 72 weeks 5
• Between 20.7% and 68.4% of patients lost more than 10% of their baseline body weight 4

Cardiometabolic Benefits

• Tirzepatide significantly improves surrogate markers of cardiovascular disease in people with and without diabetes 2
• Reductions in blood pressure, visceral adiposity, circulating triglycerides, and liver fat have been demonstrated 3
• Meta-analysis showed no cardiovascular safety concerns, with hazard ratios <1.0 for MACE-4 events versus pooled comparators 4

Safety Profile and Adverse Effects

Common Adverse Events

• The most common adverse reactions (≥5% of patients) are nausea, diarrhea, vomiting, constipation, abdominal pain, dyspepsia, injection site reactions, fatigue, hypersensitivity reactions, eructation, hair loss, and gastroesophageal reflux disease 1
• Gastrointestinal events are mostly mild to moderate in severity and similar to the GLP-1 receptor agonist class 6, 5
• Slow dose titration reduces the risk of gastrointestinal adverse reactions 1

Hypoglycemia Risk

• Tirzepatide is associated with a low risk of clinically significant or severe hypoglycemia when used without insulin or insulin secretagogues 6, 3
• When initiating tirzepatide in patients on insulin or insulin secretagogues, reduce the dose of these medications to minimize hypoglycemia risk 7
• Concomitant use with insulin or an insulin secretagogue may increase the risk of hypoglycemia, including severe hypoglycemia 1

Serious Warnings and Precautions

Thyroid C-Cell Tumors (Boxed Warning)

• Tirzepatide causes thyroid C-cell tumors in rats at clinically relevant exposures 1
• Contraindicated in patients with personal or family history of medullary thyroid carcinoma (MTC) or Multiple Endocrine Neoplasia syndrome type 2 (MEN 2) 1
• Counsel patients regarding potential risk and symptoms of thyroid tumors (neck mass, dysphagia, dyspnea, persistent hoarseness) 1

Gastrointestinal Adverse Reactions

• Severe gastrointestinal adverse reactions have been reported 1
• Not recommended in patients with severe gastrointestinal disease 1
• Monitor for signs of acute pancreatitis; discontinue promptly if suspected 1

Acute Kidney Injury

• Monitor renal function in patients reporting adverse reactions that could lead to volume depletion 1

Acute Gallbladder Disease

• Acute gallbladder disease has been reported in clinical trials 1
• If cholecystitis is suspected, gallbladder studies and clinical follow-up are indicated 1

Pulmonary Aspiration Risk

• Pulmonary aspiration during general anesthesia or deep sedation has been reported in patients receiving GLP-1 receptor agonists 1
• The 2025 multidisciplinary consensus recommends considering delayed gastric emptying in peri-operative management 2
• Instruct patients to inform healthcare providers of any planned surgeries or procedures 1

Hypersensitivity Reactions

• Serious hypersensitivity reactions (anaphylaxis, angioedema) have been reported postmarketing 1
• Contraindicated in patients with known serious hypersensitivity to tirzepatide or any excipients 1
• If suspected, advise patients to promptly seek medical attention and discontinue tirzepatide 1

Suicidal Behavior and Ideation

• Monitor for depression or suicidal thoughts 1
• Discontinue tirzepatide if symptoms develop 1

Special Populations

Renal Impairment

• No dose adjustment necessary for patients with renal impairment 7
• In patients with eGFR <15 mL/min/1.73 m², use of GLP-1 receptor agonists is generally not recommended 7

Diabetic Retinopathy

• Tirzepatide has not been studied in patients with non-proliferative diabetic retinopathy requiring acute therapy, proliferative diabetic retinopathy, or diabetic macular edema 1
• Monitor patients with a history of diabetic retinopathy for progression 1

Gastroparesis

• GLP-1 receptor agonists may delay gastric emptying 7
• Use with caution in patients with clinically significant gastroparesis 7

Combination Therapy Considerations

With Insulin

• If insulin is used, combination therapy with tirzepatide is recommended for greater glycemic effectiveness as well as beneficial effects on weight and hypoglycemia risk 2
• Insulin dosing should be reassessed upon addition or dose escalation of tirzepatide 2
• Glucose-lowering agents may be continued upon initiation of insulin therapy for ongoing glycemic and metabolic benefits 2

With Other Glucose-Lowering Agents

• Reassess the need for and/or dose of sulfonylureas or meglitinides when starting tirzepatide to minimize hypoglycemia risk and treatment burden 2
• Coadministration with other tirzepatide-containing products or with any GLP-1 receptor agonist is not recommended 1

Weight Management Continuation

• Weight management pharmacotherapy indicated for chronic therapy should be continued beyond reaching weight loss goals to maintain health benefits 2
• Sudden discontinuation of weight management pharmacotherapy often results in weight gain and worsening of cardiometabolic risk factors 2
• For those not reaching treatment goals, reevaluate and intensify treatment with additional approaches 2

Key Clinical Pitfalls to Avoid

• Do not use the 2.5 mg dose as maintenance therapy—it is for initiation only 1
• Do not advance doses faster than every 4 weeks—this increases gastrointestinal adverse effects 1
• Do not combine with other GLP-1 receptor agonists or tirzepatide-containing products 1
• Do not forget to reduce insulin or sulfonylurea doses when initiating tirzepatide to prevent hypoglycemia 2, 7
• Do not discontinue abruptly once weight loss goals are achieved—this leads to weight regain 2
• Screen for contraindications including personal or family history of MTC or MEN 2 before prescribing 1