- ACRONYMS AND DEFINITIONS
- A1C - Hemoglobin A1C
- ADA - American Diabetes Association
- CVD - Cardiovascular disease
- DM - Diabetes mellitus
- FBS - Fasting blood sugar
- GFR - Glomerular filtration rate
- GI - Gastrointestinal
- GLP-1 - Glucagon-like peptide-1
- OSA - Obstructive sleep apnea
- RCT - Randomized controlled trial
- T2DM - Type 2 diabetes mellitus
- Thyroid C-cell tumor = Thyroid medullary tumor
- DRUGS IN CLASS
- Dual GLP-1 and GIP agonists
- Tirzepatide (Mounjaro®)
- MECHANISM OF ACTION
- GLP-1 and GIP
- GLP-1 stands for "glucagon-like peptide-1," and GIP stands for "glucose-dependent insulinotropic polypeptide." GIP is also sometimes referred to as "gastric inhibitory polypeptide."
- GLP-1 and GIP are hormones secreted by specialized cells in the small intestine in response to food consumption. The actions of GLP-1 and GIP on different tissues are described below. An enzyme called dipeptidyl peptidase-4 (DPP-4) rapidly metabolizes GLP-1 and GIP, rendering them inactive.
- Pancreas
- GLP-1 and GIP stimulate insulin secretion
- GLP-1 suppresses glucagon secretion during hyperglycemia
- GIP suppresses glucagon secretion during hyperglycemia and stimulates secretion during euglycemia and hypoglycemia
- Brain
- GLP-1 and GIP suppress hunger
- Stomach
- GLP-1 slows gastric emptying
- Fat tissue
- GIP increases fatty acid and glucose uptake by fat tissue [1,2,3]
- Tirzepatide
- Tirzepatide is a dual GLP-1 / GIP receptor agonist that mimics the actions of GLP-1 and GIP. It has been modified so that DPP-4 cannot metabolize it.
- FDA-APPROVED INDICATIONS
- Tirzepatide (Mounjaro®)
- Type 2 diabetes - as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus
- TYPE 2 DIABETES
Effects of Tirzepatide on T2DM in a 40-week Trial | ||||
---|---|---|---|---|
Outcome | Placebo (N=113) |
Tirzepatide 5 mg (N=121) |
Tirzepatide 10 mg (N=121) |
Tirzepatide 15 mg (N=120) |
Baseline A1C | 8.1% | 8.0% | 7.9% | 7.9% |
Change in A1C | -0.1% | -1.8% | -1.7% | -1.7 |
Change in FBS (mg/dl) |
+4 | -40 | -40 | -39 |
Baseline weight | 186 lbs (84.5 kg) | 191 lbs (87 kg) | 190 lbs (86.2 kg) | 188 lbs (85.5 kg) |
Change in weight | -2.2 lbs (1 kg) | -13.9 lbs (6.3 kg) | -15.4 lbs (7 kg) | -17.2 lbs (7.8 kg) |
- The SURPASS-2 trial enrolled 1879 adults with type 2 diabetes who were inadequately controlled with metformin at a dose of at least 1500 mg per day
Main inclusion criteria
- Age ≥ 18 years
- T2DM uncontrolled with metformin at ≥ 1500 mg/day
- A1C of 7 - 10.5%
- BMI ≥ 25 and stable for 3 months
Main exclusion criteria
- Type 1 diabetes
- GFR < 45 ml/min
- History of pancreatitis
- Significant diabetic retinopathy
Baseline characteristics
- Average age 57 years
- Average A1C - 8.28%
- Average FBS - 173 mg/dl
- Average BMI - 34
- Average weight - 206 lbs (93.7 kg)
- Average length of diabetes - 8.6 years
Randomized treatment groups
- Group 1 (470 patients): Tirzepatide 5 mg once weekly
- Group 2 (469 patients): Tirzepatide 10 mg once weekly
- Group 3 (470 patients): Tirzepatide 15 mg once weekly
- Group 4 (469 patients): Semaglutide 1 mg once weekly
- Semaglutide and tirzepatide assignment was open-label. Tirzepatide dosing was double-blind.
- Tirzepatide was initiated at a dose of 2.5 mg once weekly, and the doses were increased by 2.5 mg every 4 weeks until the randomly assigned dose was reached
- Semaglutide was initiated at a dose of 0.25 mg once weekly, and the dose was doubled every 4 weeks until 1 mg was reached
- Metformin was continued. The initiation of new antihyperglycemic medications was allowed according to specific criteria
Primary outcome: Change in the glycated hemoglobin level from baseline to 40 weeks
Results
Duration: 40 weeks | |||||
Outcome | Tir 5 mg | Tir 10 mg | Tir 15 mg | Sem 1 mg | Comparisons |
---|---|---|---|---|---|
Primary outcome | −2.01% | −2.24% | −2.30% | −1.86% | Tir (all doses) vs Sem p<0.05 |
A1C < 7% | 82% | 86% | 86% | 79% | Tir (10 and 15 mg) vs Sem p<0.05 |
Weight loss | 16.7 lbs (7.6 kg) | 20.5 lbs (9.3 kg) | 24.6 lbs (11.2 kg) | 12.5 lbs (5.7 kg) | Tir (all doses) vs Sem p<0.001 |
Nausea | 17.4% | 19.2% | 22.1% | 17.9% | N/A |
Diarrhea | 13.2% | 16.4% | 13.8% | 11.5% | N/A |
Pancreatitis | 0 | 0.4% | 0.4% | 0.6% | N/A |
Hypoglycemia (< 54 mg/dl) | 0.6% | 0.2% | 1.7% | 0.4% | N/A |
Cholelithiasis | 0.9% | 0.9% | 0.9% | 0.4% | N/A |
DM retinopathy | 0 | 0.4% | 0 | 0 | N/A |
|
Findings: In patients with type 2 diabetes, tirzepatide was noninferior and superior to semaglutide with respect to the mean change in the glycated hemoglobin level from baseline to 40 weeks.
- ADA recommendations
- WEIGHT LOSS
- Overview
- In Type 2 diabetes trials, tirzepatide caused significant weight loss. To explore this effect in non-diabetics, the SURMOUNT-1 trial detailed below compared tirzepatide to placebo in obese adults without diabetes.
- The SURMOUNT-1 trial enrolled 2539 adults with a BMI ≥ 30 or a BMI ≥ 27 and at least one weight-related complication
Main inclusion criteria
- Age ≥ 18 years
- History of unsuccessful dieting
- BMI ≥ 30 or ≥ 27 and 1 or more of the following:
- Hypertension
- Dyslipidemia
- OSA
- CVD
Main exclusion criteria
- Diabetes
- Previous bariatric surgery
- Other weight loss drug within 90 days
Baseline characteristics
- Average age 45 years
- Female sex - 68%
- Average body weight - 231 lbs (105 kg)
- Average BMI - 38
Randomized treatment groups
- Group 1 (630 patients): Tirzepatide 5 mg once weekly
- Group 2 (636 patients): Tirzepatide 10 mg once weekly
- Group 3 (630 patients): Tirzepatide 15 mg once weekly
- Group 4 (643 patients): Placebo once weekly
- Tirzepatide was initiated at a dose of 2.5 mg once weekly (or matching placebo) and was increased by 2.5 mg every 4 weeks during the dose-escalation period to reach a maintenance dose of up to 15 mg once weekly by week 20
Primary outcome: The coprimary end points were the percentage change in body weight from baseline to week 72
and a weight reduction of 5% or more at week 72
Results
Duration: 72 weeks | |||||
Outcome | Tir 5 mg | Tir 10 mg | Tir 15 mg | Placebo | Comparisons |
---|---|---|---|---|---|
% change in body weight | −15% | −19.5% | −20.9% | −3.1% | Tir (all doses) vs Placebo p<0.001 |
≥ 5% weight loss | 85% | 89% | 91% | 35% | Tir (all doses) vs Placebo p<0.001 |
Body weight lost | 35.5 lbs (16.1 kg) | 48.9 lbs (22.2 kg) | 52.0 lbs (23.6 kg) | 5.3 lb (2.4 kg) | N/A |
Nausea | 24.6% | 33.3% | 31% | 9.5% | N/A |
Diarrhea | 18.7% | 21.2% | 23% | 7.3% | N/A |
Constipation | 16.8% | 17.1% | 11.7% | 5.8% | N/A |
Pancreatitis | 0.2% | 0.2% | 0.2% | 0.2% | N/A |
Gallbladder disease | 0.8% | 1.7% | 1.0% | 0.8% | N/A |
|
Findings: In this 72-week trial in participants with obesity, 5 mg, 10 mg, or 15 mg of tirzepatide once weekly provided substantial and sustained reductions in body weight.
- Summary
- Tirzepatide caused impressive weight loss in the SURMOUNT-1 trial, with participants in the 15-mg group losing an astounding 52 pounds. Like semaglutide before it (Ozempic®, Wegovy®), tirzepatide will likely seek additional approval as a weight-loss drug.
- SIDE EFFECTS
- Gastrointestinal side effects
- Gastrointestinal side effects are the most common type of adverse reaction seen with tirzepatide. The table below gives the incidence of GI complaints from placebo-controlled trials.
Gastrointestinal Side effects | ||||
---|---|---|---|---|
Side effect | Placebo (N=235) |
Tir 5 mg (N=237) |
Tir 10 mg (N=240) |
Tir 15 mg (N=241) |
Nausea | 4% | 12% | 15% | 18% |
Diarrhea | 9% | 12% | 13% | 17% |
Decreased Appetite | 1% | 5% | 10% | 11% |
Vomiting | 2% | 5% | 5% | 9% |
Constipation | 1% | 6% | 6% | 7% |
Dyspepsia | 3% | 8% | 8% | 5% |
Abdominal Pain | 4% | 6% | 5% | 5% |
- Hypoglycemia
- Tirzepatide by itself does not pose a significant risk of hypoglycemia. When it is combined with other diabetes medications, particularly insulin and insulin secretagogues, the risk of hypoglycemia is increased. In the SURPASS-2 trial where tirzepatide was added to metformin, hypoglycemia (< 54 mg/dl) occurred in 0.6%, 0.2%, and 1.7% of patients treated with tirzepatide 5 mg, 10 mg, and 15 mg, respectively.
- Patients who are taking concomitant diabetes medications should monitor their blood sugars closely and be prepared to treat hypoglycemia if needed (see hypoglycemia for more). When adding tirzepatide to insulin or insulin secretagogue therapy, consider reducing the dose of these medications. In a study where tirzepatide was added to insulin glargine, patients with an A1C ≤ 8% reduced their insulin glargine dose by 20% when initiating tirzepatide. [1,3]
- Heart rate increase
- In trials, tirzepatide-treated patients had an average increase in heart rate of 2 - 4 bpm compared to 1 bpm in placebo-treated patients. Sinus tachycardia, defined as ≥ 15 bmp increase over baseline, was reported in 4.3%, 4.6%, 5.9% and 10% of subjects treated with placebo, tirzepatide 5 mg, 10 mg, and 15 mg, respectively.
- The clinical significance of these increases is unknown
- Injection site reactions
- In trials, injection site reactions were reported in 3.2% of tirzepatide-treated patients and 0.4% of placebo-treated patients
- Increases in amylase and lipase
- In trials, tirzepatide-treated patients had a mean increase from baseline in amylase of 33% to 38% and an increase in lipase of 31% to 42%. Placebo-treated patients had an increase in amylase of 4% and no change in lipase.
- The clinical significance of these increases is unknown
- Hypersensitivity reactions
- Serious hypersensitivity reactions, including anaphylaxis, angioedema, urticaria, and eczema, have occurred in patients receiving tirzepatide. In trials, reactions were reported in 3.2% of tirzepatide-treated and 1.7% of placebo-treated patients. Patients who develop anti-tirzepatide antibodies are at greater risk.
- Anti-tirzepatide antibodies
- In trials, 51% of tirzepatide-treated patients developed anti-tirzepatide antibodies. Antibody cross-reactivity with native GIP and GLP-1 was seen in 34% and 14%, respectively. Antibody development was not associated with a decrease in effectiveness, but it was associated with an increase in hypersensitivity and injection site reactions.
- Pancreatitis
- Acute pancreatitis has occurred in patients treated with GLP-1 agonists. In trials, the incidence of acute pancreatitis in tirzepatide-treated patients was 0.23 cases per 100 patient-years compared to 0.11 cases per 100 patient-years in placebo-treated patients. If patients develop symptoms of pancreatitis (e.g. upper abdominal pain radiating to the back, nausea, vomiting), they should be evaluated promptly.
- Patients with a history of pancreatitis were excluded from tirzepatide trials, so it is unknown if they are at greater risk.
- Acute kidney injury
- Tirzepatide may cause nausea, vomiting, and diarrhea that can lead to dehydration and, if severe, acute kidney injury. There have been case reports of acute kidney injury and worsening of chronic renal failure in patients receiving GLP-1 analogs. In most cases, symptoms of nausea, vomiting, and diarrhea were present.
- Use caution when prescribing tirzepatide to patients with renal impairment and those taking medications that may affect kidney function (e.g. ACE inhibitors, NSAIDs, diuretics). Monitor renal function closely in patients with chronic kidney disease who are experiencing significant gastrointestinal reactions.
- Gallbladder disease
- GLP-1 analogs have been associated with an increased risk of gallbladder disease. Rapid weight loss is also a risk factor. In trials, acute gallbladder disease (cholelithiasis, biliary colic, and cholecystectomy) was seen in 0.6% of tirzepatide-treated patients and 0% of placebo-treated patients.
- If patients develop symptoms of cholelithiasis (e.g. right upper quadrant pain with nausea and vomiting), gallbladder imaging should be performed.
- Thyroid cancer
- In toxicology studies, a dose-dependent and treatment-duration-dependent increase in the incidence of malignant and benign thyroid medullary tumors (C-cell tumors) was observed in rats treated with clinically relevant doses of tirzepatide. It is unknown if tirzepatide increases the risk of tumors in humans as the incidence of these events is too low to establish causality.
- Tirzepatide is contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2, a condition that increases the risk for medullary thyroid cancer
- Routine monitoring with serum calcitonin or thyroid ultrasound is of uncertain value and will likely lead to many incidental findings and unnecessary procedures. Patients with medullary thyroid carcinoma usually have calcitonin levels > 50 ng/ml. In the SURPASS-2 trial, tirzepatide did not cause relevant changes in mean calcitonin levels.
- Diabetic retinopathy
- Rapid improvements in glucose control have been associated with a temporary worsening of diabetic retinopathy. Patients with significant diabetic retinopathy were excluded from tirzepatide trials. Use caution when initiating tirzepatide in patients with diabetic retinopathy. [1]
- CONTRAINDICATIONS
- Tirzepatide
- History of hypersensitivity reaction to tirzepatide
- Personal or family history of medullary thyroid carcinoma (MTC)
- Multiple Endocrine Neoplasia syndrome type 2 (MEN 2)
- PRECAUTIONS
- Kidney disease
- No dose adjustment is recommended in patients with any degree of renal impairment
- Liver disease
- No dose adjustment is recommended in patients with any degree of liver disease
- Severe gastrointestinal disease
- Tirzepatide slows gastric emptying and may cause significant GI side effects. It has not been studied in patients with severe GI disease, including gastroparesis, and is not recommended in these patients. [1]
- DRUG INTERACTIONS
- NOTE: The drug interactions presented here are NOT all-inclusive. Other interactions may exist. Drug interaction checkers provide the most efficient and practical way to check for interactions among multiple medications. A free interaction checker is available from Drugs.com (see Drugs.com interactions checker).
- Tirzepatide
- Insulin and insulin secretagogues - When tirzepatide is added to insulin and insulin secretagogues (e.g. sulfonylureas, meglitinides), the risk for hypoglycemia is increased. Consider decreasing the dose of these medications when starting tirzepatide. In a study where tirzepatide was added to insulin glargine, patients with an A1C ≤ 8% reduced their insulin glargine dose by 20% when initiating tirzepatide. Monitor blood sugars closely after initiation and adjust medications as needed. Make sure patients are aware of the signs and symptoms of hypoglycemia (see hypoglycemia). [1,3]
- Oral contraceptives - in a pharmacokinetic study, ethinyl estradiol, norgestimate, and norelgestromin absorption was reduced by tirzepatide. The manufacturer recommends that patients using oral hormonal contraceptives switch to a non-oral contraceptive method, or add a barrier method of contraception for 4 weeks after tirzepatide initiation and for 4 weeks after each dose escalation.
- Drugs affected by decreased gastric emptying - see gastric emptying below
- Drugs that alter gastrointestinal motility - drugs that slow gastrointestinal motility may potentiate the gastric-slowing effects of tirzepatide
- Drugs affected by gastric emptying
- Medications are partially digested in the stomach before being emptied into the small intestine, where most drugs are absorbed. Tirzepatide slows the process of gastric emptying, and this may alter the absorption of some drugs. In many cases, the overall effect on the medication's therapeutic action is not significant, but the efficacy of some drugs (see below) may be altered.
- Antibiotics
- Antibiotics require rapid absorption to achieve their desired therapeutic effect
- Drugs with a narrow therapeutic index
- Drugs with narrow therapeutic index may have their steady-state altered by delayed gastric emptying
- Examples of drugs with a narrow therapeutic index:
- Carbamazepine (Tegretol®)
- Cyclosporine (Neoral®)
- Digoxin
- Levothyroxine (Synthroid®)
- Lithium
- Phenytoin (Dilantin®)
- Tacrolimus (Prograf®)
- Theophylline (Theo-24®)
- Warfarin (Coumadin®) [4]
- Metabolism and clearance
- Tirzepatide is metabolized by proteolytic cleavage of the peptide backbone, beta-oxidation of the C20 fatty diacid moiety and amide hydrolysis
- DOSING
- Dosage forms
- Single-dose pen
- 2.5 mg/0.5 ml
- 5 mg/0.5 ml
- 7.5 mg/0.5 ml
- 10 mg/0.5 ml
- 12.5 mg/0.5 ml
- 15 mg/0.5 ml
- Comes in carton with 4 pens
- No generic: $$$$ for 4 pens
- Dosing
- Starting: 2.5 mg subcutaneously once weekly. After 4 weeks, increase the dose to 5 mg once weekly.
- Maintenance: 5 - 15 mg once weekly
- Maximum: 15 mg once weekly
- Dose may be increased in increments of 2.5 mg every 4 weeks as needed. The 2.5 mg dose is not intended for glycemic control.
- Inject subcutaneously in the abdomen, thigh, or upper arm. Rotate injection sites.
- Missed doses: administer tirzepatide as soon as possible within 4 days (96 hours) after the missed dose. If more than 4 days have passed, skip the missed dose and administer the next dose on the regularly scheduled day. In each case, patients can then resume their regular once weekly dosing schedule.
- Patients taking insulin and insulin secretagogues: consider decreasing the dose of these medications when starting tirzepatide. In a study where tirzepatide was added to insulin glargine, patients with an A1C ≤ 8% reduced their insulin glargine dose by 20% when initiating tirzepatide. [3]
- The day of weekly administration can be changed, if necessary, as long as the time between the two doses is at least 3 days (72 hours) [1]
- Storage
- Store in refrigerator
- Pens can be stored at room temperature for up to 21 days [1]
- LONG-TERM SAFETY
- Tirzepatide was FDA-approved in 2022. It does not have long-term safety data.
- BIBLIOGRAPHY
- 1 - Tirzepatide PI
- 2 - PMID 34170647 - Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes, NEJM (2021)
- 3 - PMID 35133415 - Effect of Subcutaneous Tirzepatide vs Placebo Added to Titrated Insulin Glargine on Glycemic Control in Patients With Type 2 Diabetes: The SURPASS-5 Randomized Clinical Trial, JAMA (2022)
- 4 - North Carolina Pharmacy Practice Act. Article 4A. 90-85.28(b1).