Tirzepatide for the treatment of obesity with complications

Raised body weight remains a significant health issue in Aotearoa New Zealand - approximately two-thirds of adults over the age of 15 live with overweight (BMI 25 to 30) or obesity (BMI 30+)¹. As noted by Te Whatu Ora, “overweight and obesity are associated with a wide range of health conditions, including cardiovascular disease, various types of cancer, Type 2 Diabetes, kidney disease, osteoarthritis, gout, gallstones, complications of pregnancy and mental health issues.”²

Individualised lifestyle intervention is the key component of weight management for all patients. This includes:

• meal planning and dietetic education
• physical activity/movement
• behavioural modification.

However, these interventions on their own may not be sufficient to achieve or sustain long-term weight loss.  

Pharmacotherapy can be a powerful tool in treating the pathophysiology of obesity. It may augment the clinical benefits of lifestyle intervention, reducing weight-related health risks and improving quality of life. Pharmacotherapy can also play a role in preventing weight-related complications and as an adjunct to cardiovascular risk modification in individuals with obesity.

Tirzepatide is a single molecule with actions at two related receptors. It functions as both:

1. A GLP-1 receptor agonist - with the same mechanism as dulaglutide (Trulicity®), liraglutide (Victoza®/Saxenda®) and semaglutide (Ozempic®/Wegovy®).  GLP-1 is released from the gut in response to the detection of ingested nutrients and acts to enhance insulin release, reduce hunger and slow gastric emptying.
2. A GIP analogue – GIP acts similarly to GLP-1 to reduce hunger, slow gastric emptying and enhance insulin secretion, and improve insulin sensitivity. Unlike GLP-1, GIP acts to reduce nausea.

While structurally similar to both endogenous GLP-1 and GIP, tirzepatide has a much longer half-life (approx. 5 days, compared to only a few minutes for the native hormones). This enables once-weekly dosing. 

The net clinical effect of tirzepatide is a reduction in overall energy intake through reduced hunger and enhanced satiety (persistent feeling of fullness after a meal). Tirzepatide also facilitates improved glycaemic control and has direct effects on white adipose tissue, improving adipose function through GIP receptor-mediated action.
 

The efficacy of tirzepatide was demonstrated in the SURMOUNT-1 trial, with a mean loss of body weight of 15.0% to 20.9% over 72 weeks of treatment, for doses ranging from 5 mg to 15 mg weekly (compared to a loss of 3.1% in the placebo group)³.

Tirzepatide is superior to semaglutide for weight loss⁴ and glycaemic control⁵.

It has established cardiovascular safety, having demonstrated non-inferiority to dulaglutide⁶ for cardiovascular outcomes.
 

Tirzepatide is indicated internationally as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management (including weight loss and weight maintenance) in adults with an initial BMI of⁷:

•  ≥30 kg/m², or
• • ≥27 kg/m² with at least one weight-related complication, for example:
  • Hypertension
  • Dyslipidaemia
  • Obstructive sleep apnoea
  • Pre-diabetes or Diabetes
  • Cardiovascular disease.

Mounjaro is administered via subcutaneous injection using a pre-filled pen. The pen is available in pre-mixed doses of 2.5 mg, 5 mg, 7.5 mg, 10 mg, 12.5 mg, and 15 mg. Each pen contains four doses⁷.

Mounjaro is administered once weekly at any time of day, with or without meals. It is injected subcutaneously into the abdomen or thigh (it is recommended to rotate sites). Patients can be trained to self-administer the injections in their own home and will need a sharps container for safe disposal of needles.

If a dose is missed, it should be administered as soon as possible. However, if the next dose is less than 3 days away, the patient should skip the missed dose and administer the next dose on the usual day. If multiple doses are missed, the patient should not resume their previous dose and should instead return to the 2.5mg dose and begin up-titration again.

Much like insulin and GLP-1 receptor agonists, Mounjaro should be stored in the refrigerator (2-8 degrees Celsius) until first use, after which time it can be left at room temperature (below 30 degrees Celsius) for up to 30 days. Refer to the NZ Medsafe Data sheet for further information. 

Patients will usually begin on 2.5 mg sub-cut weekly for 4 weeks before increasing to 5 mg sub-cut weekly. In discussion with the clinician, the patient may choose to increase their dose in a step-wise manner every 4 weeks, to a maximum dose of 15 mg. 

If individuals are experiencing side effects, dose titration should be slowed and the dosage not increased until these abate.

Not everyone can tolerate the maximum dose; management on a lower dose is acceptable.

Weight-loss trajectory, effect on appetite suppression, portion sizes, and treatment goals are all important factors to consider when discussing dose up-titration. This should be individualised and tailored to the patient.

Given the mode of action, many of the common side effects are related to the gastrointestinal system and reduced oral intake. Clinicians should also be mindful of rarer, but more significant side effects.

Adverse effects

Cautions

Acute pancreatitis

Although rare, patients should be informed of the risk of pancreatitis and to observe for symptoms, i.e. epigastric pain radiating to the back, nausea/vomiting, and abdominal bloating.

Tirzepatide can be carefully considered for patients with a history of pancreatitis where the cause is known and treatable, e.g. gallstone pancreatitis. When acute pancreatitis develops following initiation of tirzepatide without a known trigger, treatment must be discontinued. Routine monitoring of pancreatic enzymes is not recommended as asymptomatic elevations are common and not a reason to stop treatment.

Dehydration

Dehydration is a risk due to reduced appetite and GI side effects, leading to fluid depletion and renal impairment.

Clinicians may want to monitor renal function when initiating and up-titrating tirzepatide, especially if the patient reports GI side effects. It is important to counsel the patient on the risk of dehydration and ensure adequate fluid intake. 

Visual issues

In patients with diabetes, a rapid improvement in glucose control may lead to a worsening of diabetic retinopathy. Caution should be exercised in patients with known retinopathy. There have been reports of a very rare optic condition called non-arteritic anterior ischaemic optic neuropathy (NAION), which causes sudden painless vision loss, although the association is not entirely clear.

Other cautions to consider

• Past or present history of disordered eating behaviour
• Inflammatory bowel disease
• Diabetic gastroparesis
• Age ≥85 years
• There is no efficacy/safety data available for children/adolescents aged under 18, in relation to tirzepatide and weight management
• Use of hypoglycaemic agents, e.g. insulin and sulphonylureas
• History of gallstones without cholecystectomy – one should monitor for gallstone-related complications. Patients on tirzepatide have an increased incidence of gallstones, and significant weight loss is a risk factor for gallstone formation itself. Patients need to be counselled appropriately, and the symptoms of biliary colic should be discussed early to avoid complications.
• Use of tirzepatide in patients with severe renal (CKD5) and liver impairment is limited. Patients with CKD4 should be closely monitored.

Drug interactions

As tirzepatide works to delay gastric emptying, there is a theoretical impact on the rate of absorption of oral medications with a narrow therapeutic index, although this has not been borne out in trial data so far⁷. It is still recommended to monitor patients on such medications (e.g. warfarin and digoxin), especially when initiating tirzepatide.

Oral contraceptive levels were noted to be reduced in response to co-administration of tirzepatide, and it is recommended to add a barrier form of contraception for 4 weeks after initiation, and 4 weeks after each dose escalation⁷.
 

Medications such as tirzepatide need to be prescribed in conjunction with a healthy, well-balanced diet and increased physical activity to promote holistic care, improve overall wellbeing, minimise medication-related side effects, and reduce the risk of skeletal muscle loss. 

Patients should be offered lifestyle advice and support alongside pharmacotherapy to optimise outcomes, including options such as a green prescription and dietetic support. Many patients achieve significant lifestyle changes through pharmacotherapy and advice from their well-informed primary care team, which has a good therapeutic rapport with the patient and is free from weight stigma and bias.

Associated complications of clinical obesity (e.g., hypertension, diabetes, OSA) are likely to improve with successful weight loss - these need to be optimised in the interim.

Weight stigma and bias have substantial adverse impacts on people living with obesity, affecting psychological wellbeing, physical health, and engagement with healthcare.

Experiences of stigma, such as blaming, stereotyping, or assuming poor self-discipline, are associated with increased depression, anxiety, and disordered eating, and paradoxically with weight gain and avoidance of health services⁸. In clinical contexts, weight bias can lead to poorer patient–clinician communication, reduced trust, delayed diagnoses, and underuse of preventive care.

Clinicians can reduce weight stigma by adopting person-first language (e.g. “person with obesity”), focusing on health-promoting behaviours rather than weight alone, and recognising obesity as a complex, chronic disease influenced by biological, social, and environmental determinants. 

This MedCase was created by Dr Pulasthi Mithraratne, MBChB, PGDipPaed, FRNZCGP, with expert review by Dr Chaey Leem, Bariatric Doctor.