Tirzepatide for chronic weight management

Obesity remains a significant health issue in Aotearoa/ New Zealand - approximately one third of New Zealanders over the age of 15 have obesity¹.

There remain ethnic disparities in obesity rates, with Pasifika (63%) and Māori (48%) peoples more likely to have obesity than European/Others (29%) and Asian individuals (16%). On the flipside, studies have shown that Asian peoples are at higher risk of type 2 diabetes, hypertension and dyslipidaemia at lower BMI levels than other ethnicities². 

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 support patients in maintaining lifestyle changes, reducing obesity-related health risks, and improving quality of life.

Pharmacotherapy can also play a role in preventing obesity-related complications and as an adjunct to cardiovascular risk modification in overweight individuals.

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. 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). This supports adherence to dietary and lifestyle modifications.

A Cochrane review of tirzepatide for weight loss³ demonstrated a greater reduction in body weight compared to placebo (approx.15% loss) over a follow-up period up to 3.5 years.

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

It has established cardiovascular safety with a recent large trial showing 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 Body Mass Index (BMI) of⁷:

• ≥30 kg/m², or
• ≥27 kg/m² with at least one weight-related comorbidity:
  • 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.

It 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; instead, they should return to the 2.5mg dose and resume up-titration.

Much like insulin and GLP-1 receptor agonists, Mounjaro® should be stored in the refrigerator (2-8°C) until first use, after which it can be left at room temperature (below 30°C) 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.

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 (from the NZ Data Sheet⁷).

Very common side effects – (>10% of clinical trial participants)

• nausea
• diarrhoea
• abdominal pain
• constipation.

Common side effects (1 to 10% of clinical trial participants)

• dyspepsia
• flatulence
• GORD.

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 should be discontinued if pancreatitis is suspected and not restarted if the diagnosis is confirmed.

It is not recommended to use tirzepatide in people with a history of idiopathic pancreatitis, but it can be used if pancreatitis was due to an aetiology that is no longer a risk (for example, gallstone pancreatitis with subsequent cholecystectomy).

Renal impairment
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.

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.

Other contraindications and cautions to consider

• Screen for past or present history of disordered eating behaviour
• Personal or family history of medullary thyroid carcinoma (MTC) or MEN2B
• Pregnancy or planning pregnancy
• Lactation
• Congestive heart failure (NYHA) class IV
• Inflammatory bowel disease
• Diabetic gastroparesis
• Age ≥85 years.

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 born out in trial data so far. It is still recommended to monitor patients on such medications, e.g. warfarin, 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 dose escalation.
 

This MedCase was created by Dr Pulasthi Mithraratne, MBChB, PGDipPaed, FRNZCGP with expert review by Dr James Shand, Endocrinologist.