Weight-Loss Medications \"Tirzepatide (Mounjaro)\"

About 42% of adults in the US and 800 million people worldwide have obesity. From 1975 to 2014, the prevalence of obesity increased worldwide from 6.4% to 14.9% in women and from 3.2% to 10.8% in men. By 2030, the prevalence of obesity is expected to become 48.9% of US adults. About 63% of men and 54% of women are obese or overweight in the European Region. Obesity costs about $173 billion annually. Obesity is often associated with stigma, impairing the quality of life and increasing morbidity. We define overweight and obesity through body mass index (BMI). A BMI of 25 or more is considered overweight, and a BMI of 30 or greater is considered obesity, with a lower BMI ≥25-27.5 among the Asian population.

A percentile scale based on gender and age is used to classify obesity in children. Obesity is defined as a BMI at or above the 95th percentile, and overweight is defined as a BMI in the 85th to 94th percentile. The greater the BMI, the higher the cardiovascular (CVS) risk. BMI of 30-39 among men has CVS disease rate of 20.21 per 1000 person-years, while in men with normal BMI, the rate is 13.72 per 1000 person-years. In women, CVS event rate is 9.97 per 1000 person-years in individuals with BMI 30-39, compared to the rate in women with normal BMI, which is 6.37 per 1000 person-years. Obesity has an overall mortality rate 29%, a 210% increase in diabetes-related mortality for every 5-unit increase in BMI over 25 kg/m2, and  41% increase in vascular mortality. It is predicted that obesity will be the leading preventable risk factor for cancer in some countries instead of smoking. About 1.3 million deaths each year globally are due to obesity and being overweight. 

Multiple factors may cause obesity, but in general, it is related to chronic energy imbalance with greater calorie consumption than energy expenditure.

-Genetic variants: polygenic risk factors with several variants are strongly associated with obesity.
-Environment: obesogenic environments, including school, workplace, home, and social environments affect  physical and social structures and therefore, are related to obesity. This association is due to the greater availability of fast-food restaurants, limited physical activity, and limited healthy food options.

-Depression: A bidirectional relation between depression and obesity exists. Depression increases the risk of obesity, and the opposite also happens.
-Low socioeconomic status
-Inadequate sleep
-Chronic stress
-Food insecurity
-Racial and ethnic minority populations 

A weight loss comprehensive treatment program addresses 5 major parts: nutrition, physical activity, pharmacotherapy, behavioural interventions, and metabolic/bariatric procedures. 

-Behavioural interventions include about 14 sessions or more in 6 months to induce lifestyle modifications such as dietary and physical activity counselling and self-monitoring of weight. It often results in 5-10% weight loss. However, about 25% of participants over 2 years of follow-up regain weight.

-Nutritional side focuses on reducing total caloric intake, depending on each individual. Less weight loss (2-3 kg) is noticed if physical activity is performed without reducing calorie intake. However, physical activity is important to maintain weight loss.

-Antidepressants like mirtazapine and amitriptyline, and anti-hyperglycaemic such as glyburide or insulin are commonly prescribed medications that cause weight gain. Weight loss medications are prescribed in combination with lifestyle modifications in non-pregnant, obese or overweight patients with comorbidities related to their weight. 

-About 10% to 13% weight loss at 6 months is noticed following endoscopic procedures such as the intragastric balloon and endoscopic sleeve gastroplasty. About 25% to 30%  of weight loss at 12 months following metabolic and bariatric surgeries. The difficult part is maintaining long-term weight loss.

-Weight loss can reduce the risk of cardiovascular diseases. About a 5-10% loss of weight can reduce systolic blood pressure (BP) by about 3 mm Hg for hypertensive patients, and reduce haemoglobin A1c by 0.6% to 1% for patients with type 2 diabetes. 

In 1999, Orlistat was approved for chronic weight management as it acts intraluminally, affecting the intestinal fat digestion and absorption. Interaction between orexigenic hormones "stimulates appetite and increases food consumption" (ghrelin) and anorexigenic hormones "suppresses appetite by enhancing satiation and satiety while reducing hunger" (leptin, glucagon-like peptide-1 (GLP-1), amylin, cholecystokinin, peptide YY (PYY)) with the satiety centre in hypothalamus leads to a level of calorie intake that maintains excess adiposity (the accumulation of body fat).

Incretins are a group of metabolic hormones that decrease levels of blood sugar by increasing insulin secretion from the pancreas, reducing the absorption of nutrients, and inhibiting the secretion of. Incretins include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GlP-1, which reduces appetite and food intake, its secretion is usually impaired in obese individuals. GLP-1 receptor agonists (GLP-1 RAs) are used to induce weight loss and lower blood sugar levels in type 2 diabetes. In 2005. Exenatide was the first GLP-1 RA to be approved for the treatment of type 2 diabetes. Initial issue with GLP-1 RAs was their short half-life due to rapid elimination, requiring frequent injections daily (twice daily for bid exenatide).

However, further development occurred, and nowadays there are GLP-1 RAs that can be injected once daily (Liraglutide, Lixisenatide), and once weekly (semaglutide, dulaglutide, albiglutide). A daily oral semaglutide formulation has recently shown clinical efficacy compared to the once-weekly injection formulation. GLP-1 RAs increase insulin secretion in response to hyperglycaemia (high blood sugar), suppress glucagon secretion, slow gastric emptying, and decrease caloric intake. Numerous trials have shown GLP-1 RAs as useful drugs in reducing mortality in cardiovascular (CVS) events like acute myocardial infarction and stroke, and it is recommended to prioritize GLP-1 RAs in the treatment of patients with cardiovascular risk.

According to the Kaiser Family Foundation (KFF) poll in 2024, about 12% (one in eight) have taken GLP-1 for weight loss, diabetes, or heart disease. About 6% of adults have taken one of the following drugs: Ozempic, Mounjaro, and Wegovy. The highest use was noticed in diabetes (43%), about 26% with heart disease, and 22% in individuals with obesity or overweight. About 38% (four in ten) took the drug due to obesity or being overweight, without any other indications.

Tirzepatide is a new agonist of GIP and GLP-1 receptors and an FDA-approved medication for the treatment of T2DM, showing a significant improvement in glycaemic control and weight loss. Several studies evaluated the efficacy, safety, and tolerability of tirzepatide; one study compared its effect as a monotherapy in uncontrolled type 2 diabetes to placebo, and another compared the efficacy and safety of once-weekly tirzepatide to semaglutide. Tirzepatide is administered once weekly subcutaneously. It can indirectly treat non-alcoholic fatty liver disease (NAFLD) due to its weight loss effect, and it has no toxic effect on the liver, but research is still needed.

A study included 2539 adults with an average body weight of 104.8 kg and an average BMI of 38.0; 94.5% of participants had a BMI of 30 or more. At week 72 with weekly doses of 5 mg tirzepatide, 19.5% with doses of 10 mg, and 20.9% with doses of 15 mg. About 5% weight loss was noticed in 85% of participants receiving 5 mg of tirzepatide, 89% with 10 mg, and 91% with 15 mg, compared to only 35% of participants receiving a placebo had this weight loss.

Tirzepatide is approved only for T2DM along with exercise and balanced nutrition. It should not be used in type 1 diabetes or latent autoimmune diabetes in adults. If patients are already taking other GLP-1 agents like semaglutide, tirzepatide should not be prescribed for them. 

Misuse of mounjaro can lead to several side effects, including serious ones.

 
Common side effects include:

-Nausea, vomiting, and diarrhoea
-Abdominal pain
-Constipation
-Decreasing appetite
-Bloating
-Heartburn
-Injection site reaction
-Mild allergic reaction
-Mild increase in heart rate

These are common and mild side effects that should be temporary and easily managed.

On the other hand, there are serious side effects of Mounjaro including: 

-Severe gastrointestinal symptoms (severe nausea, vomiting, and diarrhoea)
-Hypoglycaemia (Low blood sugar level)
-Pancreatitis
-Gallbladder disease
-Severe allergic reaction (Anaphylaxis)
-Risk of thyroid cancer

These are not common, but if you have any of them or if you experience any change in health while on mounjaro treatment, you have to consult your doctor.
Mounjaro side effects may last a few days or a few weeks. It differs for each individual.
The most common side effects of tirzepatide are the mild to moderate gastrointestinal events (nausea, vomiting, diarrhoea) that occur mainly due to dose escalation.

Some physicians may prescribe Mounjaro off-label, which means prescribing a drug for a purpose other than what it’s approved for. Recently, the FDA approved Zepbound, which contains the same active drug (tirzepatide) for weight loss in certain cases.

Let’s discuss some of the adverse effects of Tirzepatide:

-Diarrhoea: may be mild or severe. If it is mild, it usually improves after the body gets used to the drug. The same happens with nausea and vomiting. The problem of severe diarrhoea is dehydration that may cause acute kidney injury (AKI) in severe cases.

-Risk of thyroid cancer: The most serious side effect, according to the FDA, is the risk of thyroid cancer. It was detected in animal studies, but it's not clear in humans. Therefore, Mounjaro will not be prescribed for individuals with multiple endocrine neoplasia syndrome type 2 (MEN 2) or if a family member has had medullary thyroid cancer (MTC).
Symptoms that pays attention to a thyroid problem include:
•Shortness of breath (Dyspnoea)
•Hoarseness of voice
•Difficulty swallowing
•A lump of mass in the neck

Blood tests and a neck ultrasound are some of the investigations to check for any thyroid problems.

-Injection site reaction: includes pain, redness, or swelling. These reactions may recover within a few days. Changing the site of injection may help to avoid these reactions. Sites of injection include the back of the upper arm, thigh, or abdomen.

-Allergic reaction: range from mild reactions including itching, skin rash, flushing (redness or warmth of skin), and severe reactions (anaphylaxis) including swelling of eyelids, mouth, tongue, throat, hands, feet, and difficulty breathing. Anaphylaxis is an emergency.

-Alcohol & Mounjaro: alcohol increases the side effects of mounjaro, including nausea, vomiting, diarrhoea, and hypoglycaemia.