• Section Writer: Dr. Om J Lakhani
• Section Editor: Dr. Om J Lakhani

• Indications for pharmacotherapy in Obesity :
  • BMI > 30 kg/m^2
  • BMI 27-29.9 kg/m^2 with at least one comorbidity such as:
    • Diabetes
    • Hypertension
    • Sleep apnea
    • Dyslipidemia

• 2 kg weight loss in the first month
• Followed by at least 5% weight loss in the subsequent 3 months

• Liraglutide
• Lorcaserin- Belviq
• Phentermine – Topiramate
• Buproprion- Naltrexone
• Semaglutide
• Tirzepatide

• Hypothalamus
  • 5 HT2c receptor agonist- Lorcaserin
  • Leptin receptor agonist- metreleptin
  • GABA neurons agonist- topiramate
  • Opioid receptor antagonist- naltrexone
• Nucleus accumbens
  • Dopamine active transporter blocker- Buproprion
  • Dopamine release – Phentermine
• Gut
  • GLP1 agonist- Liraglutide
  • Amylin analogue – pramlintide

• Phentermine
• Diethylpropion
• Benzphetamine
• Phendimetrazine

• It inhibits pancreatic lipase

• Rare hepatotoxicity
• Oxalate stones and renal failure

• Serotonin receptor 2c agonist

• 5 HT 2B

• Hypertension
• CAD (Coronary Artery Disease)
• Pregnancy- Topiramate is teratogenic

• It is a carbonic anhydrase inhibitor
• Leads to metabolic acidosis

• Phentermine- 3.75 mg
• Topiramate- 23 mg
  • 1 tab x 2 weeks
  • 2 tab x 12 weeks
  • 3 tab x 2 weeks

• Buproprion – 90 mg
• Naltrexone- 8 mg
  • 1 tab OD for 1 week
  • 1 tab BD x 3 weeks
  • 2 tab BD for 8 weeks

• Buproprion
• Venlafaxine

• Reduced incidence of Type 2 diabetes in obese diabetics on Orlistat

• 10 mg BD

• Liraglutide 3 mg in non-diabetic obese patients
• Led to a loss of 8.4 kg over 56 weeks

• Causes a reduction of LDL
• This is even higher after adjustment for weight loss

• Zonisamide

• Orlistat- 120 mg TID, 60 min before meals
• Lorcaserin- 10 mg BD
• Topiramate- 23 mg / phentermine – 3.75 mg - BD for 12 weeks
• Buproprion – 90 mg/ Naltrexone- 8 mg – BD-TID for 12 weeks
• Liraglutide- 3 mg subcutaneous
• Semaglutide- 2.4 mg subcutaneous once a week
• Tirzepatide - 5, 10, and 15 mg subcutaneous

• GLP-1 Receptor agonists produce weight loss by slowing gastric emptying to slow glucose entry into the general circulation, inhibiting food intake, reducing abdominal and hepatic fat deposition, improving β-cell function, and increasing insulin sensitivity.
• GLP1 RA acts on the central nervous system, specifically on AgRP (agouti-related peptide), CART (cocaine- and amphetamine-regulated transcript), NPY (neuropeptide Y), and POMC (proopiomelanocortin).

• Yes, GLP-1RA acts on the hypothalamus. GLP-1RA has been shown to affect appetite, satiety, hunger, and food preferences, which are all regulated by the hypothalamus.

• The nucleus accumbens is a brain region located in the basal forebrain, near the septum. It is part of the mesolimbic reward system and is associated with pleasure, motivation, and reward-related behavior.
• Recent evidence suggests that the glucagon-like peptide-1 (GLP-1) neuronal projection to the nucleus accumbens core (NAcC) contributes to food intake control.

• STEP 1-8
• STEP TEENS
• SELECT TRIAL

• The STEP 1 trial was conducted to test the effectiveness of semaglutide at the higher dose of 2.4 mg/week for promoting weight loss in obese or overweight people with related comorbidities, but not diabetes.
• The trial involved 1961 participants and was published in The New England Journal of Medicine in early 2021.
• The findings revealed an average 14.9% reduction in body weight from baseline during 68 weeks of treatment with semaglutide 2.4 mg plus a lifestyle intervention, compared with just a 2.4% reduction in the placebo plus lifestyle intervention group.
• In total, 86.4% of the semaglutide group lost at least 5% of their body weight, and adverse effects were in line with those expected for the medication class.
• The STEP 1 trial demonstrated that semaglutide may be an effective treatment for weight loss.

• This compared 1 mg semaglutide to 2.4 mg semaglutide in obese diabetics.

• These were conducted on obese people with comorbidities, but not having diabetes.
• The comparator was a placebo.

• This looked at sustained weight loss in non-diabetics.
• Patients were followed up for 2 years.

• This was for the Asian population.

• Compared Semaglutide to Liraglutide.

• This was done in adolescents between the ages of 12-17 years.

• SURMOUNT-1 trial (Click to open trial details)

• 5 mg, 15 mg, and 20 mg.

• 15%, 19%, and 21% respectively.

• 72 weeks.

• Trial comparing Semaglutide to Tirzepatide .
• Doses of Tirzepatide were 5, 10, and 15 mg.
• The dose of Semaglutide was 1 mg.
• Medication was given for 40 weeks.

• Almost 2% with each of the doses.
• 

• 7, 9, and 11 kg.
• 

• Hypoglycemia was seen more compared to Semaglutide .
• Pancreatitis cases were also more.

• Potential new drugs for obesity management are currently being researched and developed. These drugs may target the underlying neurohormonal dysregulations that cause weight gain and prevent sustained weight loss. They may also aim to reduce inflammatory and pro-thrombotic markers, as well as chronic disease incidence. Additionally, they may be designed to reduce the anorexigenic hormone leptin and increase the orexigenic hormone ghrelin, in order to create a physiologic environment conducive to sustained weight loss.

• Cagrilintide is a peptide analogue developed by Novo Nordisk for the treatment of obesity and type 2 diabetes. It is part of a family of GLP1R agonists, which are drugs that act on the glucagon-like peptide 1 receptor to improve glycemic control and reduce body weight.

• Cagrilintide is a GLP1R/GcgR co-agonist that works by stimulating the release of insulin and glucagon, two hormones that help regulate blood sugar levels. It also helps reduce appetite and increase satiety, leading to weight loss.

• Adults
  • BMI ≥ 30 kg/m^2
  • BMI ≥ 27 kg/m^2 with at least one weight-related comorbidity
• Pediatric age group
  • Age >12 years
  • BMI >95th Percentile or greater for age and gender

Q. Give me the key points from the recently announced SELECT trial?

• The SELECT trial compared semaglutide 2.4 mg to placebo in overweight or obese adults with cardiovascular disease, and semaglutide showed a 20% reduction in major adverse cardiovascular events.
• Semaglutide 2.4 mg had a safe and well-tolerated profile in the trial.
• Regulatory approvals for semaglutide 2.4 mg are planned for 2023 by Novo Nordisk.
• The detailed results of the SELECT trial will be presented at a scientific conference in 2023.
• The patients were followed up for 5 years.
• The patients included in the trial were Age >45 years and BMI >27 kg/m^2.

Q. What is orforglipron ?

• Orforglipron (LY3502970) is a novel, oral non-peptide glucagon-like peptide-1 receptor agonist being investigated for the treatment of obesity.

Q. How much weight loss was seen with Orforglipron ?

• 15% weight loss over 36 weeks with maximum dose

Q. What is the dose of orforglipron used in the study ?

• The doses included 12 mg, 24 mg and 36 mg
• The study is called GZGI study and the drug is developed by Eli Lilly