week 2: case 1 - obesity

what makes obesity care so complex?

• Complex, chronic condition

• No single management strategy (patient-dependent)

• Psychological, emotion or physical barriers often make it difficult for patients to engage in various management strategies 

• There is no cure → life long work, first lose the weight then prevent regain/maintain weight 

• Until recently, no medications specifically indicated for obesity 

what are the goals of obesity care?

• Reduce excess body fat for health and not for cosmetic reasons (cosmetics should never be the reason/motivator because they always change and patients are never happy enough (often feel like they feel like they failed) → health benefits of weight loss are better motivator

  • Reducing weight by 5-10% can result in important health benefits 

• Goal is to stabilize and prevent further weight gain 

• Prevent weight gain

• Prevent obesity-related comorbidities and complications

what are the 2 treatment phases?

1. Induction of weight loss → achieved through caloric restriction 

2. Prevention of weight regain → counteracting the neurobehavioral (homeostatic) changes that seek to restore body weight to its original level

what are the drugs associated with weight loss?

• Antidepressants

• Antipsychotics 

• Corticosteroids (system use, not topical)

• Antihyperglycemic drugs (e.g. T2DM drugs)

• Lithium

how do antidepressants affect weight?

Especially tricyclic antidepressants

E.g. Amitriptyline associated with approximately 1.8 kg weight gain during first three months of therapy with slower increases thereafter (plateaus)

how do anti-psychotics affect weight?

• Both first and second generation → 9-12 kg of weight gain

how do corticosteriods affect weight?

• Corticosteroids (system use, not topical)

  • E.g. Prednisone → average of 2 kg during a 6-month daily course of therapy

how do Antihyperglycemic drugs affect weight?

• Antihyperglycemic drugs (e.g. T2DM drugs)

  • E.g. Sulfonylureas, meglitinides, thiazolidinediones → up to 5kg during 3-12 months of treatment 

  • E.g. insulin → up to 8 kg during intensive 3 month course of therapy

how does lithium effect weight?

Used to treat mania → 10 kg or more in 6-10 years of therapy

when should we consider Pharmacologic choices?

• Lifestyle modification and anti-obesity therapy/medication is superior to lifestyle modification alone in achieving a target weight loss of 5-10% over the long term

• Discontinuation of anti-obesity medication generally results in weight regain 

  • Makes it hard to decide to take pt off → lifelong?

what are the 2 appetite suppressants approved in Canada?

Bupropion alone or in combo with Naltrexone are only options approved in Canada

how does Buproprion work for weight loss? adverse effects?

• is a sympathomimetic drug (amplifies NE pathways) as a sustained-released formula and used as an antidepressant and smoking cessation aid 

• According to evidence, 300mg for 24 weeks is associated with a net weight loss of 2.2%; 400mg with 5.1% weight loss → clinically significant to start seeing health benefits 

• Weight loss maintained for 48 weeks 

• Adverse effects 

  • Dry mouth, constipation, agitation, insomnia, anxiety 

  • Can cause seizures in rare cases with higher doses 

  • Caution in patients with hepatic impairment (because bupropion is extensively metabolized by the liver)

how does Buproprion + Naltrexone work for weight loss? adverse effects?

• Indicated for weight management with diet and exercise for those with a BMI of 30 or higher (BMI can be 27 if pt has weight-related comorbidity)

• Mediates hormones involved in appetite and reward 

• Net weight loss of 4.2% over 48 weeks

• adverse effects 

  • Nausea, vomiting, constipation, headache, dizziness, insomnia, dry mouth 

  • Contraindicated with concurrent opioid therapy (due to precipitation of opioid withdrawal)

    • Because naltrexone counteracts opioids

  • Patients must be opioid free for 7 days prior to initiation of treatment

what are the cautions of Buproprion + Naltrexone?

• Avoid concurrent use of drugs that lower the seizure threshold 

• Minimize or avoid alcohol consumption (too hard on liver)

• Avoid consumption with high fat meal → because delays absorption of drug

• Avoid in pts with uncontrolled HTN, seizure disorder, severe hepatic impairment, or end-stage renal failure

what is Orlistat? how does it work?

Lipase Inhibitors → drug: Orlistat

• Pancreatic and gastric lipase inhibitor that reduces dietary fat absorption by 30%

• For an average diet of 60 g of fat per day, results in 180 kcal/day reduction

• Compared to placebo: 2.9% additional weight loss over 1 year

• Adverse effects 

  • Oily spotting, flatus with discharge, fecal urgency 

  • Decreased absorption of fat-soluble vitamins (A, D, E + K) → need to supplement 

  • Contraindicated in patients with chronic malabsorption syndrome or cholestasis (e.g. IBS)

cautions of Orlistat

• Cautions 

  • Advise patients to take multivitamin daily 2 or more hours before or after orlistat or at bedtime

  • A high fat intake is poorly tolerated 

  • Less effective in patients on low-fat diets and is difficult to take for individuals with irregular eating patterns

    • Less fat in diet so nothing for meds to work on → limited/less effect on patient

what are the incretin mimetics? what do they do?

• 2 major incretin hormones in humans: 

  • Glucagon-like peptide 1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP)

  • Responsible for most of the glucose induced insulin secretory response following glucose ingestion → good for T2DM because blood sugar regulation 

    • GLP-1 is also responsible for reduction of food intake and appetite, increased satiety and decreased gastric emptying 

    • GLP-1 affects reward-related systems in the brain → effects food choices, emotional eating and addiction 

    • GIP has less effect on other organs but delays gastric emptying and seems to play a role in fat deposition

  • Both metabolized by enzyme dipeptidyl peptidase 4 (DPP4)

how does Liraglutinide work?

• GLP-1 agonist 

• Administered subcutaneous via daily injection 

  • Peptide drug therefore gets metabolized if ingested (needs to be subcutaneous)

• Originally approved for T2DM and then rebranded for obesity 

• 3 mg subcutaneous induce 8 kg of weight loss over 2 years of therapy in conjunction with lifestyle measures

liraglutinide adverse effects?

• Nausea, vomiting, constipation and diarrhea are most common 

• GI side effects can be minimized by a slow titration (start low dose then increase)

• Can cause pancreatitis in rare instances 

• Severe hypoglycemia observed in pts with T2DM → may require adjustment of diabetes medication

liraglutide cautions

• Caution in pts with heart rhythm disturbances, hepatic insufficiency and severe renal impairment 

• Should not be used in IBD, pregnancy, breastfeeding, personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 (MEN 2) → initial study had 2 pts get these (may be a fluke or may have an association)

• Discontinue after 12 weeks if body weight loss is less than 5% → indicates will not work for particular pt

how does semaglutide work? adverse effects?

• GLP-1 agonist like Liraglutide but with a longer half-life (165 hours compared to liraglutide’s 13-15 hours)

• Administered by weekly subcutaneous injection

• Shown to reduce weight by approximately 16 kg over 2 years of therapy 

• Adverse effects 

  • Similar to liraglutide 

  • Nausea, diarrhea, abdominal pain, vomiting, constipation, digestive upset, fatigue, dizziness 

  • Increase in amylase and lipase (suggestive possible pancreatitis or pancreatic damage)

what are the effects of obesity in pregnancy?

• Effects of obesity in pregnancy 

  • Obesity during pregnancy is associated with gestational diabetes, gestational HTN, pre-eclampsia, birth defects, caesarean delivery, detail macrosomia, perinatal deaths, postpartum anemia, and childhood obesity in offspring

  • Increased risk of complications following caesarean deliver

  • Longer labor 

what are the weight change reccomendations in pregnancy?

• Despite increased risks, weight loss during pregnancy is not recommended 

• Consensus is to counsel regarding weight gain targets (to gain no more than 5-9.1 kg (11-20lb) during pregnancy 

should weight loss drugs be used in pregnant women with obesity?

• Orlistat is specifically not recommended during pregnancy due to reduced fat-soluble vitamin absorption 

• Evidence for bupropion is conflicting because it's also an antidepressant.

  • Should not necessarily be stopped if pt is already taking it before pregnancy but should not be started during pregnancy if weight loss is the goal/reason

describe the findings of the obesity meta-analysis

Obesity Meta-analysis

• Large analysis published in March 2023, included studies done prior to December 2021

• 12 RCTs studies 

• Total sample size was 445 participants 

• Mix of studies using liraglutide, semaglutide and GLP-1 infusions

• Most studies showed evidence of appetite suppression, delayed gastric emptying, and changes in taste and food preferences → neuropsychiatric shift/brain re-wiring 

what are the STEP trials?

STEP (Semaglutide Treatment Effect in People) trials 

• Series of clinical trials investigating the use of semaglutide at a dose higher than used for diabetes 

  • Dose for diabetes is 1.0mb/weel 

  • Dose in most STEP trials is 2.4mg/week 

  • More recent trials investigating 7.2 mg/week 

summarize the STEP 5 trial and its findings

• Population: 304 participants with obesity or overweight with at least one weight related comorbidity, WITHOUT diabetes 

• Intervention: 2.4 mg semaglutide weekly 

• Comparison: “placebo” (still got nutrition/lifestyle counselling like intervention group got)

• Outcomes: co-primary end points were the percentage change in body weight and achievement of weight loss of 5% or more at week 104

• Summary: 

  • drug/intervention group: 15.2% weight loss (16.05kg)

  • Placebo group: 2.6% loss (2.77kg) → still good, can be as much or as effective of some drugs 

  • Additional mean change in weight for drug group: 12.6% → amount attributed to drug alone (taken out the effect of placebo/lifestyle/diet)