L11: Drugs and obesity Flashcards
what are type 2 diabetes? What is the prevalence? what does diabetes cause?
- When you have high blood sugar and Insulin resistance
- WHO: 422 million people in 2014
- Prevalence has been rising more rapidly in low- and middle-income countries than in high-income countries.
- Diabetes is a major cause of blindness, kidney failure, heart attacks, stroke and lower limb amputation
Obesity:
how many people will be obese by 2035? what is the prevalence? what is the cost of obesity? what are the 4 drivers to obesity?
- > 50% of world population will be overweight or obese in 2035, unless action is taken (World Obesity Federation)
- 4 billion people affected, children the most
- Societal cost of obesity: $4 trillion each year, by 2035
Drivers:
* dietary preferences towards more highly processed foods
* greater levels of sedentary behaviour
* weaker policies to control food supply and marketing
* Decrease in healthcare resources for weight management and education
how is obesity related to type 2 diabetes?
1 in blank for how many people will be obese by 2034 and develop type 2 diabetes?
Obesity is fuelling a rise in type 2 diabetes
- BMI before diabetes diagnoses is high
- there is an increase risk in microvascular damage (long-term complications that affect small blood vessels) in the kidneys, nerves, and eyes
if trends persist 1 in 3 people will be obese by 2034
and 1 in 10 will develop Type 2 diabetes
what is the context of weight loss drugs:
- what were the type of pills prescribed in the 1950s and 60s and why was the popularity lowered?
- what occurred in 1997 regarding a weight loss drug? why did it occur and what was the legal fees?
- regards the ethics and non-maleficence
- 1950s and 1960s – diet pills based on amphetamines (“uppers”)
–> Popularity lowered due to addiction, etc - 1997 – drug recall, after 24 years on the market
–> Fen-fen
–> Damages heart valves
–> Legal fees: USD $14 Billion, to > 50,000 people
–> One of the most costly liability cases in history
what are hormones?
- they are chemical messengers
- many are carried through the blood and act at a distance (act on a different organ than the one that produced them)
- generally act via hormone receptors – often at the cell membrane
- ex. estrogen, testosterone
describe how glucagon and insulin work to regulate blood sugar
negatove feedback
Low blood sugar –> promotes glucagon release by pancreas –> produces glucagon –> stimulates glycogen breakdown into glucose –> raises blood sugar
High blood sugar –> promotes insulin release by pancreas –> produces insulin –> stimulates glycogen formation from glucose –> Lowers blood sugar
- can also use the produced insulin to stimulate glucose uptake from blood to the tissue cells, and lowers blood sugar
describe the GLP-1 hormone (glucagon like peptide-1)
- its a hormone and Peptide= chain of amino acids. Smaller than a protein
- Acts on the GLP-1 receptor
- Regulates insulin levels
- Affects on many organs (it’s a hormone…)
where does the GLP-1 act
the peptide/amino acid chain of the GLP-1 hormone acts importantly in the brain, by increasing neurogenesis and memory
also acts on other organs like the heart, pancreas, kidney, fat cells, liver , blood vessels, skeletal muscles
what is the difference between ghrelin and GLP-1
how does GLP-1 and ghrelin levels change overtime in blood – before and during a meal?
what is ghrelin?
* Ghrelin is a different hormone than GLP-1.
* Ghrelin is released by the stomach.
* GLP-1 is released by the intestine and by neurons (brain cells)
Brain regions are involved in the GLP-1 signaling, giving rise to the behaviours below:
before a meal;
- reactivity to food cues: ghrelin effect
- meal anticipation: ghrelin
- food motivation: ghrelin
during a meal:
preference for palatable food: ghrelin
taste sensitivity: GLP-1
Nausea and aversion: GLP-1
what is the broad history of GLP-1: 1970s and gut ulcers, what GLP-1 does, and how it related to high blood sugar
- 1970s – research on the topic of gut ulcers
–> GLP-1 identified as a powerful hormone that is secreted when people
eat - GLP-1 action
–> Stimulate insulin secretion
–> Inhibit glucagon secretion
–> so must occurrent hormone when one has high blood sugar, aka people with diabetes (hyperglycemia) - Research interest in GLP-1 –> “double
mechanism” on blood glucose
What did Dr. Daniel Drucker, University of Toronto, discover and what was his main concern: use ex. of gilia monster
- Dr. Daniel Drucker, University of Toronto, 1984 (endocrinologist)
- He discovered the human GLP-1 hormone in human gut
- However, he also found that the GLP-1 disappears very quickly in humans
- This caused him to be curious? why does it disappear so fast?
- To test this he tried to clone GLP-1 using glia monster DNA from the freezer of the ROM
- Glia monster goes for long times without food and thus has a slow metabolism and stable blood sugar levels
- wanted to see what was the difference in the Gilias physiology of hormone release vs human and how that could be used for a diabetes treatment
Dr. Daniel Drucker, University of Toronto, story of trying to discover a cure for diabetes
- he tried to clone the lizards dna at the ROM but that failed
- he needed an actual lizard to obtain the dna himself
- he called the Utah Zoo to ship the lizard to him
- he picked it up from pearson airport
- he pinned the lizard to the table so that he could easily euthanize it using animal protocols
- they found that the lizard was “very unique in that it has genes for Exendin-4, which is the protein that became the first diabetes GLP-1 treatment,”
–> Extendin-4 similar to GLP-1, but breaks down much slower
what was the scale of impact of the GLP-1 agonists?:
how many diseases and to what scale has it helped?
how many doses were administered?
what other research did it prompt?
did it find possible treatment for alzheimer’s?
VinPrize 2023 “Innovators with Outstanding
Achievements in Emerging Fields”
–
- advancements related to the GLP-1 endocrine process has made powerful therapies for type 2 diabetes impacting more than 1 billion individuals with obesity and 3 million with short bowel system
- in 2023, there were more than 20 million doses of GLP medication used globally.
- this discovery also prompted the research for other neurodegenerative conditions including Alzheimer’s, Parkinson’s, and Huntington’s diseases.
- specifically for Alzheimer’s, GLP-1 medication could slow the progression of Alzheimer’s disease, offering new hope for over 55 million patients worldwide
What did Drucker say specifically in his award speech for his GLP-1 drug
he thanked the volunteers at the clinical trial who “made reality happen”
what was some foundational clinical research that showed that the GLP-1 drug was working?
- Michael Nauck, 1993
- Infuse people with type 2 diabetes with GLP-1
–> Blood sugar levels return to normal in 4 hours
–> Insulin secretion stimulated
–> Glucagon inhibited - The dual action implied that GLP-1 is working different than other
hormones we knew about
What was the study design for the clinical trial for GLP-1? what were some problems they observed when the patients took the drug and has to eat?
- Early clinical studies with GLP-1 – needed to focus
on keeping dose low
Study design
* treat people with GLP-1
* People eat a meal
* 30 minutes later, clinical researchers check blood
glucose level (clinical study endpoint)
Problem:
* People didn’t want to finish their meal, felt nauseous
* Low appetite
* Clinical study can’t be followed as designed (deviation in
clinical research conduct)
How are the GLP-1 agonist drugs different from GLP-1?
- GLP-1: Natural hormone that is released after eating; GLP-1 agonists: Synthetic mimics.
- GLP-1 degrades quickly; agonists resist degradation.
- Agonists injected; GLP-1 released from gut.
- Agonists treat diabetes, obesity; GLP-1 not therapeutically used.
- also the agonists have a change in amino acid chains than GLP-1
- they have the same amino acids for potency, but may have some substituted amino acids, spacers, and fatty acid chains
what is the pharmacokinetics of semaglutide (ozempic)
dosing: once weekly
half life: 165-184 hrs
adminstration required before meals: no
describe the Landmark phase 3 clinical trial with semaglutide, 2021
inclusion, and exclusion criteria
conclusion
- 1961 people
- Inclusion criteria: BMI > 30
- Exclusion criteria: diabetes
- it was a dose escalation study (up till week 16 increasing doses and then stopped doses at week 68)
Conclusion:
* ”people without diabetes who were overweight or obese had clinically relevant weight loss with weekly injections of semaglutide (2.4 mg) added to lifestyle changes”
* placebo was lower weight loss than the drug
what is the impact of weight loss drugs with type 2 diabetes
are drugs approved for type 2 diabetes?
For people with Type 2 diabetes, if decrease weight by 15%, 86% of these people will have a remission of their diabetes (Scotland study)
- yes ozempic ended up being accepted for type 2 diabetes in 2017, so has other drugs
why are peptides generally not stable when taking orally?
- Oral formulation developed, mixed with an absorption enhancer
- Needs to be taken on empty stomach
- 1 hour before other meds
- 30 min before food
–> inconvenient
what was the phase 3 trial like for the oral version of semaglutide? (june 2023)
global sample, efficacy measurement, similarity in results between oral and injected, side effects
- Global: 50 outpatient clinics in nine countries across Asia, Europe, and
North America. - Efficacy measurement - % loss body weight in 68 weeks
–> Semaglutide 50mg/day: -lost 15% of weight) - Placebo:-lost 2.5% of weight
- Similarity between oral and injected:
–> near-identical relationship between semaglutide concentration and effect on biomarker (glycated haemoglobin) and bodyweight (clinical sign/symptom) - Side effects: Gastrointestinal adverse events (mostly mild to moderate)
–> 268 (80%) participants with oral semaglutide 50mg
–> 154 (46%) with placebo.
How many different GLP-1 agonist drugs has the FDA approved, and when was most recent?
approved 13 drugs and most recent is zepbound (tirzepatide) in 2023
What are the most common side effects of semaglutide (dosage for weight loss)
- Nausea
- Diarrhea
- Vomiting
- Constipation
- abdominal (stomach) pain
- Headache
- fatigue, dyspepsia (indigestion)
- Dizziness
- abdominal distension
- eructation (belching)
- hypoglycemia (low blood sugar) in patients with type 2 diabetes
- flatulence (gas buildup)
- gastroenteritis (an intestinal infection) gastroesophageal reflux disease (a type of digestive disorder).
what are the cons to the GLP1 Hormone vs the agonist GLP1
- This difference for “artificial” GLP-1 agonists might be behind the major side effects:
- Nausea
- Diarrhea
- Constipation
- Vomiting
but the GLP-1 hormone just acts locally and is degraded quickly
FDA’s update from January 2024 about safety of GLP-1 agonists as a whole
Question 1: For the specific topic addressed in this FDA update, what
are the major conclusions of the FDA based on the data they
currently have available?
Question 2: The FDA gathered safety data from which different sources?
Question 1:
- There is no evidence suggesting a causal link between GLP-1 receptor agonists and suicidal thoughts or actions.
Question 2:
- Adverse event reports in the FDA Adverse Event Reporting System (FAERS).
- Clinical trials, including large outcome studies and observational studies.
- Meta-analysis of clinical trials across all GLP-1 RA products.
- Postmarketing data analysis (health insurance claims and patient health records)
what is food noise and its effect when on GLP-1 agonists
- “Food noise”: ruminating (frequent thoughts) about food
- communication between brain and gut
- Many individuals on GLP-1 agonists talk about “food noise” being much quieter
- Reduced pleasure in eating
does weight return after treatment with ozempic stop?
Long-term data: People regain 2/3 of their weight within 2 years of stopping these drugs
- sharp increase on graph as soon as treatment stops
How long do people stay on GLP-1 agonists?
- Half of patients discontinue their GLP-1 prescriptions at 1 year
- 70% at 2 years
- Why? – side effects, cost, other treatments, efficacy, complexity
what are some Future areas/concerns for GLP-1 receptor agonists
- Chemical versions of GLP-1 receptor agonists
–> Advantages/ disadvantages? (discuss) - GLP-1 receptor agonists - effects on cognition?
- Health revolution, or cosmetic procedure for the wealthy?
- Deepen social stigma around body size?
- Off-label use? Eventual over-the-counter? But these medications can have very strong side effects…..
