Michael Weintraub, MD
@MWeintraubMD
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Endocrinologist & Clin. Asst. Prof. @NYULangone | @WeillCornell and @Sloan_Kettering endocrine fellow alum. ABOM Diplomate. Opinions = own
New York, NY
Joined July 2008
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How much is 1 unit of insulin?
1 international unit of insulin is defined as the amount of insulin to induce hypoglycemia (blood glucose of 45) in a fasting rabbit (determined in 1922).
Now you know more than most endocrinologists!
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766
3K
#Ozempic
drives an impressive 15% weight loss. What happens when the drug is stopped❓
The limited data we have so far shows people regain most of the weight.
Obesity is a chronic disease and requires chronic treatment.
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765
Why is there a creatinine bump when starting an SGLT2 inhibitor?
Constriction of the afferent vessel to the kidney corrects the hyperfiltration seen in diabetes.
Just like after starting an ACE inhibitor, the initial creatinine bump protects renal function in the long-run.
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Levothyroxine monotherapy is the standard of care for hypothyroidism, but 15-20% report persistent symptoms despite normal TSH.
Reasons include relative tissue deficiency of T3 from ⬇️ peripheral conversion of T4➡️T3, genetic variations of thyroid hormone transport/metabolism.
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Why do initial successful weight losses with diet and exercise seem to always fail?
Our body compensates! It becomes more efficient and boosts appetite.
For each kilogram of weight loss, appetite ⬆️ 100 kcal/day and our energy expenditure ⬇️ 20-30 kcal/day.
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#Tirzepatide
lowered HbA1c to less than 7% in 90% of patients with
#type2diabetes
and
#obesity
.
Even more impressive: HbA1c normalized to <5.7% in half of patients 😲. All this with minimal hypoglycemia.
And an average 15.7% weight loss 📉
SURMOUNT-2:
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SGTL2 inhibitors💊 are the gift that keep on giving.
In addition to ⬇️ hyperglycemia, heart failure, and kidney disease, did you know if can improve gout?
SGLT2i ⬇️ gout episodes and gout drug use by 15%.
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Primary aldosteronism is the most common form of secondary hypertension.
It is SEVERELY under-diagnosed. Everyone should know when to screen for primary aldosteronism
#ENDO2023
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Do you know where
#Ozempic
comes from?
GLP-1 agonists were initially isolated from Gila monster saliva 🦎
The saliva of the Gila monster contains exendin-4, a structural analogue of human GLP-1, but with a much longer half-life.
#obesity
#medtwitter
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What is the optimal steroid tapering regimen in patients no longer requiring long-term steroids? 🤔
The 🆕 glucocorticoid-induced adrenal insufficiency guidelines gives us great guidance ‼️
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How to safely taper steroids in those at high risk for
#adrenalinsufficiency
?
An early morning cortisol >10 mcg/dL rules out adrenal insufficiency. Glucocorticoids can be safely stopped.
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Individuals with class 3 obesity (BMI > 40) have up to 17 years of lower life expectancy.
Compare this to smokers who have 8.9 years of lower life expectancy to non-smokers.
#ADA2024
#ADASciSessions
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NEW Data drop at
#ADA2023
: Retatrutide, a triple agonist (GLP1, GIP, glucagon) lost an incredible 24.2% of their body weight, which amounts to 58 lbs!
This data suggests retatrutide is the most effective anti-obesity med to date and approaches bariatric surgery outcomes.
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Beta blockers should NOT be first line to treat hypertension. They should be reserved for treating Afib, heart failure, etc.
β-blockers when used first line were paradoxically associated with ⬆️ cardiac risk 💔
We have so many more effective options.
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It was later determined this amount of insulin is equal to 34.7 micrograms of pure crystalline insulin. Rabbits are no longer sacrificed to calibrate Lantus pens
#endotwitter
#diabetes
#medtwitter
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The
#Mediterranean
diet outranked 6 other popular diets in reducing heart attack, stroke, and all-cause mortality in a recent study.
Dietary counseling should be part of every care plan in those at high risk for
#cardiovascular
disease
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Is BMI a good predictor of fat mass? At a population level, yes. We can see a good correlation in the below graph.
However, for a given BMI, there is large inter-subject variability in body fat percentage.
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Not all bisphosphonates are created equal!
Different drug holidays are needed to match each drug's unique characteristics.
Slide credit Peter Ebeling
#ENDO2024
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Replacing sugar sweetened beverages with tea, coffee, or water are associated with increased survival.
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Primary aldosteronism is incredibly common and underdiagnosed
🔹5-10% in those with hypertension
🔹20-50% with treatment-resistant hypertension.
All those with hypertension should be screened following this algorithm
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The pharmacologic options for treatment of MASH/NASH, from a primary care and endocrinologist lens.
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Tirzepatide has just been approved under the brand Zepbound for the treatment of
#obesity
.
Keep the names straight! 🫨
Semaglutide: Ozempic = Diabetes, Wegovy = obesity
Tizepatide: Mounjaro = Diabetes, Zepbound = obesity
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We now have added tools beyond the traditional ASCVD 10-year risk estimator to guide statin therapy 💊
🔹Coronary artery calcium score is a cheap, quick test that can help further risk stratify whether added lipid lowering therapy is needed in those uncertain cases
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🔹Over 30% of GLP-1 users discontinue medication within the 1st month, according to commercial insurance data.
🔹Over half discontinue before 3 months.
🔹There is a lower discontinuation rate when meds are prescribed by endocrinologists or obesity medicine specialists, and
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Why are many clinicians reluctant to test for primary hyperaldosteronism?
They are unsure what to do with the patient's current blood pressure meds.
What's the easy answer? Screen anyway!
Take into account the effect of each interfering med with this handy chart:
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The earlier onset of Type 2 Diabetes directly reduces life expectancy.
For every decade earlier the onset of Type 2 Diabetes, there is a 3-4 year reduces life expectancy.
#ADA2024
#ADASciSessions
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Which medications cause weight gain?
When assessing causes of
#obesity
take a look at the medication list.
Switch to a weight-neutral or weight-negative medication if feasible.
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Elevated LDL is a necessary condition for atherosclerosis, and easily modifiable with underutilized treatments.
“If the entire population maintained LDL concentrations akin to those of a neonate (20-40mg/dL), atherosclerosis might well be an orphan disease” -
That’s powerful🤯
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🚨New Trial Results🚨
Semaglutide improves chronic kidney disease outcomes by 24% in pts with type 2 diabetes and CKD, in
@NEJM
today.
⬇️29% cardiovascular death
⬇️18% cardiovascular events
⬇️20% all-cause mortality
Slower GFR decline 1.16 vs 1.73 / year
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🚨NEW Data drop 🚨
#SELECT
trial:
17,604 pts BMI >27 & preexisting cardiovascular dz 🫀 but no diabetes,
#semaglutide
2.4 mg vs. placebo
⬇️ 20% risk of a composite of cardiovascular death ❤️, nonfatal myocardial infarction, or nonfatal stroke🧠
Presented today at
#AHA2023
!
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Once weekly insulins are almost here.
Insulin icodec and ifsotera alfa (BIF) are two different ways to give insulin weekly. This can complement once weekly GLP1s in those with
#type2diabetes
.
These unique tools will fill the recent void of innovation in the
#insulin
space.
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Tirzepatide was associated with 48% decreased kidney events compared to GLP1 RA, in a retrospective analysis of 140,308 patients with type 2 diabetes.
Also with:
⬇️ 20% 🫀MACE
⬇️ 42% ☠️all cause mortality
⬇️ 0.34% a1c
⬇️2.9kg body weight
We need full randomized clinical trials
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The prevalence of hypercortisolism was an alarmingly high 24% in difficult-to-control type 2 diabetes.
This was based on a dexamethasone suppression test with cortisol > 1.8mcg/dL in the CATALYST trial.
Targeting hypercortisolism such as with a glucocorticoid receptor
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Endocrine disorders commonly occur after cancer
#immunotherapy
:
🔹Hypothyroidism
🔹Thyroiditis
🔹Hypophysitis
🔹Type 1 Diabetes
Monitor thyroid, pituitary/adrenal, glycemic control initially and periodically in all patients on immunotherapy.
#medtwitter
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Routine advice is to take metformin with meals in order to minimise potential gastrointestinal adverse effects, despite the lack of an evidence base.
However, taking metformin 30-60 min before a meal improves postprandial hyperglycemia.
There were similar rates of nausea
Taking metformin 30-60 minutes before a meal can significantly improve postprandial glucose control in individuals with type 2 diabetes. Timing matters!
#diabetes
#metformin
#glucosecontrol
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#GLP1s
, just like any other medication, should be prescribed if the benefits outweigh the risks. There are some well-established side effects, and others are possible or doubtful.
🔹 Gastrointestinal side effects are well-known adverse events from GLP1 medications.
🔹 Muscle
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😌 Metabolic-dysfunction associated liver disease (MASH), formerly called NASH, has been long overlooked.
🥇However, now we have the first FDA approved therapy, resmetirom, for the treatment of MASH.
💯 There are now a multitude of agents with unique mechanisms in the pipeline
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#retatrutide
, a triple agonist, released phase 2 results in type 2 diabetes with impressive results 😲
a1c ⬇️ 2.2%
body weight ⬇️ 16.9%
This weight loss is the largest seen in a 💊 trial in Type 2 Diabetes, a condition traditionally challenging to garner weight loss.
#ADA2023
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Cagrilintide, an amylin analogue 💉, when combined with semaglutide, generated greater weight loss and glucose control than
#semaglutide
alone, in their phase 2 trial of patients with
#type2diabetes
⬇️ 15.6% body weight 📉
⬇️ 2.2% a1c
All in just 32 weeks 👀
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NEW DATA drop: In SURPASS 6, tirzepatide added to insulin glargine in T2DM had greater a1c reduction (⬇️2.1%) than adding meal-time insulin (⬇️1.1%).
Tirzepatide ⬇️ 12kg than meal-time insulin and ⬇️ hypoglycemia.
And 20 less jabs per week!
#EASDRME
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How can we prevent loss of lean mass (muscle mass) during weight loss interventions?
Higher protein intake.
This study shows higher protein diet led to half as much lean mass loss compared to a low protein diet
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Currently GLP1s have a warning about the risk of medullary thyroid cancer. This was an effect seen in rodent studies.
However, the available data does not suggest a causal relationship between GLP1 and medullary thyroid cancer in humans.
The thyroid GLP-1 connection- how much does increasing detection and ascertainment bias contribute to possible associations with GLP-1 medicines?
#ADA2024
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There are clear
#cardiovascular
benefits 💟 with
#GLP1
agonists.
What about
#Stroke
risk 🧠, specifically?
In a recent meta-analysis there was a 17% reduction 📉in fatal and non-fatal stroke😲
#Semaglutide
leads the pack with 35% reduced stroke risk in the SUSTAIN-6 trial👀
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Not all
#GLP1
agonists are created equal.
Larger molecules (dulaglutide) are unable to cross the blood-brain barrier thus have less weight loss.
Depending on which amino acid is modified, some have shorter half lives and require daily (liraglutide) rather than weekly injection
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#Semaglutide
shows cardiovascular ❤️benefit in those WITHOUT diabetes in
#SELECT
trial.
Weight-dependent and independent hypotheses:
⬇️Perivascular & epicardial adipose tissue
⬇️inflammatory & prothrombotic milieu
⬆️endothelial & left ventricular function
⬆️plaque stability
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Semaglutide reduced the risk of major kidney outcomes, MACE and death in people with T2DM and CKD, irrespective of baseline SGLT2 inhibitor use, according to a subanalysis of FLOW presented today at
#ADA2024
Visually on the right panel with the concomitant SGLT2 use, the
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Using BMI to define obesity has issues.
Body fat % is a better predictor of risk.
Clinically relevant "overweight" can be defined as body fat >25% in men and >36% in women.
Obesity can be defined as body fat >30% in men and > 42% in women
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Ever heard of Type 3 Diabetes?
Those with T2DM have ⬆️ risk of Alzheimer’s, some are calling Type 3 diabetes due to the state of insulin resistance in the brain.
There is graveyard of drugs that failed to show benefit in Alzheimer’s.
Could GLP1 agonists buck this trend?
#ADA2023
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GLP1s were associated a gastric emptying delay that was of low and limited clinical significance, in a meta-analysis of 15 randomized trials.
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Today, the FDA approved resmetirom, a thyroid hormone receptor partial activator, for the treatment of NASH.
Resmetirom demonstrated NASH resolution and improvement in liver fibrosis in its recent phase 3 trial published in NEJM ()
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Why is combination therapy the BEST for
#type2diabetes
❔
We can hit all the causes of hyperglycemia in the "Ominous Octet"
GLP1 agonists act upon multiple organ systems, so a great initial therapy, but adding SGLT2i is a great complement.
Slide by Ralph DeFronzo at
#ADA2023
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SURMOUNT-4 results just published in
@JAMA_current
🛑Stopping
#tirzepatide
leads to regain of the majority of the lost weight.
Is this a surprising result ⁉️
No
#Obesity
is a chronic disease and requires chronic treatment, just like high blood pressure or diabetes.
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How do we work up an adrenal incidentaloma?
It depends on the Hounsfeld Unit (HU) density on a simple non-contrast CT scan:
If HU < 10, you have 100% ruled out a malignancy!
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In SELECT, those receiving semaglutide had improvement in MACE regardless of baseline a1c.
🫀 This implies the cardiovascular protection provided by semaglutide is not due to the glucose lowering effect alone.
The SELECT symposium
#ADA2024
cardioprotection with semaglutide does not depend on A1c
#obesity
@DiabetesCareADA
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New data dropped at
#ENDO2023
In men with low testosterone at high risk for cardiovascular disease,
#testosterone
replacement did NOT increase major adverse cardiovascular events
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If someone has adrenal insufficiency (AI) after taking long-term steroids (>1 yr), how likely is their adrenal function to recover?
In patients taking long-term steroids, 56% were found to have AI at baseline, and 25% still had AI even 6 months later‼️
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#tirzepatide
in GADA positive and low c-peptide pts showed ⬇️2% a1c in post-hoc SURPASS analysis.
Does this provide more evidence on tirzepatide use in new-onset
#type1diabetes
?
Interesting data at
#EASD2023
!
@BevTchangMD
#EASDRME
@radcliffeCARDIO
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Adding bupropion/naltrexone to GLP1 generated an added 4-5% weight loss
This is not surprising. Each has a unique and complementary mechanism.
Knowing how to use all our tools- meds, lifestyle, surgery is needed to best care for this chronic disease
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Continuous glucose monitoring (CGM) has benefits in Type 1 and Type 2 diabetes but what about
#prediabetes
? 🤔
CGMs helped to visualize impact of carbohydrates 🍞 on glucose trends 📈, inciting dietary changes in a study of those with prediabetes.
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The
#Mediterranean
diet continues to show impressive results!
The Mediterranean diet ⬇️ 45% cardiovascular 🫀 mortality compared to no intervention in those at high risk.
Also ⬇️ 28% all-cause mortality 😲
These benefits are on par with statins!
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New
#semaglutide
trial results just dropped 👀
⬇️ 20% decrease in major cardiovascular events 💟 in adults with obesity & established cardiovascular dz.
These ppl did NOT have
#type2diabetes
.
Semaglutide not only ⏬ weight but prevents the downstream 🫀consequences of obesity
‼️Our long awaited SELECT trial results
👉 RCT adults w/
#obesity
/overweight +
#CVD
on semaglutide 2.4
#Wegovy
vs placebo x ~4 yrs
👏 ⬇️20% incidence of CVD death, nonfatal MI, nonfatal stroke
👉1st GLP1 to prove ⬇️ CVD in ppl w/o
#T2DM
#CardioTwitter
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Liraglutide, a daily GLP-1 agonist, will be produced as a generic medication, TEVA announced today.
This could be a large step toward allowing increased access for patients with Type 2 Diabetes and Obesity.
GLP1 Generics: It Has Begun
Generic Liraglutide (Victoza) Becomes First Generic GLP-1 Receptor Agonist
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The different ways to assess adiposity.
They vary in accuracy, ease of use, and cost. Ultimately we must come up with a standardized method to assess adiposity that correlates well to cardiometabolic risk.
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Reverse T3 Syndrome is a pseudo-endocrine disorder touted on the internet. The claim is that increased conversion of T4 to reverse T3 outcompetes T3 and causes low energy levels.
This is false.
T3 has 100x higher binding to receptor than reverse T3. So any mildly higher
3
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Today, the FDA approved
#semaglutide
to reduce risk of CV disease in
#obesity
&
#overweight
This is the FIRST approval for such an indication
The decision is based on SELECT trial with semaglutide lowering CV events by 20%
Cardiovascular outcome trials are costly but worth it
🥳
@FDA
Approves First Treatment to Reduce Risk of 🩷Problems Specifically in Adults with
#Obesity
or Overweight
#cardiotwitter
#obesity
#medicine
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Weight loss interventions can lead to a loss of lean muscle mass in addition to fat mass. How can we mitigate lean mass loss?
Add some resistance training!
This study shows resistance training attenuated lean mass loss and improved overall strength.
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What is the benefit of diagnosing primary aldosteronism?
Diagnosis and surgical cure improves cardiovascular and overall mortality compared to medically controlling blood pressure.
Surgical treatment (ADX) of an aldosterone producing adrenal adenoma ⬇️ 43% all-cause mortality
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Obesogenic substances are EVERYWHERE!
We consider the western diet obesogenic because of its high fat, high sugar.
But what about the the plastics that hold that food?
Bisphenol and phthalates in plastics leach into our food/drinks that also cause weight gain
#ENDO2023
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Why is weight loss so difficult to sustain?
Our body adapts.
For every ⬇️ weight 1 kg:
⬆️ appetite 95 kcal/day
⬇️ Decreased energy expenditure 25 kcal
We have increased hunger, altered food perceptions, greater muscle efficiency. No wonder weight regain is so common!
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How do the GLP1s/incretins stack up in a meta-analysis?
Tirzepatide showed the greatest a1c lowering, then semaglutide among the FDA-approved meds.
CagriSema showed the greatest weight loss, then tirzepatide among FDA-approved and pipeline agents.
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In the newly updated PCOS guidelines, diagnosis still uses the Rotterdam criteria with 1 important modification:
Anti-mullerian hormone (AMH) can now be used instead of ultrasound
This is a significant practice change and offers a lower cost alternative
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Type 2 diabetes often required long-acting and meal-time insulin or 28 injections/week 💉💉💉
Combined semaglutide + weekly insulin icodec would be 1 injection/wk 🤯
In COMBINE 3, Sema+icodec was non-inferior to glargine+aspart in a1c reduction with less hypoglycemia.
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How do we diagnose Cushing's? We have 3 screening tests:
1. 24-hour Urinary Free cortisol
2. dexamethasone suppression test
3. Late night salivary cortisol
Late night salivary cortisol is THE BEST first test for Cushing's. Let's explore why the other two have their problems:
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To lose weight do we need to kill ourselves at the gym? No.
Moderate intensity exercise 🚶♀️ 2000kcal/wk lost more weight than vigorous intensity 🏃♀️ 1000kcal/wk. So duration matters more than intensity.
It's not high intensity exercise or bust. A brisk walk will do!
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Ever heard of "exercise snacks”? These small bits of physical activity can lower glucose levels.
Those who walked for 2 min every half hour during the day had ⬇️ average glucose than those with the same total walk time before breakfast.
Even better? Do what fits your schedule!
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🤰Origins of obesity start before birth.
🧠Excessive nutrient exposure in the mother changes fetal growth and brain pathways that extend into adulthood.
🫄Gestational diabetes in the 1st trimester before it is commonly discovered caused fetal hypothalamic changes that predicted
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Recognize the symptoms of hypoglycemia and how to treat, from fasting acting oral carbs to glucagon treatment.
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Sustained weight loss can reverse many metabolic abnormalities, yielding meaningful benefit in several disease states.
Depending on a patient's comorbidity they may have different weight loss targets.
#obesity
#diabetes
#endocrinology
#meded
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#Diabetes
care used to just be about the ABCs (a1c, blood pressure, cholesterol).
Now there is a 4th pillar equal to all the others:
Agents with
#Cardiovascular
and Kidney Benefit
#GLP1
agonists and SGLT2 inhibitors remain underutilized.
2
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71
Do GLP1s cause thyroid cancer?
Yet another review concludes there is no evidence of higher thyroid cancer risk.
But we need longer term followup with more patients for more definitive conclusions.
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70
We are halfway up the mountain of clinical trial data to be produced for
#tirzepatide
.
So far it has demonstrated the greatest efficacy at treating
#type2diabetes
and
#obesity
outside of bariatric surgery
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Survodutide 💊 has a novel dual GLP1 and glucagon receptor agonist mechanism, and achieved an impressive 18.7% body weight loss 👀 in the actual treatment arm of their phase 2 trial.
The ever expanding list of medications with unique mechanisms is a huge win for the field!
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15
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Orfoglipron is an oral
#GLP1
agonist that showed an impressive 14.7%
#weightloss
at 36 wks in a P2 trial 🙌
This weight loss is on par with
#Wegovy
with the advantage of a daily pill rather than a weekly injection
This will be a great addition to our toolkit to treat
#obesity
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15
65
What is the diagnostic evaluation for PCOS?
One main reason is to exclude other conditions. The prevalence of these conditions is rather low, but we should still always think about them.
#ENDO2023
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Semaglutide maintains sustainable weight loss over 4 years in SELECT, its longest trial to date.
PPL lost weight across all BMI, age, gender, race, glycemic status, GFR.
A new analysis of anthropomorphic data just published in Nature
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Osteoporosis management is a lifelong journey. The management strategy changes as the patient’s age, fracture risk changes.
Regular discussions with patients on the best treatment options for each patient at each visit are needed.
Excellent talk by Peter Ebeling
#ENDO2024
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#Tirzepatide
has 5%-7% more weight loss than
#semaglutide
when indirectly comparing trials.
Why? A few hypotheses exist:
🔹Added GIP receptor agonism engages more cell types
🔹GLP1 and GIP receptor agonism at a single cell generates more activity
🔹Tirzepatide is a stronger GLP1
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The Look AHEAD trial, an RCT of intensive lifestyle therapy in those with Type 2 Diabetes, is famously known to have failed to show a cardiovascular (CV) benefit.
Why? The weight loss may have been insufficient.
CV benefit was shown in those who had >10% weight loss, in a
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#Testosterone
thought to improve bone density and quality 🦴.
BUT there was a significant increase in fracture in those treated with testosterone, in the TRAVERSE fracture trial dropped at
#ENDO2023
!
There was a 43% higher fractures in testosterone treated pts than placebo!
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No one person has the ability to manage all the problems in the cardio-renal-hepatic-metabolic patient.
How can we coordinate care among all the specialists and PCPs, and how can we do it well?
Potential answer: Creation of a cardiometabolic clinic 🏥
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23
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Phentermine-topiramate and semaglutide generated the most weight loss in a meta-analysis of 132 randomized trials.
Pharmacotherapy for adults with overweight and obesity: a systematic review and network meta-analysis of RCTs
Just published
@TheLancet
But already out of date-searches to March 2021
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The LOOK AHEAD trial failed to show intensive lifestyle changes reduced mortality relative to placebo in those with T2DM and obesity. This was a disappointing result.
However, those who lost >10% weight had a 21% reduced mortality rate.
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The menopausal transition is a period of accelerated cardiovascular disease risk.
More research is needed to determine how to intervene during this critical window to improve symptoms and prevent disease formation.
Marlatt et. al Obesity, 2021
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Is the cardiovascular benefit from GLP1 receptor agonists entirely due to weight loss or is there an added weight-independent benefit? 🤔
🫀The GLP1 albiglutide demonstrated a 22% reduction in cardiovascular composite endpoint compared to placebo but did not lead to weight loss.
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Albiglutide, a GLP1 agonist, demonstrated 22% cardiovascular event reduction📉in T2DM pts despite not generating much glucose lowering or weight loss.
These trial results suggest GLP1a has cardiovascular benefit ❤️even without improving risk factors.
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Obstructive sleep apnea (OSA) and obesity have a bidirectional causal relationship🔁
Obesity:⬆️adipose tissue around the airway, ⏫OSA
OSA: hinders appetite control⬆️food intake, ⏫obesity
Both ⬆️inflammation driving heart disease 🫀
We can break this cycle by treating both
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The numbers of obesity:
🌎 By 2035 nearly 3.3 billion adults will live with overweight or obesity
☠️ Excess body weight accounts for >4 million deaths between 1980 and 2015
🫀 Obesity is linked to 5x risk of heart disease, stroke and type 2 diabetes
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The GLP1 dulaglutide reduces alcohol consumption by 29% compared to those receiving placebo in a small RCT
We are happy to share our most recent paper, published today in
#JCIinsight
about GLP-1 agonist dulaglutide effectively reducing alcohol intake. GLP-1 agonist as a future treatment for substance use disorders?
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