UDLCO summary :
New pharmacological intervention with extended indications for diabetes, weight gain as well as heart failure in the form of a novel GLP1 inhibitor recently flying off the shelves has raised eyebrows and the journal club raises certain issues. There is also some discussion around a typical face that Semaglutide produces.
UDLC glossary : http://
UDLC transcripts :
Metacognitist metapsych group journal club conversational transcripts logged here earlier :
[4/9, 12:35 AM] Pediatric endo NJ :
Semaglutide in HFpEF
[4/9, 8:28 AM] Rakesh Biswas: We left this journal club midway with our students around the question of trying to understand the clinical significance of the statistically significant changes in :
"in the mean KCCQ-CSS as 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and mean percentage change in body weight as −9.8% with semaglutide and −3.4% with placebo"!
The next step was reviewing all the points in the KCCQ-CSS to understand the clinical significance of it's numbers
[4/9, 8:59 AM] Rakesh Biswas: Would it be possible for you to share the full text.
I realized that our students had been discussing a full text of an earlier 2022 study published open access but probably ignored this as there was no full text
[4/9, 9:20 AM] Rakesh Biswas: Journal club conversational critical appraisal and the point where we got stuck shown in the transcripts below :
"[4/3, 8:41 AM] Sai Charan Kulkarni 2020 KIMS Pg: https://www.frontiersin.org/
an observational, retrospective, real-world study on obese outpatients with T2D and chronic HF at the HF Units of Internal Medicine Department at the Hospital Regional Universitario de Málaga in Málaga; the Hospital Costal de Sol, in Marbella; and the Hospital Helicopteros Sanitarios, in Marbella, Spain.
P - total of 136 patients were included ( out patients )
I - safety and efficacy of semaglutide as management for obesity in TY2DM and HF.
C - clinical, laboratory and therapeutic variables of pre and post Semaglutide therapy at 3, 6, 12 months in same patients.
O - From baseline to 12 months, there was a significant improvement on the Kansas City Cardiomyopathy Questionnaire total symptom score (59.0 ± 24.1 vs 79.9 ± 28.4 points, p<0.01), a reduction in the proportion of patients with New York Heart Association functional class III (40.4% to 16.2%, p<0.01), and a reduction in N-terminal pro-brain natriuretic peptide levels (969.5 ± 653.5 vs 577.4 ± 322.1 pg/mL, p<0.01). Emergency department visits due to heart failure, hospitalizations due to heart failure, and all-cause hospitalizations also declined. Additionally, significant reductions in glycated hemoglobin (-1.4%) and body weight (-12.7 kilograms) were observed as well as a de-intensification of antidiabetic therapy.
[4/3, 8:42 AM] Sai Charan Kulkarni 2020 KIMS Pg: *primary endpoint* : was to evaluate the clinical efficacy in the HF health status, as determined by the improvement in the total symptom score on the Spanish version of the Kansas City Cardiomyopathy Questionnaire (KCCQ) (19), reduction in the New York Heart Association (NYHA) classification, and reduction in NT-pro-BNP levels.
*Secondary outcomes* : included the glycemic efficacy, as determined by the reduction in HbA1c levels and the proportion of patients who achieved good glycemic control (HbA1c <7%) prior to starting semaglutide and at 3, 6, and 12 months; weight loss (changes in body weight, BMI, and waist circumference); de-intensification of T2D treatment (reduction in number of daily glucose-lowering drugs and/or insulin doses) and HF treatment (decline in number of antihypertensive agents, beta-blockers and diuretics); and the safety (adverse drug reactions, need to discontinue semaglutide due to adverse events, 3P-MACE, emergency department visit because of HF decompensation (from one year before initiation), hospitalizations (from one year before initiation), and mortality (from one year before initiation).
[4/3, 8:50 AM] Rakesh Biswas: Can you share the break up of the symptom score so that we can understand how clinically significant are the differences portrayed by the numbers in the total symptom score here :
As in what's the clinical significance between 59.0 ± 24.1 vs 79.9 ± 28.4 points? Will only become clear when we see what those points stand for?
[4/3, 8:53 AM] Rakesh Biswas: Share the numbers for these :
"Emergency department visits due to heart failure, hospitalizations due to heart failure, and all-cause hospitalizations also declined."
Also numbers for :
How many had a de-intensification of antidiabetic therapy?"
[4/3, 9:12 AM] Sai Charan Kulkarni 2020 KIMS Pg: All numbers shared here sir.
[4/3, 9:13 AM] Rakesh Biswas: Discuss their clinical significance
[4/3, 9:15 AM] Rakesh Biswas: Where's the division here between the two groups?
[4/3, 9:16 AM] Rakesh Biswas: Oh just realised there's no comparator!! 😬🧐
What's the point?
[4/3, 9:18 AM] Rakesh Biswas: How can frontiers publish such a study without a comparator especially when it's not a qualitative study either providing insights?
[4/3, 9:19 AM] Rakesh Biswas: Let's look for some RCTs for Semaglutide efficacy?
[4/9, 9:41 AM] NJ : @Rakesh: Here you go.
[4/9, 10:35 PM] Rakesh Biswas: Went through this NEJM study full text today thanks to @NJ and also through the full text of the Kansas City Cardiomyopathy
questionnaire from 2000 and as suspected there are quite a few issues!
For a start, the questionnaire says it's a 2 week recall and the study evaluates it after a year, which means the patients are simply telling us what happened in the last two weeks, not one year?
Also what would change with Semaglutide in a year when answering KCCQ questions like the one below 👇
"Heart failure symptoms can worsen for a number of reasons. How sure are you that you know what to do, or whom to call, if your heart failure gets worse?
[4/10, 12:52 AM] NJ : @Rakesh: I am not sure I understand the issues you’re referring to.
KCCQ-CSS is a validated patient reported outcome measure - although it represents a 2-week recall at any time point, it has been shown to be valid, reproducible, and sensitive to clinical changes in patients with systolic dysfunction, HFpEF, and other conditions.
So, in this case the pre-randomization score can be taken to be representative of the baseline situation, and the end of study score representative of the situation after 52 weeks of treatment. The primary efficacy endpoint is typically assessed at a pre specified discrete time point after a specific period of intervention.
From that perspective, the use of KCCQ-CSS is appropriate, despite the fact that it was measured at Weeks 20 and 36 too. The time course (Figure 1A) supports the reality of improvement at week 52.
The same is seen for weight. The trajectory of weight loss (Figure 1B) supports the between-group difference at week 52.
Evolving demand for more and more Semaglutide like drugs:
From "couch potato to couch carrots" appears to be the current drug development flavor/fervor 😅👇
[5/5, 2:47 AM] +1 (832) Nearly half of Americans are awaiting prescription for one of these GLP1 agonists
(market projected to be worth as much as $100 billion by 2030.)
There is lot of bio pharmaceutical investment in this field and science is moving fast to develop new designer molecules with triple agonists ( GLPI , GIP and glucagon/ AI models being used to accelerate drug development
Amgen has partnered with NIVDIA for drug development/ generative biology allows for the generation of new protein-based drugs that have desired structures and properties based on existing protein data inputs.
We will see flood of GLP dual and triple agonists in next few years .
April 2024, more than 50 glucagon-like peptide-1 receptor agonists are in clinical development for type 2 diabetes, obesity, or both.
Loss of lean body mass and sarcopenia remains concern with GLP- 1
Few exciting molecules in development , which reduce fat mass and increase muscle mass. No need to exercise,
Never heard of this before exerkine analogues (peptide that is released during exercise that improves metabolic and muscle function. ) can be synthesized and being developed for obesity, one stop solution for couch potatoes
Azelaprag is one of these drugs undergoing trials. Then there is Class of myostatin inhibitors.
A myostatin inhibitor called taldefgrobep alfa, undergoing trials to weight loss and increased lean tissue.
I believe, research is exploding in the field of obesity/ to its advantage is AI/ generative biology / this is unlikely to fizzle out like cox inhibitors
[5/4, 4:16 AM] +1 (301): Almost all weight reduction drugs have many different side effects reported, but in the prolong duration and long term side effects or complications data buried or under reported. Pharmaceutical industries wrecking money from these products and have to take responsibility for honest open monitoring and provide correct data to the public.
[5/4, 6:01 AM] Endocrinologist NJ: None of these studies looked at hand grip and/or 6-min walk to test muscle strength.
What I’m saying is that losing muscle (as determined by DEXA) may not be a bad thing, unless there’s loss of strength.
Talking about just muscle mass w/o data on strength and calling that sarcopenia is not appropriate. And, probably just a gimmick.
Most of the agents that have been tested for sarcopenia (e.g., age-related sarcopenia) have shown improvements in muscle mass without appreciable improvements in strength.
[5/4, 9:50 AM] Rakesh Biswas: Is Sarcopenia the reason for ozempic face?
Some of my patients who have given up sugar totally have also shared their before after facial pictures with me that suggests similar facial changes. I would wager the facial changes could be fat reduction. Any review of literature data on this?
Integrative medicine ontologies: https://userdrivenhealthcare.blogspot.com/2024/06/defining-integrative-medicine-two-world.html?m=1
[5/4, 10:49 AM] +44: Won't be surprised in few years time , this will be like cox inhibitor drugs and withdrawn
October 28 update:
Lancet review:
[27/10, 20:23] Rakesh Biswas: "The crucial roles of skeletal muscle have come to the forefront of public attention due to data on the use of GLP-1 receptor agonists, which are effective for weight loss, but can cause substantial muscle loss. Studies suggest muscle loss with these medications (as indicated by decreases in fat-free mass [FFM]) ranges from 25% to 39% of the total weight lost over 36–72 weeks.2 This substantial muscle loss can be largely attributed to the magnitude of weight loss, rather than by an independent effect of GLP-1 receptor agonists, although this hypothesis must be tested. By comparison, non-pharmacological caloric restriction studies with smaller magnitudes of weight loss result in 10–30% FFM losses.3 In context, on an annual basis, the decline in muscle mass with GLP-1 receptor agonists is several times greater than what would be expected from age-related muscle loss (0·8% per year based on 8% muscle loss per decade from ages 40–70 years)."
Unquote
https://www.thelancet.com/journals/landia/article/PIIS2213-8587(24)00272-9/abstract?dgcid=raven_jbs_etoc_email
[27/10, 21:03] Pediatric Endocrinologist NJ: However, muscle strength has not been assessed with GLP-1 RAs-induced weight loss.
Loss of muscle mass + decrease in muscle function = sarcopenia.
Age-related loss of muscle mass is sarcopenia, because it is associated with loss of muscle function.
Weight-loss meds associated decrease in muscle mass may or may not be sarcopenia. Well designed studies are needed… first, to see if objective decreases in muscle function occur, and then to assess if similar/matched loss of muscle from other weight loss modalities (e.g., bariatric surgery) cause similar loss in muscle function.
November 2024 Update on another GLP1 inhibitor used again for heart failure perhaps to make the cut as demonstrated in sglt2 inhibitor!
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