Appraising efficacy of Semaglutide in Metabolic Syndrome

[04/02, 8:59 am] Sumit CBBLE: I understand that you're extremely well regarded for metabolic syndrome and its implications. I had a question for you:

Could semaglutide help manage or possibly treat metabolic syndrome? @⁨Dr Rakesh Biswas⁩

[04/02, 9:01 am] Sumit CBBLE: Open to discussion and inputs from everyone regarding implications of semaglutide.

[04/02, 9:18 am] Dr.Dinesh Datta: No evidence to support its use in Metabolic syndrome.

It's a weight lowering agent.

Population: Patients aged 45 years or older with preexisting cardiovascular disease and a body-mass index (BMI) of 27 or greater, without diabetes.

Intervention: Weekly subcutaneous semaglutide at a dose of 2.4 mg.

Comparision: Placebo.

Outcome- Reduction in the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke over a mean follow-up period of 39.8 months. 

This multicenter, double-blind, randomized, placebo-controlled, event-driven superiority trial included 17,604 patients, with 8803 assigned to the semaglutide group and 8801 to the placebo group. The primary cardiovascular endpoint occurred in 6.5% of the semaglutide group and 8.0% of the placebo group, resulting in a hazard ratio of 0.80 (95% confidence interval, 0.72 to 0.90; P<0.001). Adverse events leading to permanent discontinuation of the trial product were higher in the semaglutide group compared to the placebo group (16.6% vs. 8.2%, P<0.001).

https://www.nejm.org/doi/full/10.1056/NEJMoa2307563

[04/02, 9:19 am] Sumit CBBLE: lower weight, lower visceral fat, would they lead to better outcomes for patients?

[04/02, 9:21 am] Dr.Dinesh Datta: study also has some limitations. Considering the observational nature of this study, we could not compare weight loss outcomes between patients receiving semaglutide and controls. The weight loss achieved may be associated with other interventions (eg, lifestyle interventions and diet) that are provided by the weight management clinic; however, we found that visits with a dietitian and a psychology group were not associated with greater weight loss. Another serious limitation is the exclusion of patients who did not reach 3 months of follow-up, which might have resulted in an overestimation of the association of semaglutide with body weight. 

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2796491

[04/02, 9:22 am] Dr.Dinesh Datta: Yep,the focus question is the efficacy and indication of semaglutide.

When it can be done through diet,exercise and lifestyle modif.

Again,MS is basically combo of hypertension,diabetes,dyslipidemia and hyperuricemia.

Does any cheaper alternatives of antidiabetic medications cause that weight loss?

[04/02, 9:23 am] Dr.Dinesh Datta: Check out any studies if it mentions the % of weight loss it caused.

Is it significant?

[04/02, 9:26 am] Sumit CBBLE: Studies show that it leads to substantial weight loss, with participants achieving weight reductions of at least 10% or 15%. In a 68-week study, some participants lost more than 2% of their body weight within 4 weeks, and at week 68, the mean change in body weight was -16.0% to -16.1% with semaglutide.

[04/02, 9:29 am] Dr.Dinesh Datta: Overweight/obese is BMI of 25+

Say for height of 6 feet height.

Weight of 100kgs will be considered overweight.

And now in 68 week,that is in 1 to 1.5years,10 to 15% weight reduction.

That is becomes 85kg to 90kg.

Do you consider it as significant?

Or Can it be done through diet/exercise as well?

Or any specific indications for semaglutide?

[04/02, 9:32 am] Dr.Dinesh Datta: Basically that visceral fat should go to reverse metabolic syndrome.

Better way is to gradually manage through diet,exercise,lifestyle and minimum meds over same 1 to 1.5 years(it took 9 months for this patient to reverse and come out of diabetes).

Again,some may not be compliant to such gradual change and may go for drugs(say semaglutide) or even for surgery.Both of which comes with their own set of side effects

[04/02, 9:33 am] Dr.Dinesh Datta: Substantial?

I doubt that.

Do some math.

And check other alternatives/or patient stories

[04/02, 9:41 am] Dr.Dinesh Datta: https://ssahamedicalcases.blogspot.com/2022/07/a-60-yr-old-male-wi.html?m=1

The above patient's case report made 9months ago by one of our amazing student teacher,who's now pursuing MBBS in China.

@⁨Dr Rakesh Biswas⁩ Whats Saptarshi doing by the way?It's been so long since we spoke.Last time when he's returning to China from India around 6 months ago,he mentioned whatsapp is not allowed there

Should be updated with latest reports and pics

[04/02, 9:42 am] Sumit CBBLE: Interesting facts and points @⁨Dr.Dinesh Datta⁩

[04/02, 9:46 am] Sumit CBBLE: So is your argument basically:

Semaglutide is too slow to cut down on visceral fat and hence might not be effective wrt. metabolic syndrome?

[04/02, 9:47 am] Dr.Dinesh Datta: Nope.

Just appraise the evidence of semaglutide,limitations of the study and compared it to other alternatives which were documented as n of 1 case reports.

It's always the patient's choice to take an informed decision

[04/02, 9:57 am] Sumit CBBLE: I looked at the 2023 study you sent. What limitations are you talking about? Evidence regarding what? MS or Weight loss?

[04/02, 9:59 am] Sumit CBBLE: regarding statistical significance, p<0.001 which is much less than the generally accepted standard of p<0.05

[04/02, 10:01 am] Dr.Dinesh Datta: 'Adverse events leading to discontinuation of trial in Semaglutide group compared to placebo group'.

Again,active dietary,exercise and lifestyle intervention-isnit placebo?(as in above blog)

Or an intervention?

[04/02, 10:03 am] Sumit CBBLE: people from both control and placebo have discontinued

[04/02, 10:03 am] Dr.Dinesh Datta: Exactly.

Not the ones followed up through PaJR

[04/02, 10:05 am] Dr.Dinesh Datta: No evidence.

Above articles also just tells it as an adjunct in MS(with or without diabetes) for weight loss.

Is it visceral adiposity loss?muscle mass loss?fluid loss?

[04/02, 10:06 am] Sumit CBBLE: yeah that's exactly what im discussing, it's statistically significant, but is it clinically significant, if yes, then whether it will be useful enough for MS

[04/02, 10:31 am] Dr.Dinesh Datta: Further case registration studies are needed to clarify the relationship between semaglutide and depression. Endocrinologists and psychiatrists should both pay attention to patients’ emotional status before and after semaglutide use. The mechanism of the possible causality between semaglutide and depression is still unclear. Further research may help to improve understanding of the mechanism of depression and even lead to new therapeutic targets of depression.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10495976/#:~:text=In%20the%20present%20case%20report,of%20depression%20in%20some%20patients.

@⁨Sumit CBBLE⁩

[04/02, 10:32 am] Dr.Dinesh Datta: A pill usually comes with an ill yo,it's better to rather metapsych natural chill.

However my opinion.Maybe wrong too.

I may not be qualified enough to tell this.

However as a rule of thumb,unless when it's very clearly indicated and there's documented evidence and no other alternative,I'm against any pills.

Herbs-yep

[05/02, 3:01 pm] Dr.Dinesh Datta: https://drsaranyaroshni.blogspot.com/2022/03/a-78-year-old-lady-with-skin.html?m=1

Interesting case report of gallbladder cancer patient taken by one of my junior student teacher under guidance of @⁨Dr Saicharan Kulkarni MD GM 2⁩ and RB.

Just got to know that the patient is still hail and hearty.

Minimalist approach in management.

She didn't get any surgery or chemo

[05/02, 3:32 pm] Dr Saicharan Kulkarni MD GM 2: I do remember seeing her.. she has a tennis ball size palpable gall bladder in her Abdomen

[05/02, 4:30 pm] Dr Rakesh Biswas: It will become clear once we put the data into PICO format. 

@⁨Dr.Dinesh Datta⁩ Can you do that?

[05/02, 4:31 pm] Dr.Dinesh Datta: Yes

[05/02, 4:32 pm] Dr.Dinesh Datta: However there's no RCTs for indicating Semaglutide in MS to begin with

[05/02, 4:53 pm] Dr Rakesh Biswas: Let's just look if it has efficacy for weight loss just to understand if it's clinically significant

[05/02, 5:11 pm] Dr.Dinesh Datta: Population-

 1961 adults with a body-mass index (BMI) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), without diabetes.

Intervention-

 Once-weekly subcutaneous semaglutide (2.4 mg) for 68 weeks plus lifestyle intervention.

Comparision-

 Placebo plus lifestyle intervention.

Outcome-

- Primary Endpoints: Percentage change in body weight and weight reduction of at least 5%.

- Secondary Endpoints: Weight reductions of 10% or more, 15% or more, improvement in cardiometabolic risk factors, and participant-reported physical functioning.

Results-

- Semaglutide group: Mean change in body weight from baseline to week 68 was -14.9%, with 86.4% achieving weight reductions of 5% or more, 69.1% achieving reductions of 10% or more, and 50.5% achieving reductions of 15% or more.

- Placebo group: Mean change in body weight from baseline to week 68 was -2.4%, with 31.5% achieving weight reductions of 5% or more, 12.0% achieving reductions of 10% or more, and 4.9% achieving reductions of 15% or more.

- Estimated treatment difference in weight change was -12.4 percentage points (95% CI, -13.4 to -11.5; P<0.001).

- Semaglutide group experienced a greater improvement in cardiometabolic risk factors and participant-reported physical functioning compared to the placebo group.

- Most common adverse events with semaglutide were nausea and diarrhea, typically transient and mild-to-moderate in severity.

Conclusion- Semaglutide, along with lifestyle intervention, led to significant weight loss and improvement in cardiometabolic risk factors compared to placebo over 68 weeks in adults with obesity (BMI ≥ 30) without diabetes. However, it was associated with higher rates of gastrointestinal adverse events.

https://www.nejm.org/doi/full/10.1056/NEJMoa2032183

[05/02, 5:16 pm] Dr.Dinesh Datta: There's no pathophysiological rationale for it's use in Metabolic syndrome.

Criteria for metabolic syndrome is T2DM,which has insulin resistance.

Semaglutide is insulin mimetic.

For weight loss,the RCT is discussed above

[05/02, 7:01 pm] Dr Rakesh Biswas: Thanks 

To understand the clinical significance of the numbers @⁨Sumit CBBLE⁩ we need to convert them into absolute values and not present them as here in relative percentages. 

Absolute values would tell us the number of patients in each group having what weight after 68 weeks and if possible the weeks in between. 

Also as you pointed out earlier a valid estimate of what weight (visceral fat or muscle protein) was reduced

[05/02, 7:05 pm] Dr.Dinesh Datta: Semaglutide Group:

- Weight reductions of 5% or more: 1047 participants

- Weight reductions of 10% or more: 838 participants

- Weight reductions of 15% or more: 612 participants

In placebo

- Weight reductions of 5% or more: 182 participants

- Weight reductions of 10% or more: 69 participants

- Weight reductions of 15% or more: 28 participants

Total participants 1961

68 weeks duration.

However,let's also see if 5% weight reduction or 10% or 15% weight reduction is significant..

And also the actual 'lifestyle interventions' advised and what were 'followed'.

In our 60M patient with PaJR followup?

Visceral adiposity visibly reduced and diet,exercise interventions are also 'followed up' daily instead of 'advised'

[05/02, 7:19 pm] Dr.Dinesh Datta: For a 6feet person and BMI 30,weight will be 100kgs.

So,that becoming 95 over 68weeks,is it significant?(5% reduction)

And for 15% reduction,implies weight becomes 85kgs in 68 weeks.

That is,BMI becomes 25 to 26,which is still considered overweight.

However,maybe considered clinically significant?

[05/02, 7:19 pm] Dr Rakesh Biswas: Again when we say a certain percentage of weight reduction to make it easier to mathematically easier to compare (statistical significance), it may make it difficult to understand the clinical significance of the weight loss. Instead of percentage loss can we check out the initial weight and later weight in these groups? There could be some interesting insights hidden there? 

Also the weight reduction is just a disease related outcome. What happened to the people's overall life events (QoL?) between the two groups? 

Why did both these two groups need the weight loss drugs in the first place? 

What were their baseline characteristics during recruitment into the study?

[05/02, 7:21 pm] Dr Rakesh Biswas: Good question! 

So we need to define what are clinically significant outcomes for us and our patients participating in this trial

[05/02, 7:22 pm] Dr.Dinesh Datta: we enrolled 1961 adults with a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or greater (≥27 in persons with ≥1 weight-related coexisting condition), who did not have diabetes, and randomly assigned them, in a 2:1 ratio, to 68 weeks of treatment with once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo, plus lifestyle intervention. The coprimary end points were the percentage change in body weight and weight reduction of at least 5%. The primary estimand (a precise description of the treatment effect reflecting the objective of the clinical trial) assessed effects regardless of treatment discontinuation or rescue interventions

https://www.nejm.org/doi/full/10.1056/NEJMoa2032183

[05/02, 7:23 pm] Dr.Dinesh Datta: Exactly.

For metabolic syndrome,it had got to do more with visceral adiposity,rather than absolute weight numbers.

Sumit asked if semaglutide can be used for MS

[05/02, 7:24 pm] Dr.Dinesh Datta: 43.7% of participants had prediabetes and might have responded differentially to the effects of semaglutide on weight 'gain'

[05/02, 7:29 pm] Amey Shrotri AI group: Very interesting

[05/02, 7:38 pm] Dr Rakesh Biswas: So the study design and approach leaves a lot to be desired in terms of data that matters to patient outcomes except just weight and BMI reductions as we are not sure of the clinical significance of the weight reduction in those patients who were selected for the trial?

[05/02, 7:38 pm] Dr.Dinesh Datta: Yep

[05/02, 7:39 pm] Dr Rakesh Biswas: You need to do a better study and publish it in blogspot! NEJM is overrated!!

[05/02, 7:40 pm] Dr.Dinesh Datta: I'd rather enjoy our n of 1 pajr studies and try to dissect NEJM and other articles in journal clubs with you and our team

[05/02, 7:42 pm] Dr Rakesh Biswas: While dissection is fun, somebody has to create the body too!

[05/02, 7:42 pm] Dr.Dinesh Datta: NEJM

[05/02, 7:44 pm] Dr Rakesh Biswas: Someone has to do the study and create the NEJM article for you to dissect and blogspot articles can also be dissected similarly. It's the content that matters not the platform

[05/02, 8:19 pm] Dr Rakesh Biswas: Effectively if only each one of those 1961 patients were dug deep into while randomizing them and following them for 68 weeks! 

Similar thoughts in the past blogged here:

https://pubmed.ncbi.nlm.nih.gov/17683292/