The discussion on this journal club formed organically and randomly out of a group of physicians excited about the launch of a new drug hits a climax when a user points out a particular side effect that is pivoted on to explain in terms of absolute values why taking the drug is akin to trading off and bearing some distaste in the tongue (side effect), just so that they can become one with the group of (4825-191=4634) higher number of people (taking the drug oral semaglutide) that could avoid a nonfatal myocardial infarction as opposed to the lesser (4825-253=4572) number in the
placebo group who still had the joy of taste but then 62 more of their placebo brethren developed a non fatal myocardial infarction compared to those on oral semaglutide!
If that is interpreted as a primeval herd instinct to find safety in numbers and if we can imagine the two groups of 4825 people as wildebeests wading to cross a crocodile filled African river of metabolic syn then can we really spot the difference of 191 vs 253 missing in each group when the wildebeest cross over to the other side?
While the above provides an apparently polarised anti big pharma biased viewpoint, the same day this author discovered a new AI LLM tool from a Stanford lab called med pharma and unboxing it here:
Key words:
Big pharma Journal club influencers
Proportional risk reduction
CRH Critical realist heutagogy
Journal club collective conversational Transcripts:
[29/03, 19:46]wa user 1: Have a few paid links for live SOUL relay at about 1.15 am tonight. Anyone interested pls DM me
[29/03, 19:52]wa user 2: Morning heading news plz
Breaking news
[29/03, 19:56]WA user 3 : What?
[29/03, 19:57]: Ok SOUL
[29/03, 20:08]WA user 4: 1:00 am. I have free link 😂
[29/03, 20:22]: Any last minutes guess on expected results of SOUL? Closest guess maker will get prize 🏆 from me 😊
[29/03, 20:22]u2: MI
[29/03, 20:22]: Outcome
[29/03, 20:22] group moderator gm: I hope ,you know it now
[29/03, 20:23]u2: I'm sure AK knows
[29/03, 20:24]u4: Oreyy Dada…bhogwan 😨
[29/03, 20:24]u2: I guess 14%reduction in MACE and stroke due to sema
or is that old news
[29/03, 20:26]u4: Your AI 🤖 didn’t work here 😂😂
[29/03, 20:28]u2: I know. It can't find out what is not leaked on the net
[29/03, 20:28]u4: If oral sema reduces MI significantly - would you prefer it over SGLT2i ?
[29/03, 20:30]gm: No
[29/03, 20:30]u4: Why not ? Due to cost ?
[29/03, 20:31]gm: Cost and tolerance issues
More confidence with SGLT2I
[29/03, 20:31] u3: In certain situations
1. If MI is the prominent risk and not HF
2. If eGFR is less than 30
3. If weight is a major concern sema I would prefer
[29/03, 20:32]u2: I prefer
Need close look of the study
[29/03, 20:32]u4: STRIDE trial of injectable Semaglutide in PAD is being live presented at ACC now
[29/03, 20:34]u3: I guess what you are trying to say u4 is the data being presented today may reestablish sema to be a superior cardiac and cv drug over SGLT2i.
I was fortunate to attend your brilliant comparison of dapa and empa in MAHARSSDI 2025 here in Mumbai
[29/03, 20:34]u4: Did any drug reduce MI in past? If it is true it would add great value to the money with oral sema beside best Hba1C and body weight reduction amongst all anti diabetes drugs!
[29/03, 20:39]u2: Yup
[29/03, 20:39]u3: Understood where this argument is going.
I guess at 1.20 am history is going to be created with sema
[29/03, 20:39] u4: 1.15am
[29/03, 20:40]u3: Waiting for the prize from u4🫶🫶🫶
[29/03, 20:41]u3: Just as Dapa is now a mandatory arsenal in the therapeutic armamentarium of cardiologists i guess after 1.15 am Sema will be a mandatory prescription for most cardiologists dealing with MI
[29/03, 20:41]u2: Sir me too
🙏🙏
[30/03, 08:25] u6: My humble observations:
1) Happy that MI was reduced
2) Surprised to see stroke wasn`t reduced
3) Limb events – upto 2 years no benefit – actually at one point it was worse than placebo - then all of a sudden the line diverges
4) A1C > 8 far better than < 8 (but p value for interaction not given) – so again the question arises – was better glycaemic control partially responsible for the benefits? Of course just glycaemic control on its own does not matter but still
In summary, my humble thoughts
_*Great for Sema*_
• MI reduction for the first time
• Limb events reduction for the first time
• Better in Asians (however no p value for interaction given)
*Not so great*
• No reduction in stroke
• No reduction in CKD
• No reduction in HF
• Less than 3 kg weight loss
[30/03, 08:33]gm: Thank you 🙏
[30/03, 08:33] u6: The distribution of participants who were receiving the 3-mg, 7-mg, and 14-mg doses of oral semaglutide over time is summarized in Figure S3A (but I don`t have access to it)
27% discontinued the drug so would have been interesting to know the trial product estimand
[30/03, 08:36]u1: 1. What are the anti diabetics used alongside Sema?
2. Do statin and aspirin continued as per present guidelines?
[30/03, 08:39]u6: I don`t know the exact figures but as it was a double blind randomised control trial it is expected that both groups would have equal distribution of statin and aspirin
[30/03, 08:48]u3: Here is the summary from AI
Here are the salient points from the discussion and results sections of the article, presented in point format:
**Results:**
* The SOUL trial randomized 9650 participants aged 50 years or older with type 2 diabetes and either atherosclerotic cardiovascular disease, chronic kidney disease, or both, to receive either once-daily oral semaglutide (maximal dose 14 mg) or placebo, in addition to standard care.
* **Oral semaglutide was associated with a significantly lower risk of major adverse cardiovascular events (MACE), the primary outcome (a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke), compared to placebo**. The hazard ratio was 0.86 (95% CI, 0.77 to 0.96; P = 0.006).
* The incidence of the primary outcome was 12.0% in the oral semaglutide group and 13.8% in the placebo group, with incidence rates of 3.1 and 3.7 events per 100 person-years, respectively.
* In a prespecified analysis of events occurring through week 156 (3 years), the absolute risk reduction was 2.0 percentage points, and the number needed to treat to prevent one event was 50.
* The effect of oral semaglutide on the primary outcome was consistent across prespecified sensitivity analyses and most subgroups, including those defined by age, sex, body-mass index, history of cardiovascular or kidney disease, eGFR, and medication use at baseline.
* Among the components of the primary outcome, **nonfatal myocardial infarction occurred less frequently in the oral semaglutide group** (hazard ratio, 0.74; 95% CI, 0.61 to 0.89).
* The first confirmatory secondary outcome, major kidney disease events (a five-point composite), did not differ significantly between the two groups (hazard ratio, 0.91; 95% CI, 0.80 to 1.05; P = 0.19).
* Due to the non-significant result for the first confirmatory secondary outcome, the subsequent confirmatory secondary outcomes (death from cardiovascular causes and major adverse limb events) were not formally tested for significance.
* Supportive secondary outcomes showed that oral semaglutide was associated with a lower risk of a five-point composite of MACE and fatal or nonfatal myocardial infarction.
* Oral semaglutide led to a greater reduction in mean glycated hemoglobin level and mean body weight from baseline to week 104 compared to placebo.
* The incidence of serious adverse events was lower in the oral semaglutide group (47.9%) compared to the placebo group (50.3%; P = 0.02).
* **Gastrointestinal disorders were more common with oral semaglutide** (5.0%) than with placebo (4.4%) and were the main reason for permanent discontinuation of the trial regimen in the oral semaglutide group.
**Discussion:**
* **Oral semaglutide significantly reduced the risk of major adverse cardiovascular events compared to placebo** in persons with type 2 diabetes and atherosclerotic cardiovascular disease, chronic kidney disease, or both. This represents a relative risk reduction of 14%.
* This cardiovascular benefit is consistent with results reported for injectable semaglutide and other GLP-1 receptor agonists with established cardiovascular efficacy.
* The dominant beneficial effect of oral semaglutide in SOUL was the reduction in nonfatal myocardial infarction, which differs from the PIONEER 6 trial where the dominant effect was on cardiovascular death. This difference might be related to the longer follow-up and larger sample size in SOUL.
* The non-significant finding for major kidney disease events in SOUL contrasts with the significant kidney benefits observed with injectable semaglutide in the FLOW trial. This discrepancy could be due to differences in baseline eGFR of the study populations or the lower bioavailability of oral semaglutide compared to subcutaneous semaglutide.
* The availability of an effective oral GLP-1 receptor agonist is relevant to patient preference for oral over injectable diabetes medications.
* The overall safety profile of oral semaglutide in SOUL was consistent with previous trials, and no new safety signals were observed. The lower incidence of serious adverse events in the oral semaglutide group was mainly driven by fewer cardiac disorders and infections.
* The higher rate of discontinuation in the oral semaglutide group was primarily due to gastrointestinal symptoms, which are known side effects of GLP-1 receptor agonists.
* Strengths of the trial include its large sample size and long follow-up duration. The cardiovascular benefits appeared consistent across age subgroups and with injectable semaglutide. The cardioprotective effect was observed even with high concomitant use of other cardiovascular protective drugs like SGLT2 inhibitors.
* Limitations of the trial include the inclusion criteria that enriched the population for cardiovascular and kidney disease, making it less representative of the general type 2 diabetes population. There was also underrepresentation of women and Black individuals in the trial. The effects of oral semaglutide on kidney-related outcomes require further clarification.
[30/03, 08:48]u3: and here is the audio podcast
[30/03, 11:59]u4: SOUL stratified on and off SGLT2i!
Another publication happened last night in circulation!
[30/03, 12:19]u4: This is 3rd publication happened last night in Diabetes Care after SOUL. MA of all 10 GLP-1RA trials conducted to date including FLOW and SOUL
[30/03, 13:17] CBBLE cable moderator cm: Thanks for sharing.
The authors list one of the limitations of their study as ecological bias (aka aggregation bias).
"in meta-regression on aggregate data, associations between average patient characteristics and the pooled treatment effect do not necessarily reflect true associations between the individual patient-level characteristics and treatment effect.
The difference between associations of treatment effects with average patient characteristics at group level and true associations with individual patient level characteristics has been referred to as ecological fallacy or aggregation bias."
[30/03, 13:57] u4 in response to u6:
Good summary:
Few point to note -
1. Even more 28.5% permanently withdrew in placebo arm
2. PP analysis/Trial product estimand showed even larger 18% reduction in primary endpoint
3. No additional benefit or harm with or without SGLT2I on CV endpoints
4. No analysis of kidney outcomes stratified on or off SGLT2i currently available
5. 12% insignificant stroke reduction must be read in light of lesser HTN pt and higher HF patients in SOUL compared to SUSTAIN6
I will come with even more details tonight
[30/03, 14:01] cm : Interesting to see sulphonylurea still leading in both groups ahead of the new gen!
"Adverse events that led to permanent discontinuation of oral semaglutide or placebo occurred
in 749 participants (15.5%) in the oral semaglutide group and in 559 participants (11.6%) in the
placebo group."
The 28.5% figure is from another paper?
[30/03, 14:19]u4: Adverse event and withdrawal is not same. Read full paper you will find what I wrote..😊
[30/03, 14:21]cm: Adverse events that led to permanent discontinuation definitely sounds same as withdrawal?
30/03, 14:55] u4: 1. Adverse events is one thing
2. Adverse events leading to drug withdrawal is another thing
3. Drug discontinued due to any cause is another but final thing
We are saying 21.7% vs 28.5% didn’t complete the treatment in Sema vs PBO, respectively. Hope it’s clear now 😊😎
[30/03, 15:11]cm: Agree! Withdrawal and "Didn't continue treatment" are definitely not the same as per their trial definitions as there were other causes of discontinuation other than voluntary withdrawal such as getting lost to follow up (which is kind of absconding withdrawal vs LAMA withdrawal)!
[30/03, 14:24]u7: Many people get tired of not feeling the joy
of eating - some have told me that’s why they stopped, not because they did not tolerate…
[30/03, 14:34]u3 sharing more articles presumably detailing the effect of GLP1s on taste:
[30/03, 15:05] cm: As per yesterday's soulful release here:
https://www.nejm.org/doi/pdf/10.1056/NEJMoa2501006, they can still derive some joy from the fact that: by trading off some distaste in the tongue, they can become one of the (4825-191=4634) higher number of people (because of oral sema) who could avoid a nonfatal myocardial infarction as opposed to the lesser (4825-253=4572) number in the
placebo group who still had the joy of taste but then 62 more of their placebo brethren developed a non fatal myocardial infarction compared to those on oral sema!
That kind of sums up this entire soulful trial for me. Would be happy to stand corrected from others who have read the full paper. 🙂🙏
30/03, 20:50]u4: Somebody was asking which dose of Oral Sema in SOUL...Here is the answer. Nearly 80% were on 14 mg.
[30/03, 20:53]u2: What % of your patients tolerate 14mg?
[30/03, 20:59]u4: I hate personal experience kind wala answer
[31/03, 19:08]cm: Summarising some learning points from yesterday's soulful journal club:
The estimand here is essentially the relative risk reduction and going by a Hazard Ratio (HR) = 0.86 (95% CI: 0.77–0.96).
- **14% RRR** = \( 1 - 0.86 = 0.14 \) (14% is the reduction in relative risk for the oral semaglutide group).
The trial’s primary estimand uses an **intention-to-treat (ITT) analysis**, which includes all randomized participants regardless of adherence.
A separate **per-protocol (PP) estimand** (accounting for discontinuations) showed a larger 18% RRR, but this was not the primary estimand.
The more important learning point could be around the 👇
- Absolute Risk Reduction (ARR) = 1.8% (12.0% vs. 13.8% event rates).
One person in this journal club emphasized **absolute differences** (e.g., 62 fewer nonfatal MIs in the semaglutide group: 191 vs. 253 events).
- Pharma often highlights **relative risk** (14% RRR) because it appears more impressive, while absolute risk (1.8% ARR) may seem modest.
