Conversational learning around orlistat

Below are the early conversations around our orlistat project and our early conversational learning attempts to understand it's role in improving diabetes outcomes through its action on the glp1 pathway: 

- The incretin pathway as a new therapeutic target for obesity 

Source: https://www.maturitas.org/article/S0378-5122(10)00246-X/fulltext

  1)What are the objectives of the study?

  2) Can u share the summary the background literature reviewed of previous studies? 

  3)Is the permission from ethical committee taken??

 4)Please, share the reference for the diet mentioned. And why is it only mentioned for breakfast? 

 5) Is multivitamin given to the patient along with this? (Usually, orlistat inhibits the absorption of fats and fat-soluble vitamins so the multivitamin is to be given and this is for 12 weeks.

 6) I see some gaps in the administration of orlistat. 

  Let's also discuss why is orlistat asked to take with the fat-containing meal?

- https://en.m.wikipedia.org/wiki/Ketogenic_diet

- 4) they can take their regular diet and their regular oral antihyperglycaemic agents as well but the day when they visit us that is weekly once we give them this breakfast.

  5) multivitamins are also given.  As orlistat is gastric lipase inhibitor thus fats are not digested and lead to fatty stools.  Fat soluble vitamins in food can also be excreted out without digestion and absorption so these fat-soluble vitamin supplements should be given 2 hours before or after the administration of orlistat.

 - 1) objectives will I be clear by Monday meet.  

    2) by tomorrow I will make a literature review. 

    3) permission is not taken yet.  Protocol changes may be there so in Monday meeting it can be done.

  

- Orlistat inhibition of intestinal lipase acutely increases appetite and attenuates postprandial glucagon-like peptide-1-(7-36)-amide-1, cholecystokinin, and peptide YY concentrations. 

Source: https://www.ncbi.nlm.nih.gov/pubmed/18647814/

- Alright, the above links suggest that 120 mg orlistat would reduce postprandial GLP1. Does this effect translate to promoting hyperglycemia in type 2 diabetics or this may not happen in early diabetics (the reverse may happen, if so how)?

-https://scholar.google.com/scholar_url?url=https://www.physiology.org/doi/pdf/10.1152/ajpgi.90209.2008&hl=en&sa=T&oi=ucasa&ct=ufr&ei=20e4W97-CNSSygTI64K4BA&scisig=AAGBfm1RJOnRg-RppyuuyhP97856jVZ-CQ

- Yes, it may be statistically significant but obviously, a 5-10 % emptying may not be clinically significant?

- So in effect, you are contesting this study's results?

- All these above questions are to find out the rationale for using orlistat in early diabetics

- Is the rationale such that by treating obesity with orlistat in early obese diabetics we are hoping to prove its efficacy in reducing obesity and in effect reducing diabetes?

- In which case we need to find out the efficacy of orlistat in reducing obesity

- Evaluation of efficacy and safety of orlistat in obese patients

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3125014/#!po=29.0000

- Here the efficacy of orlistat in slight mean weight reduction has only been demonstrated with 120 mg three times daily with the effect maximizing at 24 weeks. In our study, we seem to be using a suboptimal dose of 60 mg daily although we propose to check for 6 months?

- https://www.eurekalert.org/pub_releases/2010-01/epr-apt012710.php

  https://onlinelibrary.wiley.com/doi/full/10.1038/oby.2011.143

  https://academic.oup.com/ajcn/article/79/1/22/4690061

- I have been thinking about a title for our project which may be somewhat like the above case series where we may individualize every patient's treatment intervention where some can receive orlistat, some just post-prandial exercises and some fasting. 


Recent conversation and reviews around the BIT's Pilani project: 

Dear Bedside 1: 

Please find below the explanation (in bold font) for the queries raised by the reviewer as received. 

Reviewer 1: I went through the proforma and the dissertation and let me begin by saying that it's an amazing project! I always assumed orlistat for hunger pangs in obese patients so its use in DM was something new that I learned. So it's an exciting project. 

Null Hypothesis: Orlistat will not cause any changes in blood sugar 

Aims: I am not sure about this- if we say it's to study by how much orlistat causes lowering blood sugar then my query is: 

Query 1: why does the methodology include exercise and then checking blood sugar again after taking orlistat?

Benchside 1 explanation: 
Please note the protocol calls for orlistat administration before meal.  The glucose measurement is after moderate exercise for 15-20 minutes (as measured by walking rate of 3-4km/hr) hoping that as the duration of intervention proceeds in time (till 12 weeks) the time taken for lowering of PP glucose might serve as an index or improved Insulin secretion/sensitivity--which is mediated through the incretin pathway induced by orlistat at low doses.

Query  2: How was the dose of 60 mg OD decided?

Becnchside 1 explanation: 
Based on a pilot study conducted in three patients who had volunteered to get a CGM device implanted.  Proposed study is an attempt to have a pilot study with 60 T2DM patients (with 30 on orlistat+exercise regimen and the other 30 being on exercise alone) Both the duration of PP hyperglycemia and pre and post HbA1c is expected to help us dissect the role of stimulation of incretin pathway. 

Query 3: In the inclusion criteria is there anything as to why only 7.5-8.5 HbA1C patients are taken?

Benchside 1 explanation: 
Just reflects newly diagnosed or better managed T2DM patients where the degree of uncontrolled hyperglycemia has not progressed too far and thereby indicates lower degree of insulin resistance, may be.

Query 4:  Is there any criteria for years of diagnosis of DM to be included in the study ?

Benchside 1 explanation: 
The plan is to recruit patients diagnosed in last two years and with HbA1C between 7.5 to 8.5

Query 5: What is the meaning of moderate exercise ? 

Benchside 1 explanation: 

This could be in the form of a brisk walk over a target distance in a target or better time (to reflect a pace of about 3 miles an hour or better), or a session on a recumbent bike, elliptical or any other type of defined exercise. 

Brief exercise after a meal should be safe for folks on medications other than Orlistat—(but one should caution them to not engage in it if they have an infection or other sickness since other medications can enhance the risk of hypoglycemia) 

Query 6: Will patients with chronic complications of DM like renal disease/ retinopathy/ neurological symptoms etc be taken assuming they can exercise ?

Benchside 1 explanation: 
No

Query 7: Any other OHAs other an insulin will be taken ?  I'll have to check for OHAs with cross reactivity to orlistat 

Benchside 1 explanation: 
Yes, We are not aware of any reports on cross reactivity between OHAs and orlistat

Query 8: Why are obese patients where orlistat is useful excluded from the study ?

Benchside 1 explanation:  
The dose recommended for obese patients is 180mg TDS and is known to lead to adverse reactions such as deficiency of fat soluble vitamins, fatty stools, flatulence, etc.

Query 9: Similarly with hypothyroidism ? 

Benchside 1 explanation:  
Orlistat can interfere with Levothyroxine which is used in patients with hypothyroidism

Query 10:  Is there any specific lab/physical parameter that needs to be monitored for orlistat ?

Benchside 1 explanation:  
Not envisaged as yet. Would welcome suggestions, if any

Query 11: How do we differentiate the weight loss cause by exercise /by orlistat which decreases hunger pangs/both which then causes upregulation of insulin receptors leading to low blood sugar ?

Benchside 1 explanation: 
By comparison between the the two groups--one on exercise alone and another on 60mg of orlistat once a day premeal and exercise

Query 12: Materials: This is out of personal interest but how is the sample size calculated?

Benchside 1 explanation: 
This is pilot study and if the hypothesis shows promise it will be extended to the required number of patients (based on %age of "responders" identified)  to have an appropriate statistical power.

Query 13: Also this part: 

"After other meals, participant records two readings: (i) postprandial blood glucose level at about 30 minutes after a meal (no exercise). (ii) blood glucose level after another fifteen minutes during which moderate exercise is undertaken. If fasting blood glucose levels trend lower, the anti-diabetic medication dose is reduced by the physician and the reduction is noted in the chart."

I am not quite sure as to what this entire paragraph means. 

Endpoints: We are hoping that orlistat is causing decrease in FBS to normal range but the endpoint says after exercise so I was wondering what this means as well.  

Benchside 1 explanation: 

The expectation is that the glucose metabolism in these patients will shift towards normoglycemia and in case with OHAs the FBS may tend to be lower.  In such cases only a dose titration may be required--and this is decided by the treating physician

Reviewer 1: 

I still have a couple more questions- 

1) What is the meal? Is it tailor-made like a number of calories and specific percentages of fats, carbs, protein?

2) How will we differentiate decrease in blood sugar caused after orlistat alone vs orlistat and exercise together? I still believe exercise alone and exercise and orlistat has too many confounding factors and should be done separately. Maybe orlistat as one arm and not on orlistat as other which is probably how we can figure that the PPBS drop is due to orlistat alone 

The thing is if we say that PPBS drop is due to a cumulative effect of orlistat and exercise then it means if we apply this to the general population we are recommending that the way orlistat works is with exercise only. So is there any point in prescribing orlistat alone to any patient? Cause DM management guidelines start with weight loss and diet modifications and then we move to OHAs so are we saying now that orlistat should be a part of the behavioural modifications fr control? Cause everyone says workout and exercise 5 times a week but who really does it?  

3) Is the aim then finding out changes in sensitivity of insulin to orlistat NOT how much blood sugar is decreased due to orlistat? And is time to decrease PPBS [rate of drop of PPBS]the only variable that's an indicator of that?

4) Can Ma'am please send me the paper for the pilot study of 60 mg OD dose?

5) For exercise it's still very variable- brisk walking and elliptical workouts are quite different in term of the intensity of workouts. May skew the data?

6)How many minutes of exercise and after what time will the PPBS be checked?