obesity: weight changes when stop tirzepatide

 An updated study assessed the longer-term effects of the medication tirzepatide on weight reduction, comparing those who continued the tirzepatide versus those who stopped it, in the SURMOUNT4 trial (see obesity tirzepatide discont and inc wt JAMA 2024 in dropbox, or doi:10.1001/jama.2023.24945)

 

Details:

-- this is a phase 3, randomized withdrawal clinical trial in 70 sites in 4 countries (Argentina, Brazil, Taiwan and the US) from 2021 to 2023, with two phases:

    -- all patients took open-label tirzepatide weekly to their maximum tolerated dose, in this lead-in period lasting until week 36

        -- initiation for tirzepatide therapy was by the standard approach: 2.5 mg weekly initially with an increase of 2.5 mg every four weeks until the maximum tolerated dose of up to 15 mg

    -- 670 patients at week 36 were then randomized to continuing to receive tirzepatide versus a switch to placebo, with follow-up for 52 more weeks; this part of the study included only those patients who had attained a maximum tolerated dose of tirzepatide of 10 to 15 mg:  93% of whom achieved the 15 mg dose and 7% achieved the 10 mg dose

-- all patients were at least 18 years old, had a BMI of at least 30 (or >27 plus the weight-related complication of hypertension, dyslipidemia, OSA, or cardiovascular disease), 70% had at least one or more weight-related complication

    --but those with diabetes were excluded from this study

-- mean age 48 (90% were <65 years old, 10% greater), 71% women; 80% white/11% Black or African-American

-- all patients received lifestyle counseling by a qualified healthcare professional throughout the study, with a goal to achieve a healthy 500 kcal/day deficit diet and at least 150 minutes of physical activity per week

-- mean weight 107.3 kg, BMI 38.4 (BMI 30-35 in 32%, 35-40 in 32%, >40 in 34%), duration of obesity 15.5 years, waist circumference 115.2 cm

-- blood pressure 126/81, pulse 72, A1c 5.5%, fasting glucose 95/fasting insulin 14, total cholesterol 192/HDL 52/LDL 114/triglycerides 136, eGFR 98

-- comorbidities: hypertension 35%, dyslipidemia 32%, anxiety/depression 23%, osteoarthritis 20%, obstructive sleep apnea 12%, asthma/COPD 10%, NAFLD 7%, atherosclerotic disease 6%

-- SF-36 v2 scores (the mean score in the US general population is 50, with a standard deviation of 10, and a higher score is better):

    -- physical functioning domain: 47

    -- role-physical domain: 50

    -- role-emotional domain: 50

    -- mental health domain: 53

-- primary endpoint: the mean percent change in weight from week 36 (at the time of randomization) to week 88 (1 year later)

-- secondary endpoints: proportion of participants at week 88 who maintained at least 80% of their weight lost achieved during the lead-in period

 

Results:

-- weight loss at week 36 (the lead-in period) for the whole group: 20.9%

    -- during this lead-in period:

        -- BMI decreased 8.0, waist circumference 18.2 cm, blood pressure 12/5 mmHg, HgbA1c 0.5 percentage points; but LDL cholesterol increased 2.5 mg/dL, HDL decreased 3.6 mg/dL

        -- for SF-36 domains: physical functioning increased 5.9 versus 5.5 for placebo, role–physical increased 4.5 versus 3.5 for placebo, role–emotional increased 2.3 versus 3.2 for placebo, mental health increased 1.8 versus 2.5 for placebo

 

-- from week 36 to week 88 after randomization, weight change:

    -- tirzepatide group: 5.5% more weight lost

    -- placebo: +14.0% gained weight

        -- mean percent weight difference: -19.4% (-21.2% to -17.7%), p<0.001

 

-- Percentage of participants at week 88 who maintained at least 80% of the weight lost: 89.5% who continued on tirzepatide versus 16.6% who switched to placebo, p<0.001

 

-- Overall mean weight loss, from week 0  to  week 88:

    -- tirzepatide: -25.3%

    -- placebo: -9.9% (ie, these individuals regained much but not all of their weight loss one year later)

 

--adverse effects:

    -- 81% had at least one treatment emergent adverse event during the lead-in tirzepatide period, most frequently nausea (36%), diarrhea (21%), constipation (21%), and vomiting (16%)

    -- during the double-blind period: 60.3% of participants continuing the tirzepatide had at least one treatment related adverse event versus 55.8% who switched to placebo:

        -- tirzepatide vs placebo, more common adverse events: diarrhea (11% versus 5%), nausea (8% versus 3%), and vomiting (6% versus 1%), most being mild-to-moderate in severity, with new events decreasing over time while on the tirzepatide (this is a typical finding on the GLP-1 agonists: adverse events tend to get better over time)

        -- treatment discontinuation:

            -- lead-in period: 7% in tirzepatide (mostly gastrointestinal)

            -- double-blind period: tirzepatide 2%, placebo 1%

      --serious adverse events: 2% in the lead-in and 3% in the double-blind periods:

          -- one death on  tirzepatide during the lead-in period due to Covid-19 pneumonia; two deaths during the double-blind period (one in each group), one for congestive heart failure and one for adenocarcinoma

    -- cholelithiasis was diagnosed in seven patients (1%) on tirzepatide in the lead-in time, one participant (0.3%) in both the tirzepatide and placebo groups during the double-blind time periods. acute cholecystitis in 4 on tirzepatide and 3 in the placebo group

    -- no findings of pancreatitis, thyroid carcinoma, or pancreatic cancer

 

Commentary:

-- reinforcing lifestyle changes remains the cornerstone intervention for all weight reduction therapies, though lifestyle changes often require long-term additional medications to achieve major weight loss (that being said, lifestyle changes largely directed at diet and exercise may lead to similar weight reduction in some people as with medications)

    -- long-term follow-up of patients on semaglutide, for example, have found continued weight loss at year two of follow-up (see https://gmodestmedblogs.blogspot.com/2022/11/obesity-semaglutide-continues-to-work.html)

-- tirzepatide seems to be more potent than semaglutide, and has the additional physiologic benefit of adding a glucose-dependent insulinotropic polypeptide (GIP) effect on top of a GLP-1 receptor agonist effect

    -- tirzepatide seems to be more effective than semaglutide for both diabetes and weight loss: https://gmodestmedblogs.blogspot.com/2021/07/diabetes-and-weight-loss-tirzepatide.html

    -- the SURMOUNT-1 investigators, in a 72-week trial in patients with obesity on tirzepatide, found a 20.9% decrease in body weight in those on the 15 mg dose (see obesity tirzepatide NEJM2022 in dropbox, or DOI: 10.1056/NEJMoa2206038)

-- many of the medications now are potent in terms of preventing weight gain with their continued use, including GLP-1 receptor agonists, naltrexone/bupropion, phentermine/topiramate, and orlistat

-- but, one concern with these medications is significant body weight regain after the medications stop

 

--This current study basically found that continuing tirzepatide through week 88 was associated with even more decrease in body weight by 5.5%, and improvements in BMI, cardiometabolic parameters (waist circumference, hemoglobin A1c, fasting glucose, insulin levels, lipid levels, and systolic and diastolic blood pressure) as well as patient-reported outcomes (though the lipid parameters did not change in a positive direction, the LDL actually increased and the HDL actually decreased, both by small amounts)

-- But, notably, those who stopped tirzepatide still maintained significant benefit 52 weeks later:

    -- in particular, though 55.5% on the tirzepatide had at least a 25% weight reduction from week 0 to 88, 5.0% did so on placebo

    -- thought these was a 14% weight increase in those switched to placebo:

        -- there was a  mean 9.9% weight reduction, and there still was much of the initial improvement in cardiometabolic risk factors

        – also, notably, 89.5% who continued on tirzepatide until week 88 maintained at least 80% of their weight loss, 16.6% who switched to placebo did!!!

 

Limitations:

-- people with diabetes were excluded from this trial, which would limit generalizability to these overweight individuals

-- essentially no one had significant CKD: 78% had an eGFR of stage II or better, also limiting generalizability

    – in fact, looking at the array of comorbidities in this group of patients with an average BMI of 38, there were remarkably few comorbidities or abnormal lab tests: an unusually healthy population, both physically and mentally

-- though most patients in the study did achieve at least a 10 mg dose of tirzepatide, some did not and they were not included in the subsequent randomization part of the study. The results of the study may therefore not apply to those who were unable to achieve this higher dose of tirzepatide

-- it is important to note in the study that all patients received regular lifestyle counseling by a trained counselor, and this may not be available to this extent in many clinical settings, thereby limiting the generalizability of the conclusions

-- no information on overall medications taken during the study, which could also have affected the results

-- no information about the diet and exercise changes that actually occurred in the study. i would assume that these individuals had a high protein diet (to minimize the muscle loss associated with the weight loss) and that they pretty much achieved the 150min/week of exercise prescribed. but no details were provided on either the diet or exercise actually done

    -- though all interventions for weight loss are associated with muscle loss (meds, bariatric surgery, diet), it would be useful to have assessments of the relative decreases in fat and muscle tissue in studies like this one, since loss of muscle mass is a real concern with weight loss strategies (of course, some muscle loss is expected, as the necessity for muscles to carry the person's weight decreases with weight loss).

 

So, a few points from this trial:

-- as with all classes of medications used for weight reduction, weight is substantially regained after stopping the meds

    -- which suggests that overweight/obesity needs to be considered a chronic metabolic condition requiring long-term therapy, as is found with many of the other chronic conditions such as hypertension, hyperlipidemia, diabetes, etc. And, as with these conditions, many need life-long medications

        -- however, there certainly are some patients who are able to have complete remissions of these conditions with aggressive lifestyle changes, and it is important to continue to support people in their attempts to lose weight on their own

        -- but, in those on tirzepatide as in this study, there was a remarkable degree of weight loss, similar to the results of gastric sleeve surgery

        – and, there was a persistent significant weight loss after 1 year of being off the active medication!!!

            -- perhaps some people could decrease their medication dose over time (especially since the initial weight loss might allow them to do more exercise and motivate them to continue eating less); and maybe some could be completely weaned off the meds with their acheived dramatic weight loss....

geoff

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