tirzepatide helps with MASH (aka NASH)

 Tirzepatide, the combo of a potent  glucagon-like peptide-1 receptor agonist (GLP-1) plus a glucose-dependent insulinotropic polypeptide (GIP) agonist, was found to be highly effective in patients with metabolic dysfunction-associated steatohepatitis (MASH): see NASH tirzepatide NEJM2024 in dropbox, or DOI: 10.1056/NEJMoa2401943)

 

Details:

-- 190 participants who had biopsy confirmed MASH and stage F2 or F3 (moderate or severe) fibrosis were randomized in a phase 2, dose-finding, multicenter, double-blind, randomized, placebo-controlled trial to tirzepatide 5 mg, 10 mg or 15 mg versus placebo subcutaneously weekly for 52 weeks

-- mean age 54, 57% female, 86% white/12% Asian/36% Latino, body weight 100 kg/BMI 36

-- type II diabetes in 58%

-- liver fibrosis stage: F2 in 43%/F3 in 57%; NAFLD activity score 5.3 (unweighted sum of scores for steatosis, lobular inflammation, and hepatocellular ballooning), ALT 62, AST 51, A1c 6.5%, liver fat content 18.4% (MRI imaging of proton density fat fraction, values of 5% or higher consistent with hepatic steatosis), extracellular hepatic water content 913 ms (a measure of hepatic fibroinflammation), liver stiffness 11.8 (measured by FibroScan), FIB-4 score 1.6 (a score below 1.3 means advanced fibrosis is unlikely, greater than 2.67 means it is more likely), NIS-4 score 0.8 (a NAFLD activity score of 4 or higher and fibrosis stage F2 or higher is considered unlikely if the value is below 0.36 and likely if higher than 0.63), enhanced liver fibrosis test score 9.8 (advanced fibrosis is considered unlikely if that the scores below 7.7 and likely if higher than 9.8), and Pro-C3 19.6 mcg/L (a score of higher than 13.45 mcg/L is indicative of advanced fibrosis (see the article for more information on these fibrosis surrogate markers)

    -- the NAFLD activity score was divided into subcomponents, higher scores indicating more severe disease:

        -- the 3 subcomponents: steatosis, hepatocellular ballooning, and lobular inflammation

-- exclusion criteria in the study included other chronic liver diseases besides MASH, cirrhosis, evidence of hepatic decompensation, excessive alcohol consumption (>14 drinks per week for women and  >21 drinks per men), and uncontrolled diabetes (defined as A1c>9.5%)

 

-- primary endpoint: resolution of MASH without worsening of fibrosis at 52 weeks

-- secondary outcome: improvement of at least one fibrosis stage without worsening of MASH at 52 weeks

 

Results:

-- 157 of the 190 patients had repeated liver biopsy at 52 weeks (the rest had their 52-week results imputed, with the assumption that they had results similar to the placebo group)

-- the percentage of participants who ultimately received the randomly assigned tirzepatide dose with escalation:

    -- 5 mg dose: 96%

    -- 10 mg dose: 96%

    -- 15 mg dose: 85%

-- the percentage of patients who had resolution of MASH without worsening of fibrosis, the primary endpoint (all of the following were highly statistically significant, with p<0.001 when compared to placebo):

    -- placebo group: 10%

    -- tirzepatide 5 mg: 44% (difference from placebo 34%, confidence interval 17-50%)

    -- tirzepatide 10 mg 56% (difference from placebo 46%, confidence interval 29-62%)

    -- tirzepatide 15 mg: 62% (difference from placebo 53%, confidence interval 36-69%)

-- the percentage of participants who had an improvement at least one fibrosis stage without worsening of MASH, the secondary endpoint:

    -- placebo group: 30%

    -- tirzepatide 5 mg: 55% (difference from placebo 25%, confidence interval 5-46%)

    -- tirzepatide 10 mg 51%  (difference from placebo 22%, confidence interval 1-42%)

    -- tirzepatide 15 mg: 51% (difference from placebo 21%, confidence interval 1-42%)

    -- tirzepatide did not have an apparent effect on the percentage of participants who had a decrease of at least two fibrosis stages with worsening MASH, an increase of at least one fibrosis stage, or the absence of fibrosis at week 52

 

 

-- in terms of the three components of the NAFLD activity score (with range of tirzepatide doses):

    -- steatosis score, 1 point improvement in 62-75% of participants on tirzepatide versus 32% on placebo

    -- lobular inflammation, 1 point improvement in 61-62% on tirzepatide versus 36% on placebo      

    -- hepatocellular ballooning, 1 point improvement in 77-82% on tirzepatide versus 54% on placebo

 

-- progression to cirrhosis: 4 participants in the tirzepatide groups (3%) and 2 participants in the placebo group (4%)

 

-- Other effects of being in the tirzepatide group:

    -- HDL cholesterol increased from 2.4-9.2%, versus decreasing 7.5% on placebo

    -- LDL cholesterol decreased 3.7% versus decreasing 9.3% on placebo

    -- triglycerides decreased 20% versus decreasing 5.2% on placebo

    -- hemoglobin A1c in those with type II diabetes decreased 1.4 percentage points versus decreasing 0.1 percentage point on placebo

 

-- adverse events: reported in 92% of participants in the tirzepatide group and 83% in the placebo group

    -- most common were GI events in the tirzepatide group, 96% were mild to moderate severity

    -- discontinuation of tirzepatide was 4%, also 4% in those on placebo

    -- serious adverse events were in 6% in the tirzepatide groups and 6% in the placebo group

  

 Commentary:

-- MASLD (metabolic dysfunction-associated steatotic liver disease) is remarkably common, affecting approximately 30% of the worldwide adult population, and is one of the leading causes of cirrhosis as well as hepatocellular carcinoma in both middle-income and high-income countries

-- the estimated annual direct medical costs in the US was $103 billion and in Europe €35 billion in a 2018 study on MAFLD

-- though MASLD is predominantly a disease of overweight people, about 10-20% of those with MASLD are lean, and lean individuals seem to have an even worse prognosis: https://gmodestmedblogs.blogspot.com/2023/10/lean-nafld-higher-mortality-than-non.html

-- there is typically a dose-response relationship between the severity of liver fibrosis and the future risk of liver-related events

-- prior studies have shown that VCTE (FibroScan) is a good predictor of HCC, portal hypertension, and varices

-- MASLD includes a spectrum to disease reflecting hepatic steatosis (fatty liver) unrelated to heavy alcohol use and can evolve from a pretty benign liver disease into MASH, the most aggressive end of the spectrum (MASH is present in about 20% of those with MAFLD)

 

-- as you no doubt know, NASH (nonalcoholic steatohepatitis) was recently renamed MASH (metabolic dysfunction-associated steatohepatitis) in order to appeal to the older generation who really related to the aforenamed movie and TV show comedy. It turns out that the movie was really not that funny on recent review, and the disease is even much less so...

    -- the disease MASH is a bad one: it is associated with increased cardiovascular risk as well as bad liver outcomes (cirrhosis, hepatocellular cancer, hepatic decompensation) and all-cause mortality. And MASH is the second most common indication for liver transplantation

    -- MASH Is typically associated with obesity and diabetes, of increasing concern because of all of these diseases (MASH, diabetes, obesity) are all increasing in prevalence together

    -- but, notably, weight reduction is very effective and is the primary therapy for MASH, whether done by diet/exercise, bariatric surgery, meds (previous drug recommendations included the GLP-1 receptor agonists liraglutide and semaglutide)

    -- in patients with diabetes, metformin does not improve liver histology, hence it might be better to go directly to a GLP-1 in those with MASH (and, is seems that tirzepatide may well be a reasonable addition to the GLP1 group) or pioglitazone, all of which have been shown to improve liver histology

    -- that all being said, though these meds (and nonpharmacologic approaches) do improve liver histology and quality of life (especially clear in those who lose weight), and it does seem quite likely that improving liver histology is a good surrogate marker for clinical outcomes (there is typically a logical progression from worsening histology to worsening liver problems, though there are insufficient data to show a clear correlation between the specific degree of liver histology and cardiovascular outcomes: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9919281/ ), it is important to remember that liver histology is just a surrogate marker for the bad liver/cardiovascular outcomes, and we have often found that what we think are good surrogate markers for many diseases does not always pan out clinically (eg see https://gmodestmedblogs.blogspot.com/2024/06/using-surrogate-markers-for-disease-are.html ). So, it seems to me that, barring really long-term studies with clear clinical outcomes, using a surrogate marker in this case is the best we have. And, especially for the GLP-1 receptor agonists in those with diabetes, there is clear evidence that they do help with clinical outcomes (heart and kidney disease)

 

 -- tirzepatide is a GLP-1 receptor agonist, similar to the approved GLP-1 agonists for MASH (semaglutide and liraglutide), but with the addition of GIP receptor agonist activity. This latter component adds improved insulin sensitivity, improved lipid storage in white adipose tissue, and increased fat oxidation during weight reduction

-- MASH resolution is hypothesized to result in fibrosis regression and reduction in major adverse liver outcomes (people who have spontaneous decreases in MASH activity have improvements in fibrosis/those with increased activity have more fibrosis over time)

-- weight reduction is a key factor in MASH improvement, as documented in several bariatric surgery studies showing reduced major adverse liver outcomes

    -- it is notable in some of the bariatric surgery studies that there was continued improvement of fibrosis over a five-year period, suggesting that this 52-week study may not reveal optimal outcomes

-- the safety outcomes found in this study were quite impressive. Although there were more cases of nausea, diarrhea, and constipation, these were of mild to moderate severity, and rarely led to stopping the meds. And nausea and diarrhea were actually more commonly reported in the placebo group

 

-- In sum, this study, a multicenter international double-blind RCT with actual liver biopsy outcomes, found that at 52 weeks, all three doses of tirzepatide were superior to placebo with respect to resolution of MASH without worsening the fibrosis (the primary endpoint) and that tirzepatide treatment was associated with changes in fibrosis, the NAFLD activity score, and all of the subscores for the individual components of the NAFLD activity score

    -- there were also changes in all of the associated MASH items: serum levels of ALT, AST, GGT, and cytokeratin 18; and the array of biomarkers of liver fat, inflammation, and fibrosis assessed including those assessed by FibroScan

-- however, the dose of tirzepatide was not relevant to the secondary outcome of improvement of at least one fibrosis stage without worsening of MASH at 52 week

 

Limitations:

--the imputation done above is a worst-case scenario by including the results of the patients on tirzepatide who did not have a repeat liver biopsy at 52 weeks  as if they were in the placebo group (i.e., the actual results likely were better than what was reported)

-- this study, as with other studies, excluded from the definition of MASH those with excessive alcohol consumption (>14 drinks per week for women and >21 drinks per men). It is clear that heavy alcohol use is associated with a more aggressive liver disease. However, it is very unclear what the effects of lower alcohol consumption is on liver inflammation and progression of fibrosis/cirrhosis with MAFLD or MASH. ie, smaller intakes of alcohol might well muddy the waters here: are some people having less benefit of tirzepatide  because they are drinking but less than the arbitrary point of “heavy drinking”; perhaps they might have had a much greater response to the medication if they were abstaining completely from alcohol??

-- this was also a relatively small study with a short outcome of 52 weeks. The relatively low number of patients involved limit the statistical power to look at major subgroups or more comparisons of the groups; the study being too short may not reveal the full effects of tirzepatide (as noted above)

-- though this was a large international study, there were few people of African and Indian descent involved in the study. and it excluded people with poorly controlled diabetes (who, in clinical practice often have dramatically better control with tirzepatide)

 

So, a pretty impressive study:

-- as probably most of you are aware, the GLP-1 receptor agonists have become a game-changer in terms of both diabetes control and weight loss. Patients with really uncontrolled diabetes or overweight have these quite well-tolerated alternatives to bariatric surgery, with similar clinical benefits to surgical band gastroplasty

-- tirzepatide is a step up on the GLP-1s, with more profound improvements in diabetes/weight loss (https://gmodestmedblogs.blogspot.com/2021/07/diabetes-and-weight-loss-tirzepatide.html)

-- this study strongly suggests that patients with MASH, a condition associated with very severe liver and cardiovascular outcomes, seem to benefit from tirzepatide. And even if they do not tolerate higher doses of tirzepatide, they seem to get pretty impressive benefit from lower doses

-- and, though MASH is the second most common condition leading to liver transplant (and continuing to move up this ladder), the price of tirzepatide (though overpriced, as with all newer and many older meds) is still a relative bargain vs hepatitis C meds…

 

geoff

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