NASH: semaglutide helps

 A recent placebo-controlled trial found that semaglutide in patients with nonalcoholic steatohepatitis (NASH) significantly increased stabilization of hepatic fibrosis, but without significant improvement in fibrosis stage (see nafld semaglutide NEMJ2020 in dropbox, or DOI: 10.1056/NEJMoa2028395) 

 

Details: 

-- 320 patients 18 to 75 years old, BMI > 25, activity score for NAFLD (nonalcoholic fatty liver disease) at least 4 with biopsy-confirmed NASH and liver fibrosis, conducted at 143 sites in 16 countries, were randomized to various doses of semaglutide vs placebo, and followed for 72 weeks in a double-blind phase 2 trial 

-- mean age 55, 60% female, 70% white, BMI 36, diabetes 62%, A1c 7.3%, ALT 54, AST 43 

-- liver fibrosis stage: F1 28%, F2 22%, F3 49% (230 of the 320 patients had F2 or F3 fibrosis)

-- total activity score by biopsy assessment: 4.9 (score ranges from 0 to 8, higher scores with increased likeliness of NASH) 

-- noninvasive measures (e.g. fibroscan) were done when available, but this test is not routinely done in patients without biopsy-proven NASH 

-- exclusion criteria included hemoglobin A1c> 9.5%, or alcohol consumption > 20 g in women or > 30 g in men 

-- patients were randomized to 3 doses of semaglutide, 0.1, 0.2, or 0.4 mg daily subcutaneously vs placebo. If they did not tolerate the dose they were assigned to, they stopped the medicine completely 

    -- 302 patients (94%) completed the trial through the final scheduled visit and 285 (89%) completed treatment 

-- primary endpoint: resolution of NASH with no worsening of fibrosis 

-- secondary endpoint: improvement of at least one fibrosis stage with no worsening of NASH in patients with F2 or F3 fibrosis 

 

Results: 

-- weight loss, percent bof body weight: 

    -- semaglutide 0.4 mg group: 13% 

    -- placebo: 1% 

    -- the weight loss with semaglutide continued until approximately 28-44 weeks and was sustained thereafter, in a dose-dependent fashion: semaglutide 0.1 mg, 0.2 mg, and 0.4 mg were respectively associated with body weight decreases of 4.8%, 8.9%, and 12.5% 

-- primary outcome of resolution of NASH with no worsening fibrosis: 

    -- semaglutide 0.1 mg group: 40% 

    -- semaglutide 0.2 mg group: 36% 

    -- semaglutide 0.4 mg group: 59% 

    -- placebo: 17% (comparing those in the semaglutide 0.4 mg group to placebo, odds ratio 6.87 (2.60 - 17.63,), p<0.001) 

-- improvement in fibrosis stage: 

    -- semaglutide 0.4 mg group: 43% 

    -- placebo: 33% (nonsignificant difference: odds ratio 1.42 (0.62-3.28), p=0.48 

    -- the results of patients at any fibrosis stage were consistent with this 

    -- the percent of patients who had both NASH resolution and an improvement in fibrosis stage: 37% in those on semaglutide 0.4 mg and 15% on placebo 

    -- improvement of at least 1 point in the NAFLD activity score: 71% on semaglutide 0.1 mg, 80% on 0.2 mg, and 83% on 0.4 mg; vs 44% in placebo 

--worsening of fibrosis: 

    -- for semaglutide 0.1 mg, 0.2 mg, and 0.4 mg respectively: 10%, 8%, and 5% 

    -- for placebo: 19% 

--changes in liver enzyme levels and biomarkers: semaglutide improved them, in dose-dependent fashion; hemoglobin A1c improved by slightly greater than 1% in those in the 0.2 and 0.4 mg  semaglutide groups 

-- fibroscan liver stiffness (in those where it was done) decreased from 1.02 in the placebo group to about 0.73 in all 3 of the semaglutide groups 

-- adverse events, comparing semaglutide 0.4 mg group vs placebo: 

    -- nausea: 42% vs 11% 

    -- constipation 22% vs 12% 

    -- vomiting: 15% vs 2% 

    -- malignant neoplasms: reported in 3 patients on semaglutide (1%) vs number placebo; overall neoplasms (benign, malignant, or in specified): 15% vs 8%. No pattern of occurrence was elicited.

        -- malignant neoplasms: 1 breast cancer, 1 endometrial adenocarcinoma, and 1 peripheral T-cell lymphoma

        -- overall neoplasms: most common were colonic polyps 

    -- no cases of acute pancreatitis (a concern with the GLP-1 agonists) though small increases in amylase and lipase levels and hypoglycemia, but there was some increase in "gallbladder-related disorders" ( 6% on semaglutide vs 2% in placebo)

    -- overall,7% in semaglutide in 5% and placebo groups discontinued treatment because of adverse effects 

 

Commentary: 

-- so, this trial did find that semaglutide at the dose of 0.4 mg/d did result in a significant resolution of NASH without worsening of fibrosis, though no significant difference regarding improvement of at least one stage of fibrosis 

    -- this latter finding was unexpected: in general improvements in the NAFLD activity score are associated with fibrosis regression. And, many of the comparisons noted above did seem to favor the semaglutide

-- though there no approved therapies for treatment of NASH, there is evidence of improvement with several meds including pioglitazone, vitamin E, and liraglutide (liraglutide being of the same ilk as semaglutide, both GLP-1 receptor agonists, though the latter is stronger) 

    -- most of the liraglutide studies, of which there are several,  have had positive results on hepatic steatosis and liver histology, usually proportional to the magnitude of weight loss (see nafld liraglutide dec inflam hepatol2019 in dropbox, or DOI 10.1002/hep.30670)

--the background here is that persistent NASH is associated with progressive liver fibrosis, cirrhosis, hepatocellular carcinoma, and the need for liver transplants

-- Weight loss and physical activity do help a lot for those with NAFLD, and are the mainstay of treatment. 

    --A recent analysis of the US National Health and Nutrition Examination Survey data found that with follow-up after 10.6 years, increased duration of physical activity was associated with reduced risk of death from any cause by 48%, HR 0.52 (0.32-0.86) for highest vs lowest quartile, and lower risk for cardiovascular disease-related death, by 72%, HR 0.28 (0.08-0.98). see nafld phys activity helps clingasthep2020 in dropbox, or doi.org/10.1016/j.cgh.2020.07.023 

    --and lots of studies on the benefit of diet, eg http://gmodestmedblogs.blogspot.com/2017/10/mediterranean-diet-helps-nafld.html , http://gmodestmedblogs.blogspot.com/2019/02/low-sugar-diet-dec-nafld-in-adolescents.html . overall, there seems to be benefit by losing 5-10% of body weight 

 

-- Several years ago, I sent out blogs on NAFLD from a 3-part series, which highlighted much of the known data, associations, non-med and med treatments at that time, see http://gmodestmedblogs.blogspot.com/2016/08/there-have-been-several-articles.html , http://gmodestmedblogs.blogspot.com/2016/08/non-alcoholic-fatty-liver-disease-2.html , http://gmodestmedblogs.blogspot.com/2016/08/non-alcoholic-fatty-liver-disease-3.html 

 

Limitations of the trial: 

--they only included patients with biopsy-proven NASH (which is really the only way to document NASH within the larger cohort having NAFLD)

--there is interobserver variability in diagnosis of NASH, hence some room for error in classification

--though this study was pretty long (72 weeks), it did not have the really important long-term clinical outcomes, such as progressive fibrosis, hepatocellular carcinoma, liver transplant, mortality

So, this trial adds semaglutide to potential therapies for NASH. But a few points: 

-- it is clear that weight loss is a primary focus in NASH treatment 

-- it seems likely that at least a large part of the benefit of GLP-1 agonists is through the associated weight loss 

-- semaglutide works quite well, and is more potent than the other GLP-1 agonists (including liraglutide), with pretty impressive weight loss as found in this study. And it seems like a reasonable choice for overweight/obese people with NASH

-- interestingly, metformin does not seem to be associated with NASH resolution (?not enough weight loss, though this does challenge the specific role of glucose intolerance since metformin helps so much with that); there are some positive data also for the SGLT-2 inhibitors, also likely associated with weight loss 

-- But this study reinforces the use of GLP-1 agonists in those with diabetes and NASH

 

this article brings up the common questions in primary care: what about patients with NAFLD who do not get a biopsy to determine if they have NASH? And, particularly, what about those with unbiopsied NAFLD who have glucose intolerance?? The data are significantly less clear for these remarkably common scenarios in primary care, but I would suggest the following seem reasonable: 

-- for those who have increased transaminases (especially ALT) in the setting of having ruled-out other causes of hepatic inflammation (including alcohol), and with glucose intolerance:

    -- aggressive nonpharmacologic therapy, focusing on diet, exercise, and weight loss

    -- GLP-1 agonists might be considered for first-line therapy for NAFLD if medication is needed, given that metformin (the usual choice) by itself has unclear benefit for NAFLD; GLP-1s are associated with a pretty predictable weight loss (liraglutide in fact has an FDA indication as a weight loss medication, and semaglutide is stronger). 

    -- semaglutide is available as a weekly injection which can be titrated to maximal effect, but with lower levels more tolerable to those with significant adverse effects (especially GI) 

-- and, in those who are obese with unbiopsied NAFLD without glucose intolerance/diabetes, semaglutide seems reasonable, though can also consider using vitamin E 800IU/d. though that dose may be associated with a slight increased risk of prostate cancer (see http://gmodestmedblogs.blogspot.com/2016/08/non-alcoholic-fatty-liver-disease-3.html 

-- and, even though metformin is a great first-line med for diabetes, maybe GLP-1 agonists are better for those who areobese?? clearer cardiac benefits, more weight loss, at least stabilization of NASH???

geoff

 

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