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In populations with added comorbidities, results are lower: TRIUMPH-2 (obesity + diabetes) showed 20.8%, TRIUMPH-3 (obesity + cardiovascular disease) showed 22.6%, and TRANSCEND-T2D-1 (diabetes-specific, 40 weeks) showed 16.8% all consistent with patterns seen across the GLP-1 drug class, where comorbidities reduce achievable weight loss
One possible explanation for such a response is that inhibition of mTORC1 and activation of GCN2 collectively suppresses global translation to conserve nutrients, while selective translation of mRNA such as ATF4 (mediated by increased p-eIF2) activates the expression of AARE genes to mitigate cellular stress
however, they are localized to distinct neuronal populations [30, 35]
Stable markers during dose reduction support continued tapering
Ashwani Pareek, Jawaharlal Nehru University, India
