New Horizons. A New Paradigm for Treating to Target with Second-Generation Obesity Medications

Abstract

In treating obesity as a chronic disease, the essential goal of weight loss therapy is not the quantity of weight loss as an end unto itself but rather the prevention and treatment of complications to enhance health and mitigate morbidity and mortality. This perspective on obesity care is consistent with the complications-centric American Association of Clinical Endocrinology (AACE) obesity guidelines and the diagnostic term of adiposity-based chronic disease (ABCD). Many complications require 10% to 20% weight loss to achieve therapeutic goals; however, existing obesity medications fail to produce ≥10% weight loss in the majority of patients. In June, 2021, semaglutide 2.4 mg/week was approved for chronic weight management. Phase 3 clinical trials demonstrated that this medication produced > 10% placebo-subtracted weight loss, more than half of patents lost ≥15%, and over one third lost ≥20% of baseline weight. This essentially doubles effectiveness over existing obesity medications, provides sufficient weight loss to ameliorate a broad range of complications, and qualifies as the first member of a second-generation class of obesity medications. The advent of second-generation medications fully enables a treat-to-target approach for management of ABCD as a chronic disease. Specifically, with this degree of efficacy, second-generation medications permit active management of body weight as a biomarker to targets associated with effective treatment and prevention of specific complications. ABCD can now be managed similar to other chronic diseases such as type 2 diabetes, hypertension, and atherosclerosis, which are treated to biomarker targets that can be modified based on the clinical status of individual patients [ie, hemoglobin A1c (HbA1c), blood pressure, and low-density lipoprotein cholesterol (LDL-c)] to prevent the respective complications of these diseases.

Keywords: anti-obesity medications; chronic disease; obesity; obesity complications.

Figure 1.

Treating chronic diseases to target. Abbreviations: ABCD: adiposity-based chronic disease; CHF: congestive heart failure; CKD: chronic kidney disease; CVD: cardiovascular disease; HTN: hypertension; LDL: low-density lipoprotein; MI: myocardial infarction; NAFLD: non-alcoholic fatty liver disease: NASH, non-alcoholic steatohepatitis.

Figure 2.

Treating ABCD/obesity to target for prevention and treatment of complications. Abbreviations: ABCD: adiposity-based chronic disease; CVD: cardiovascular disease; HTN: hypertension; NASH, nonalcoholic steatohepatitis; T2D, type 2 diabetes.