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In this randomized trial, adults with obesity treated with weekly tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, had major weight loss over 72 weeks.

Obesity is a major risk factor for many leading causes of illness and death worldwide. Data are needed regarding the efficacy and safety of the nonpeptide glucagon-like peptide-1 (GLP-1) receptor agonist orforglipron as a once-daily oral therapy for weight reduction in adults with obesity. In this phase 2, randomized, double-blind trial, we enrolled adults with obesity, or with overweight plus at least one weight-related coexisting condition, and without diabetes. Participants were randomly assigned to receive orforglipron at one of four doses (12, 24, 36, or 45 mg) or placebo once daily for 36 weeks. The percentage change from baseline in body weight was assessed at week 26 (primary end point) and at week 36 (secondary end point). A total of 272 participants underwent randomization. At baseline, the mean body weight was 108.7 kg, and the mean body-mass index (the weight in kilograms divided by the square of the height in meters) was 37.9. At week 26, the mean change from baseline in body weight ranged from -8.6% to -12.6% across the orforglipron dose cohorts and was -2.0% in the placebo group. At week 36, the mean change ranged from -9.4% to -14.7% with orforglipron and was -2.3% with placebo. A weight reduction of at least 10% by week 36 occurred in 46 to 75% of the participants who received orforglipron, as compared with 9% who received placebo. The use of orforglipron led to improvement in all prespecified weight-related and cardiometabolic measures. The most common adverse events reported with orforglipron were gastrointestinal events, which were mild to moderate, occurred primarily during dose escalation, and led to discontinuation of orforglipron in 10 to 17% of participants across dose cohorts. The safety profile of orforglipron was consistent with that of the GLP-1 receptor agonist class. Daily oral orforglipron, a nonpeptide GLP-1 receptor agonist, was associated with weight reduction. Adverse events reported with orforglipron were similar to those with injectable GLP-1 receptor agonists. (Funded by Eli Lilly; GZGI ClinicalTrials.gov number, NCT05051579.).

In a randomized trial, once-weekly insulin efsitora, administered in a fixed-dose regimen, was noninferior to once-daily glargine in reducing hemoglobin levels in patients with type 2 diabetes who had not previously received insulin.

Republicans muster just enough votes in the Senate to move ahead on health care, but the future of replacing Obamacare is far from clear. President Trump takes aim at Jeff Sessions, publicly airing frustrations with his own attorney general, as talks of a replacement ramp up. Mr. Trump's son-in-law and top adviser, Jared Kushner, heads back to Capitol Hill after testifying to the Senate in the Russia probe. One food bank is helping fill in the gap during summer, so kids don't go hungry. Seattle's new seawall doubles as a science experiment. GUESTS: Adam Schiff, Chris Stewart, Sari Horwitz, Jon Tester

After a contentious debate, the nation's top Republican won't defend Donald Trump, focusing instead on trying to keep control of the U.S. House. Hurricane Matthew leaves a path of destruction throughout the nation's Southeast, as dangerous flooding continues to threaten North Carolina. Supreme Court Justice Ruth Bader Ginsburg discusses her new book and breaking boundaries. GUESTS: Michael Hanna, Tamara Keith, Amy Walter, Tom Davis, Barry Bennett, Ruth Bader Ginsburg