Welcome to the  8^TH Edition of The Clinical Chronicle!

From a once-monthly injectable GLP-1/GIP agent driving up to 16% weight loss to dapagliflozin’s promise in reversing liver damage in MASH, this edition highlights game-changing advances in metabolic and chronic disease care. We explore tirzepatide’s head-to-head win over semaglutide in obesity, the first twice-yearly HIV PrEP injection, and oral semaglutide’s cardiovascular protection in diabetes.

Post-stroke care now favors early DOAC initiation backed by strong evidence, while methotrexate challenges prednisone as first-line for pulmonary sarcoidosis with fewer side effects. For residents stepping into PGY-2, we close with seven actionable strategies to lead with confidence and grow with purpose.

Stay sharp. Stay ahead.

Featured Story

Is this the Once a Month Game Changer for Obesity?

 Maridebart Cafraglutide, a new GLP-1/GIP injectable, helped patients lose up to 16.2 % of body weight in 52 weeks.

A phase II trial of 592 adults tested maridebart cafraglutide, a GLP-1/GIP injectable requiring just one dose every four weeks. In the obesity-only group (n=465), patients lost 12.3% to 16.2% of body weight at 52 weeks versus 2.5% with placebo. In those with type 2 diabetes (n=127), weight loss ranged from 8.4% to 12.3% vs 1.7% with placebo. HbA1c improved by 1.2% to 1.6%.

The agent—also called MariTide—has a long 21-day half-life, enabling monthly auto-injections. Additional benefits included reductions in waist circumference, BMI, blood pressure, CRP, and lipids. Fat mass loss outpaced lean mass, with no significant changes in bone density.

GI side effects were common but mostly mild. Discontinuation due to nausea/vomiting reached up to 27% in some groups. Dose escalation strategies reduced these events. With no weight loss plateau seen by 52 weeks, experts believe 20% loss may be achievable.

Source: NEJM

In Focus

Can a Diabetes Drug Help Reverse Liver Damage in MASH?

Dapagliflozin led to MASH resolution in 23% and fibrosis improvement in 45% over 48 weeks, without major side effects.

In a randomized trial of 154 adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis (MASH), dapagliflozin (Farxiga) significantly outperformed placebo. After 48 weeks, 53% of patients on dapagliflozin had MASH improvement without fibrosis worsening vs 30% with placebo, (RR 1.73, P=0.006). Resolution of MASH occurred in 23% vs 8%, and fibrosis improved in 45%vs 20%.

Participants were younger (mean age 35), 85 percent male, and had relatively lower BMI and fibrosis compared to other MASH trials. Dapagliflozin lowered liver fat, inflammation, ballooning, and stiffness as measured by FibroScan, while also improving liver enzymes and NAS scores. Only 5% had fibrosis worsening versus 22% in the placebo group.

Despite being designed for diabetes, dapagliflozin showed promise in liver disease, with no serious adverse events reported. Dropout due to side effects was minimal (1 percent vs 3 percent placebo). These results highlight its potential dual benefit: metabolic and hepatic, especially in younger patients with mild to moderate fibrosis.

As the only current FDA-approved treatment for MASH is resmetirom, this trial adds momentum to repurposing SGLT2 inhibitors in liver disease. Dapagliflozin may soon join semaglutide and resmetirom as part of a new multi-front pharmacologic approach to managing MASH.

Source: BMJ

Weight Wars: Is Tirzepatide the New Champion in Obesity Care?

Two powerful injectables go head to head in a landmark trial, reshaping the future of weight loss treatment.

In the SURMOUNT-5 head-to-head trial (n=751), tirzepatide (Zepbound) significantly outperformed semaglutide (Wegovy) for obesity treatment. Over 72 weeks, tirzepatide users lost 20.2% of body weight (average 22.8 kg) versus 13.7% with semaglutide (15.0 kg). Waist circumference shrank 18.4 cm with tirzepatide vs 13 cm with semaglutide (P<0.001).

Higher proportions of tirzepatide users hit major weight-loss milestones: 48.4% lost ≥20% body weight vs 27.3% on semaglutide. Tirzepatide also led to greater improvements in systolic BP (-10.2 vs -7.7 mm Hg) and comparable gains in glycemic and lipid profiles. Cardiometabolic benefits were closely tied to the degree of weight loss.

GI side effects were common but mostly mild; treatment discontinuation was lower with tirzepatide (6.1% vs 8%). Injection-site reactions were more frequent with tirzepatide (8.6% vs 0.3%). The trial wasn’t powered for safety comparison, but no major adverse cardiovascular or cancer events were reported.

While semaglutide already has an indication for cardiovascular risk reduction, ongoing trials may soon expand tirzepatide’s label. With nearly 1 in 3 patients achieving 25% weight loss, tirzepatide appears to be setting a new standard in obesity pharmacotherapy.

Source: NEJM

Can Prophylactic Vancomycin Prevent C. diff Relapse—or Just Raise New Risks?

CDI recurrence fell to 43.6% with vancomycin vs 57.1% with placebo, but VRE colonization doubled.

In a small phase II double-blind trial (n=81), oral vancomycin prophylaxis modestly lowered Clostridioides difficile infection (CDI) recurrence compared to placebo—43.6% vs 57.1% at 8 weeks—but the difference wasn't statistically significant (P=0.22). The high recurrence in both groups highlights the ongoing challenge of managing patients with recent CDI who need systemic antibiotics for unrelated infections.

However, vancomycin users had a higher rate of vancomycin-resistant Enterococcus (VRE) colonization: 50% vs 24%, raising concern over unintended microbial shifts. Notably, adverse events were comparable between groups and mostly unrelated to treatment.

This study, conducted across four Midwest health systems, included adults with prior CDI within 180 days and excluded those currently on vancomycin or with suspected new CDI. Although findings weren't conclusive due to the small sample size and early closure of enrollment, editorialists suggest the results may still be clinically meaningful, especially for high-risk patients.

With no clear consensus across societies ACG gives conditional support, IDSA withholds recommendations: a larger, multicenter trial is urgently needed to determine if vancomycin prophylaxis is a reliable shield or a double-edged sword.

Source: JAMA

Next in Practice

Could a Twice-Yearly Injection Revolutionize HIV Prevention?

Lenacapavir (Yeztugo) is the first FDA-approved six-monthly injectable PrEP, cutting new HIV infections by up to 100% in trials.

The FDA has approved lenacapavir, a novel long-acting HIV-1 capsid inhibitor, as the first-ever twice-yearly injectable pre-exposure prophylaxis (PrEP). This marks a major breakthrough in HIV prevention, addressing adherence and stigma barriers associated with daily oral regimens.

Phase III trials PURPOSE 1 and 2 demonstrated remarkable efficacy: in adolescent girls and young women in Africa, lenacapavir completely prevented new infections compared to daily oral PrEP, while in cisgender men and transgender/gender-nonbinary persons, it reduced HIV incidence by 89%. Safety was favorable, with injection site reactions, headache, and nausea as the most common side effects.

Lenacapavir’s unique multi-stage mechanism targets HIV throughout its life cycle, and it shows no cross resistance to other drug classes. Patients must be tested for HIV before and during treatment due to drug resistance risks if used in undiagnosed infection. GILEAD is actively working to improve access, including zero co-pays for some patients, and is exploring even longer dosing intervals, including once-yearly injections.

Source: YEZTUGOHCP

Can a Pill Protect the Heart Like a Shot? Oral Semaglutide Shows It's Possible.

In a 9,650-patient trial, oral semaglutide cut major cardiovascular events by 14% over 50 months.

Oral semaglutide, a GLP-1 receptor agonist, demonstrated meaningful cardiovascular protection in adults with type 2 diabetes and established cardiovascular or kidney disease. In the SOUL trial, which enrolled 9,650 participants over the age of 50, oral semaglutide reduced the risk of major adverse cardiovascular events (MACE): a composite of CV death, nonfatal MI, and nonfatal stroke by 14% compared to placebo (HR 0.86, 95% CI 0.77–0.96, P=0.006) over a median follow-up of 49.5 months.

The absolute event rate was 12.0% in the treatment group vs 13.8% with placebo, a 2% absolute risk reduction. Notably, the only individual component of the composite that reached statistical significance was nonfatal myocardial infarction. Serious adverse events occurred in 47.9 percent of patients on semaglutide vs 50.3 percent on placebo, and GI side effects were comparable (5.0% vs 4.4%).

These findings confirm that oral and injectable semaglutide offer similar cardioprotection, giving injection-averse patients a viable alternative that could improve adherence and access. Given the high cardiovascular burden in diabetes, this could shift how clinicians initiate therapy in at-risk populations.

Source: ADA

Evidence at a glance

Can Biologics Break the COPD Exacerbation Cycle? Mepolizumab Gains Ground.

In patients with eosinophilic COPD, mepolizumab cut moderate-to-severe flare-ups by up to 21 percent.

In patients with eosinophilic COPD (blood eosinophils ≥300 cells/μL) who continued to experience exacerbations despite inhaled triple therapy, mepolizumab significantly reduced flare-ups. The MATINEE trial, involving over 800 patients, showed a reduction in moderate or severe exacerbations with monthly subcutaneous mepolizumab (100 mg) compared to placebo (0.80 vs 1.01 events/year, RR 0.79; 95% CI 0.66–0.94; P=0.01). While lung function and symptom scores did not improve, the reduction in emergency visits and hospitalizations suggests meaningful clinical benefit.

The FDA approved mepolizumab (Nucala) in 2025 as an add-on for COPD with an eosinophilic phenotype, expanding treatment options beyond asthma. It is the first biologic approved for COPD in patients with a blood eosinophil count of at least 150 cells/μL, a group representing over 1 million US patients who remain uncontrolled on inhalers alone. Dupilumab has also shown benefit in this population but lacks direct head-to-head comparison.

Source: GSK

A Weekly Revolution: Basal Insulin Simplified with Efsitora.

Efsitora matches daily insulins in HbA1c control—while cutting hypoglycemia by 43%.

In three major phase III QWINT trials, once-weekly insulin efsitora proved non-inferior to daily basal insulin regimens for adults with type 2 diabetes. In QWINT-1, insulin-naïve participants saw HbA1c drop from 8.2% to 7.05%, closely matching results with daily insulin glargine. In QWINT-3, those switching from basal insulin alone had nearly identical reductions in HbA1c compared to insulin degludec. Similarly, QWINT-4 showed efsitora to be as effective as glargine in patients using both basal and prandial insulin.

At week 52, total insulin use was lower in the efsitora group (289 U/week vs 333 U/week), and rates of hypoglycemia were 43% lower than with glargine. Most patients remained on fixed weekly doses, suggesting straightforward titration and potentially better adherence.

With efficacy on par with daily insulins, fewer hypoglycemic events, and a simplified regimen, efsitora could reshape insulin therapy, especially for patients delayed by complexity or injection burden.

Source: THELANCET

The 4-Day Window: DOACs Post-Stroke Now Backed by Strongest Evidence Yet.

CATALYST meta-analysis shows early initiation cuts stroke recurrence without added bleeding risk

In a breakthrough meta-analysis pooling over 5,400 patients from the TIMING, ELAN, OPTIMAS, and START trials, researchers found that starting direct oral anticoagulants (DOACs) within 4 days of an acute ischemic stroke in Afib patients significantly reduced stroke recurrence (2.1% vs 3.0%, OR 0.70), with no increase in symptomatic intracerebral hemorrhage (0.4% in both arms).

The benefit held steady across stroke severities, prior anticoagulant use, and use of thrombolysis. Median time to DOAC start was 3.0 days in the early group. Despite trial heterogeneity and limits in severe stroke representation, the findings strongly support early DOAC use as routine practice in most mild-to-moderate stroke cases.

Source: THELANCET

Methotrexate Rivals Prednisone for Pulmonary Sarcoidosis in First-Line Setting.

PREDMETH trial supports methotrexate as a less toxic, noninferior alternative for initial treatment

The randomized PREDMETH trial found that methotrexate was noninferior to prednisone for first-line treatment of symptomatic pulmonary sarcoidosis, with similar improvements in FVC over 24 weeks (6.1% vs 6.7%) and comparable quality-of-life scores. While prednisone acted faster, methotrexate caught up by week 24, and had a different side effect profile—less weight gain and insomnia but more GI upset and liver enzyme elevations.

These findings challenge the long-standing prednisone-first approach, especially for patients without urgent symptom relief needs. About 14% in both groups switched therapies due to adverse events. Experts suggest a potential hybrid strategy—brief prednisone induction followed by methotrexate maintenance—to balance efficacy with safety.

Source: NEJM

Resident’s Radar

The PGY-2 Playbook: 7 Strategies to Lead, Learn, and Thrive

Transitioning from intern to senior: What every second year resident should know

As July marks a new beginning for PGY-2s, the shift in responsibilities can feel both exciting and overwhelming. You’re no longer the intern. You're the go-to person for your team, your interns, and often the floor. Here’s a refined look at how to own this role with confidence, clarity, and resilience.

1. Know Your Limits
PGY-2 brings more autonomy, but also burnout risk. Satisfaction drops, stress spikes. Prioritize safety, learning, and rest. You can’t do it all.

2. You’re Still in Training
You’re not expected to know everything. What matters is knowing when and whom to ask.

3. Delegate Wisely
You’re no longer the workhorse. Teach interns, trust them, and gradually step back. Supervise, don’t micromanage.

4. Use Your People
Your co-residents, chiefs, pharmacists, and social workers are essential. Ask, text, check in. You’re not alone.

5. Ask for Feedback
Refine your teaching and leadership by asking what’s working and what isn’t. Interns and attending’s will help if you ask.

6. Communicate Like a Leader
Build real time relationships with the team. Others will look to you for plans, updates, and direction.

7. Don’t Hesitate to Call
When in doubt, call your attending. Patient safety always comes first.

Source: AMA

Upcoming Events & Deadlines

1. CHEST 2025: 19-22 October, 2025 - Chicago

2. IDWeek 2025 : October 8 - 12, 2025 - Philadelphia

3. ACP Arizona 2025: Oral Vignettes Competition - Deadline September 14