Knee osteoarthritis (OA) is caused and worsened by obesity, as both mechanical stress and obesity-induced inflammation accelerate joint destruction. Weight loss improves knee OA, with studies showing a 2% improvement in the WOMAC pain, function, and stiffness scores for every 1% reduction in body weight. To evaluate the effects of Wegovy-induced weight loss on knee OA (based on clinical and X-ray findings), researchers randomized 407 patients (82% female | average age 56) with a BMI of 30 or greater and moderate knee OA to Wegovy (target dose 2.4 mg/week) or placebo. The primary outcomes were percent change in body weight and change in the WOMAC pain score (scale 0 - 100, with higher scores meaning worse outcomes) at week 68. At baseline, the average BMI was 40.3 and the average WOMAC score was 70.9. After 68 weeks, the percent decrease in body weight was 13.7% in the Wegovy group and 3.2% in the placebo group (p<0.001). Reductions in the WOMAC pain score were superior with Wegovy (41.7 vs 27.5, p<0.001), as were measures of knee function. Drug discontinuations due to adverse events were slightly higher in Wegovy-treated patients (6.7% vs 3%) [Full trial summary].

As expected, Wegovy-induced weight loss improved knee pain and function in a predominantly female population (82%) with moderate knee OA. A missed opportunity in the study was the absence of follow-up imaging to assess for changes in joint pathology.

Wegovy and Zepbound continue to rack up positive studies, as the health benefits of significant weight loss are profound. Other obesity-related conditions improved by GLP therapies include heart failure with preserved ejection fraction, cardiovascular disease, nonalcoholic steatohepatitis, and obstructive sleep apnea.

• Wegovy review
• Article with full trial summary

Orlynvah, a combination of sulopenem and probenecid, was recently approved to treat uncomplicated female UTIs. Sulopenem is a beta-lactam antibiotic in the penem class that inhibits bacterial cell wall synthesis. Probenecid inhibits renal organic anion transporter 3 (OAT3), reducing sulopenem clearance and increasing its exposure. Orlynvah was compared to ciprofloxacin (250 mg BID for 3 days) in 1671 women with acute uncomplicated UTI. The primary endpoint - resolution of UTI symptoms and a urine culture showing less than 10³ CFU/mL of the culprit bacteria at day 12 - occurred in 65.6% of the sulopenem group and 67.9% of the ciprofloxacin group (diff -2.3%, 95%CI [-7.9 to 3.3]). In the subgroup of patients with ciprofloxacin-resistant bacteria, cure rates were 62.6% and 36%, respectively (p<0.001). [PubMed abstract]

Orlynvah is dosed as one tablet with food twice daily for 5 days. Common side effects include diarrhea (10%) and nausea (4%). Drug interactions, which are related to probenecid's OAT1/3 inhibition, include ketorolac, ketoprofen, indomethacin, naproxen, methotrexate, rifampin, lorazepam, and sulfonylureas.

Orlynvah is considerably more expensive than available therapies, creating issues with insurance coverage and affordability that likely limit its use to cases of multidrug-resistant bacteria. However, sulopenem is not a part of standard urine culture sensitivity reports. Imipenem, a carbapenem related to sulopenem, is often included and may be used as a surrogate marker of sulopenem sensitivity, with the understanding that cross-sensitivity between the drugs has not been validated in a study.

Orlynvah is the second new drug approved for UTIs in 2024. Pivmecillinam (Pivya), a penicillin antibiotic, was approved in April; however, it was discontinued by the manufacturer shortly after its approval for reasons that are unclear.

• Orlynvah prescribing information
• Urinary tract infection treatment recommendations
• Article on webpage

The FDA recently approved Cologuard Plus, the next generation of the Cologuard fecal DNA test used to screen for colon cancer. Cologuard Plus includes a new molecular panel intended to improve the test's specificity (i.e., fewer false positives). Like the original Cologuard test, a fecal immunochemical test (FIT) is performed with the DNA assay. If either test is positive, results are deemed positive without details on the individual tests. Cologuard Plus was evaluated in the BLUE-C cohort study, where 20,176 participants 40 years and older (average age 63 years) took the test before undergoing screening colonoscopy. The original Cologuard test was evaluated in a similar study published in 2014. A comparison of how the two tests performed is presented in the table below.

• PMID 38477986, PMID 24645800

Measure	Cologuard	Cologuard Plus
Colorectal cancer (Sensitivity)	92.3%	93.9%
Colorectal cancer (Specificity)	89.8%	92.7%
Precancerous lesion (Sensitivity)	42.4%	43.4%

While the absolute difference in specificity may seem small (2.9%), when applied to a large screening population, the improvement is meaningful. Consider the following: Since its launch in 2014, over 16 million Cologuard tests have been processed. Assuming 2 million tests are performed annually on a population with a colorectal cancer prevalence of 0.3%, an improvement in specificity of 2.9% equates to 57,826 fewer false positives (and follow-up colonoscopies) per year. On the sensitivity side, a 1.6% improvement means 96 fewer cancer cases will be missed. Presumably, the manufacturer, Exact Sciences, will now phase out Cologuard and replace it with Cologuard Plus.

• Colon cancer screening recommendations (average-risk)
• Colon cancer screening recommendations (increased-risk)
• Article and table on webpage

Patients with atrial fibrillation (AF) and coronary artery disease (CAD) have indications for both an anticoagulant and an antiplatelet agent. Past guidance on managing these patients was indecisive. In 2019, the AFIRE study was published, which found that anticoagulant monotherapy was equally effective and safer than dual therapy (anticoagulant + antiplatelet). A second study addressing this issue was recently published. In the EPIC-CAD study, 1040 patients with AF and stable CAD were randomized to edoxaban monotherapy or dual therapy (edoxaban + aspirin or P2Y12 inhibitor). After 12 months, major ischemic events were similar between groups (edoxaban 1.6%, dual therapy 1.8%), while major bleeding or clinically relevant nonmajor bleeding was higher with dual therapy (4.7% vs 14.2%).

After AFIRE was published, AHA guidelines recommended anticoagulant monotherapy in AF with stable CAD, and EPIC-CAD supports this guidance.

I still encounter patients who are taking aspirin with anticoagulants. Since aspirin is not prescribed, providers sometimes forget to ask about it. Likewise, patients forget to report it. When initiating anticoagulants, it is important to take a moment and discuss antiplatelet agents with patients, including OTC NSAIDs like ibuprofen and naproxen. Conditions where dual therapy may still be recommended include AF with recent cardiac stent placement and a subgroup of patients with mechanical heart valves.

• EPIC-CAD - Edoxaban vs Dual Therapy in AF and CAD, NEJM (2924) [PubMed abstract]
• Antiplatelet therapy in CAD

Finerenone (Kerendia®), a nonsteroidal mineralocorticoid receptor antagonist (MRA) approved for diabetic kidney disease, was recently evaluated in heart failure with preserved ejection fraction (HFpEF). The FINEARTS-HF trial randomized 7463 patients with symptomatic heart failure and an EF of 40% or more to finerenone 20 - 40 mg/day or placebo. After a median of 32 months, the primary outcome, a composite of heart failure events and death from CVD causes, was lower in the finerenone group (14.9%/year vs 17.7%/year, p=0.007). There was no significant difference in overall mortality (16.4% vs 17.4%), while hyperkalemia (14.3% vs 6.9%) and hypotension (18.5% vs 12.4%) were more common in finerenone-treated patients.

Finerenone blocks aldosterone receptors in the renal collecting duct, similar to spironolactone and eplerenone. Spironolactone was studied in patients with HFpEF in the TOMCAT study (N=3445), where it reduced heart failure hospitalizations (12% vs 14.2%, p=0.04) but did not achieve significance for the primary outcome, a composite of CVD events (18.6% vs 20.4%, p=0.14). However, a post-hoc analysis that excluded data from Russia and Georgia, where events were unusually low, found a significant benefit for the primary outcome.

The ACC 2023 HFpEF guidelines recommend spironolactone or eplerenone in most patients with volume overload. Finerenone appears to provide a similar benefit with the drawback of no generic and higher cost. Regardless of the MRA used, patients should be monitored closely for hyperkalemia and hypotension.

• Finerenone (Kerendia®) review
• Heart failure review