Eli Lilly's tirzepatide received a much-anticipated weight loss indication, making it the third GLP drug approved for obesity; Saxenda was approved in 2014 and Wegovy in 2021. In its pivotal study, tirzepatide caused an average weight loss of 21% at its highest dose (15 mg), which is greater than that seen with Wegovy (16%) and Saxenda (8%). The diabetes version of tirzepatide is Mounjaro, while the weight-loss version will be marketed as Zepbound. Both drugs have the same prescribing information, with identical dosage forms and dosing ranges.

Given the popularity of Wegovy, Zepbound is sure to be a blockbuster. Hopefully, Eli Lilly is more prepared than Novo Nordisk, which has been unable to meet Wegovy demand, leaving many patients in limbo.

These highly-effective weight loss medications are on track to become one of the biggest drug classes ever. Right now, insurance coverage and costs are barriers for many. But oral versions are coming down the pipeline, which will help lower prices through competition and cheaper manufacturing.

• Tirzepatide (Zepbound®) review
• Weight loss review

Emergency contraception, also known as the morning-after pill, can be taken up to five days after unprotected intercourse to help prevent pregnancy. A common regimen is a single 1.5 mg dose of levonorgestrel, marketed as Plan B One-Step® and available over the counter to anyone 17 and older.

NSAIDs, which block prostaglandins necessary for ovarian follicle rupture, have been shown to inhibit ovulation in studies. A recent trial (N=860) published in the Lancet found that adding a single 40 mg dose of the long-acting NSAID piroxicam (half-life 50 hours) to levonorgestrel 1.5 mg within 72 hours of unprotected intercourse lowered the absolute risk of pregnancy by 1.5% (1 vs 7 pregnancies, 0.2% vs 1.7%, p=0.036).

While the absolute risk reduction was only 1.5%, when talking about unwanted pregnancies, the consequences are life-changing. Most emergency contraception is obtained over the counter, and piroxicam is only available by prescription. The question then arises as to whether an OTC NSAID like naproxen would have the same effects. One can't say for certain, but naproxen is generally safe in young, healthy patients, so advising women to take it for 3 - 4 days with levonorgestrel seems prudent, given the potential benefit.

• Levonorgestrel + Piroxicam for Emergency Contraception, Lancet (2023) [PubMed abstract]
• Oral contraceptive review

Abrysvo, a new RSV vaccine recently approved in adults 60 and older, has received an indication in pregnancy to prevent RSV infections in newborns. It is the second therapy in recent months approved for this purpose; the antibody nirsevimab (Beyfortus) discussed below is the other treatment. The effects of Abrysvo were evaluated in a randomized controlled trial (N=7358) detailed at the link below.

• Abrysvo in pregnancy for RSV prevention in newborns
• RSV infection review
• RSV vaccines in adults 60 and older

Testosterone replacement therapy (TRT) has become its own industry, with providers and clinics dedicated solely to its promotion and distribution. Randomized trials evaluating long-term TRT effects are lacking, and the risks of potential adverse events (e.g. prostate cancer, thromboembolism) are mostly unknown. Cardiovascular disease (CVD) is a significant concern, as TRT has been shown to accelerate atherosclerosis in small studies. To evaluate the effects of TRT on CVD events, the TRAVERSE study randomized 5246 men with testosterone levels < 300 ng/dl and established CVD or multiple CVD risk factors to testosterone gel (titrated to serum level of 350 - 750 ng/ml) or placebo. After an average follow-up of 33 months, the incidence of the primary outcome, a composite of CVD events, was similar between groups (TRT - 7%, Placebo - 7.3%).

This study was framed as positive and "reassuring" by many news outlets and TRT proponents, but it has limitations. The average treatment period was only 22 months, and the median testosterone level in the TRT group was 371 ng/dl, meaning half of the participants were below or at the bottom of the target range. Furthermore, arrhythmia requiring intervention (5.2% vs 3.3%), atrial fibrillation (3.5% vs 2.4%), and acute kidney injury (2.3% vs 1.5%) occurred significantly more in the TRT group. The effects of TRT on hypogonadism symptoms (e.g. ED, mood, libido) were also analyzed, and those findings will be released in a future publication. Sixty-one percent of TRT-treated patients discontinued their therapy early, so it will be interesting to see what those results show.

• Low testosterone
• Testosterone replacement therapies

Colchicine, an antiinflammatory drug used for decades to treat gout, was recently approved to prevent CVD events in patients with established CAD or multiple CAD risk factors. Approval was based on the LoDoCo2 trial where 5522 patients with stable CAD were randomized to colchicine 0.5 mg once daily or placebo. After a median follow-up of 29 months, a composite outcome of cardiovascular events (MI, CVD death, stroke, revascularization) occurred in 6.8% of the colchicine group and 9.6% of the placebo group (difference 2.8%, p<0.001). A similar study ( COLCOT trial | N=4745) had comparable findings in patients with recent MI (5.5% vs 7.1%, difference 1.6%, p=0.02).

Colchicine had a modest effect on CVD in the LoDoCo2 and COLCOT trials, reducing the absolute risk of CVD events over 2 - 3 years by 1 - 3%. It had no significant effect on mortality in either trial, and noncardiovascular death was higher in colchicine-treated patients in the LoDoCo2 trial (1.9% vs 1.3%, HR 1.51 95%CI [0.99 - 2.31]); the reason for this is unclear, as there were no apparent trends in the individual causes of death. Colchicine side effects, including diarrhea, were similar to placebo, and an increased risk of myopathy from combining colchicine with statins - a common drug interaction warning - was not observed.

Colchicine for CVD prevention may be a logical option for certain high-risk CVD patients, particularly those with gout; however, the increased risk of noncardiovascular deaths in the LoDoCo2 trial is concerning. The 0.5 mg dose, which has been given the trade name Lodoco, is not available yet, but the 0.6 mg dose is widely prescribed and has a cheap generic.

• Colchicine for CVD prevention