#488 DIGEST: Cytisinicline for smoking cessation, partner treatment for BV, combination therapy with statins and ezetimibe, and exercise and survival in colon cancer

June 23, 2025 | By Nora Taranto

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Join us as we review recent practice-changing articles on the effect of combination statin and ezetimibe in reducing myalgias, male partner treatment for BV, semaglutide for MASH/liver fibrosis, exercise and cancer risk, and cytisinicline for smoking cessation. Fill your brain hole with some delicious apps and entrees from our spring Digests! Featuring Paul Williams (@PaulNWilliamz), Nora Taranto (@norataranto), special guest epidemiologist Alexander Chaitoff (@alexchaitoff) and Matt Watto (@doctorwatto).

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Show Segments

• Intro, disclaimer
• Self-collected HPV tests for cervical cancer screening 
• Semaglutide for MASH/Liver Fibrosis
• Male Partner Treatment for BV 
• Statins plus ezetimibe versus high-dose statins alone for statin-associated muscle symptoms 
• Exercise and Colon Cancer Risk 
• Cytisinicline for Smoking Cessation 
• Outro

Apps

Home self-test kits for Cervical Cancer Screening 

Covered by Dr. Beth Garbitelli, DIGEST #65 

Exciting cancer screening news–a wand-shaped tool (brand name: Teal Wand) just received FDA approval for self-collected, at-home cervical cancer screening. Cervical cancer is one of the most preventable cancers, thanks to both screening tests and the human papillomavirus (HPV) vaccine. But screening uptake has remained a challenge (especially since the pandemic). And per NCI, about half of US cervical cancer cases are diagnosed in patients who report never or infrequent screening. The Teal Wand device (price TBD) operates a bit like a tampon, with a retractable sponge tip that collects a sample for HPV testing–with a telehealth service to review use and test results.  Data reviewed by the FDA comes from the industry-funded Self-CERV study, which showed similar test performance of the Teal Wand’s self-collected samples to clinician-collected samples, and patient preference for self-collection at home. Other studies have also increasingly demonstrated the efficacy of at-home HPV collection kits (Arbyn 2022, Inturrisi 2021), and the ongoing SHIP trial will provide essential information about clinical validity and utility of self-collection compared to clinician-collection. (BG)  

Cohost comments: This is likely to meaningfully lower barriers to cervical cancer screening access.

Once weekly semaglutide in MASH/ liver fibrosis 

Covered by Dr. Alyssa Mancini, DIGEST #65

NEJM recently published the results of a planned interim analysis of ESSENCE, a phase 3, multicenter, randomized, placebo-controlled trial of 1197 patients with biopsy-proven metabolic dysfunction-associated steatohepatitis (MASH) and moderate or advanced liver fibrosis (stage 2 or 3). Patients were randomized (2:1) to receive once-weekly subcutaneous semaglutide 2.4mg or placebo for 240 weeks. This interim analysis assessed liver biopsy results at week 72 for the first 800 randomized patients. Resolution of steatohepatitis without worsening of fibrosis occurred more with semaglutide (62.9% with semaglutide vs 34.3% with placebo, estimated difference 28.7%, 95% CI 21.1 to 36.2, p<0.001). Reduction in liver fibrosis occurred in 36.8% of those receiving semaglutide (compared to 22.4% with placebo). Combined resolution of steatohepatitis and liver fibrosis reduction (a secondary outcome) occurred more with semaglutide (32.7% vs 16.1% with placebo). Greater change in body weight occurred with semaglutide (-10.5%  vs -2.0% with placebo), and gastrointestinal adverse events occurred more frequently with semaglutide.  

Cohost Comments: This is yet another study that seems to demonstrate the metabolic benefits of GLP-1 agonists across multiple organs and disease processes. It’s worth noting that a majority of patients in this study did also have cardiometabolic comorbidities, for which there’s also documented benefit. Patients with cirrhosis were not included in this study and will be an important endpoint–Part 2 of this study will report cirrhosis-free survival (and progression to cirrhosis).

Entrees

DIGEST #1 Male-Partner Treatment for BV (Paul)

Vodstrcil LA, et al; StepUp Team. Male-Partner Treatment to Prevent Recurrence of Bacterial Vaginosis. N Engl J Med. 2025 Mar 6;392(10):947-957. doi: 10.1056/NEJMoa2405404. PMID: 40043236. 

High-Yield Summary by Dr. Beth Garbitelli in Digest #63:   

Bacterial Vaginosis (BV) is a challenging common concern in primary care patients, often with frequent recurrences and frustrating symptoms. An open-label RCT published in NEJM offers a new paradigm to co-treat male partners of female patients with BV.  Standard of care first line treatment for female patients (no partner treatment) was compared to standard of care plus male partner treatment with oral metronidazole (twice daily x 7 days) and topical clindamycin to apply to the penis and foreskin (twice daily x 7 days). Couples were instructed to avoid sexual contact during the treatment period, and only women in a monogamous relationship with a male partner were eligible. Due to the reduction in BV recurrence with partner treatment at 12 weeks (35% recurrence rate in partner treated dyads versus 63% recurrence in female-only treatment, with an absolute reduction of -2.6 recurrences per person year), the study was stopped early! It is notable that the control group did not receive sham penile cream, due to concerns it might alter skin flora. 

Additional Details, Cohost Comments, and Limitations:

The stats are pretty crazy – BV affects a third of reproductive aged women and has a high risk of recurrence.  Prior studies have failed to show that oral antibiotics alone in male partners improve rates of cure (and reduce recurrence)–but these studies have been limited in statistical power, size, and adherence.  Premenopausal women were screened if they had symptoms and met diagnostic criteria for bacterial vaginosis (3 of 4 Amsel criteria and a Nugent score of 4 to 10).  Women who met criteria were asked to refer their male partner. The couple could enroll if the male partner could enroll within a week after their female partner’s enrollment.  All participants had to be over 18 years of age, understand English, not have other partners at enrollment, not be sex workers, and not be known to have HIV.   Couples assigned to treatment were asked to synchronize their treatment, and male partners in the control group were offered treatment if there was recurrence.  Questionnaires and vaginal samples were collected at weeks 4 and 12 in the clinic, and at home on day 8 and week 8.  The primary outcome was recurrence of vaginosis defined by Amsel criteria and Nugent score.  81 couples were assigned to the treatment and 83 to control groups.  14% of men in the treatment group reported taking less than 70% of prescribed medication.  No serious adverse events were reported.

So is BV now considered a sexually transmitted infection? There isn’t a test for men that is routinely used, and this study did not require testing of male partners–all male partners were empirically treated on the partner-treatment arm. And while BV has typically been categorized as dysbiosis, this study’s results do suggest an infectious component, transmitted from the partner.  The Editorial accompanying the article confirms this framework shift. 

Limitations: This was an open label study, allowed crossover, and follows prior negative studies in this space, so would be worth validating in another study.  The study enrolled only monogamous female-male partner pairs, and did not include female-female partner pairs, so it is unclear how and whether this topical-oral regimen should extend to other pairs.  The patients studied were also higher risk at baseline.  About 80% of male partners were uncircumcised, and participants also had fairly high IUD use–both of which increase risk for BV.  This higher risk population might explain why the addition of topical treatment yielded results.  Given this higher risk population, it’s unclear how exactly this would translate into partner-based treatment for all women with BV who are sexually active.

Bottom line (Is this practice changing?):  Neat study that provides an additional tool in high-risk individuals. It ultimately remains unclear how this will be incorporated into guidelines, and what the antimicrobial resistance risks are with this sort of empiric partner-based therapy. 

Additional Reading: Treatment of Male Sexual Partners of Women With Bacterial Vaginosis: A Randomized, Double-Blind, Placebo-Controlled Trial 

DIGEST #2 Statin plus Ezetimibe (Watto)

Cha JJ, et al. Safety and efficacy of moderate-intensity statin with ezetimibe in elderly patients with atherosclerotic cardiovascular disease. J Intern Med. 2025 Apr;297(4):400-408. doi: 10.1111/joim.20029. Epub 2024 Dec 22. PMID: 39709592. 

High-Yield Summary by Josh Gilman (DIGEST #65) 

Combination lipid-lowering therapy – better than a statin alone? A moderate-intensity statin + ezetimibe may lead to fewer statin-associated muscle symptoms (SAMS) and similar LDL target achievement compared to high-intensity monotherapy, according to the SaveSAMS trial, just published in  J. Intern. Med. This prospective, multicenter, open-label trial in South Korea randomized 561 statin-naïve adults > age 70 with atherosclerotic cardiovascular disease (ASCVD) to rosuvastatin 5 mg + ezetimibe 10 mg (combination group) or rosuvastatin 20mg (high-intensity), with a primary outcome of positive SAMS (defined as a score of >7 on the statin myalgia clinical index, including myalgias, cramps, stiffness, and weakness) at 6 months. The combination group experienced a lower incidence of SAMS compared to the high-intensity group (0.7% vs. 5.7%; OR 0.12; 95% CI, 0.03-0.53; p=0.005). Secondary outcomes were notable for similar rates of LDL-target achievement and a lower rate of new-onset diabetes with combination therapy. (JG) 

Additional Details, Cohost Comments, and Limitations:

Yet again, this was an open-label study, with a relatively subjective primary outcome (symptoms from statins), which are widely known about. So this may be a limitation. Another question is about whether this was the perfect patient population for this study, as these weren’t necessarily adults who hadn’t tolerated a statin, and instead were adults who did have ASCVD for whom guidelines would likely have recommended a high-dose statin. On the other hand, the patients were older (>70)–so they may both be more likely to get myalgias–but also are at risk of polypharmacy.  

Another limitation – the combination pills still have limited availability.  The follow up was short, and the primary endpoint also wasn’t a hard cardiovascular clinical endpoint, which limits interpretation as well. 

This ezetimibe/moderate-intensity statin combination does potentially provide another tool to use, if patients need cardiovascular risk reduction but don’t want to take a high-intensity statin or aren’t able to obtain PCSK9s. It may be most useful for a patient who is not tolerating a statin or not at goal and don’t want to go up to high-dose statin therapy–though if they are high risk (e.g. had an event), it would still be hard to argue against PCSK9 inhibition. 

Bottom line (Is this practice changing?): Sort of. LDL-C is a surrogate endpoint, and their primary endpoint was statin-associated muscle symptoms, so we don’t know for sure that the combination of statin and ezetimibe has the same reduction in MACE vs high-intensity statin. That said, I have been using more low- to moderate-intensity statins for patients who are worried about muscle symptoms and adjusting the dose up or down based on symptoms and LDL response. For patients who do not reach their LDL goal on a statin alone, cannot tolerate a higher-intensity statin, and do not want or cannot afford a PCSK9 inhibitor, I will add ezetimibe or prescribe a statin-ezetimibe combination pill (if affordable). 

Additional Reading: 

Editorial by Mats Eriksson

DIGEST #3 Exercise and Colon Cancer (Nora)

Courneya KS, et al; CHALLENGE Investigators. Structured Exercise after Adjuvant Chemotherapy for Colon Cancer. N Engl J Med. 2025 Jun 1. doi: 10.1056/NEJMoa2502760. Epub ahead of print. PMID: 40450658. 

High Yield Summary (To Be Written Up in a Future Digest): CHALLENGE was an international, phase 3 randomized trial comparing a 3-year structured exercise program plus health-education materials to health-education materials alone after adjuvant chemotherapy for colon cancer. Patients had either high-risk stage II colon cancer (10%) or stage III colon cancer (90%), had undergone complete resection and finished adjuvant chemotherapy within the past 2-6 months. Patients had to have an ECOG performance status of 0 or 1, report < 150 minutes per week of moderate-to-vigorous intensity exercise, and be able to complete 2 stages of the submaximal treadmill test or the 6-minute-walk test. The primary endpoint was disease-free survival (DFS), defined as time from randomization to the first colorectal recurrence (local/distant), new colorectal primary, second primary cancer, or death from any cause.  889 individuals were randomized (mostly in Canada and Australia) between 2009 and 2024 to the exercise or health-education arms. The median age was 61, with 51% women and 90% stage III disease, and participants reported 11.5 MET-hours per week of moderate-to-vigorous physical activity at baseline.  At a median follow-up of 7.9 years, there was significantly longer DFS with exercise than with health-education alone (80.3% vs 73.9%, HR 0.72, 95% CI 0.55-0.94, p=0.02, NNT of 16).  Overall survival (OS) also appeared longer in the exercise group (8-y OS 90.3% vs 83.2% with HEM, HR 0.63, NNT 14-15). There were no significant differences in waist circumference or body weight, though participants did report more exercise in the exercise arm.  Adherence to the exercise program was 79% in phase I (6 months, mandatory supervised exercise), 54% in phase 2 (6 months, recommended supervised exercise),and 44% in phase 3 (2 years, recommended supervised exercise).   

Additional Details, Cohost Comments, and Limitations:

This is a great example of a headline grabbing study, with a large apparent effect size (as John Mandrola noted in his piece on Sensible Medicine). And most of us would agree that exercise is good for you. But the effect size, an absolute benefit of around 7% for both DFS and OS, is quite large, and similar to absolute benefits with game-changing therapies such as trastuzumab for breast cancer.  The structured exercise program was labor-intensive, and included 3 phases, with support from a physical activity consultant for 3 years–with the first 6 months including 12 mandatory behavioral support + supervised exercise sessions, the next 6 months including 12 mandatory behavioral support sessions and recommended supervised exercise sessions, and the last 2 years including 24 monthly behavioral-support sessions plus recommended supervised exercise sessions. The goal of this intervention was to increase activity by 10 MET hours per week above baseline (a.k.a. 2.5 hours of moderate intensity exercise weekly, like brisk walking).   

Studying something like exercise (something without significant industry funding), can be challenging, so it’s impressive that this study was completed.  And the curves do separate after a reasonable length of time, so it’s not as if one group was much sicker (or different) from the start than the other.  But it took a really long time (around 15 years) to recruit these patients. And this standardized exercise program, which is described in detail in the supplement, appeared quite labor-intensive to administer.  There were also limited physiologic and metabolic changes in the patients in the standardized exercise program compared to the control arm (e.g. no significant differences in waist circumference or body weight)–so what exactly the intervention was doing remains unclear.   And, as noted by resident expert epidemiologist Rahul Ganatra, reverse causality could explain some of the effect – are people with less severe disease better able to exercise, or does exercise cause less severe disease?  Lastly, we also know from other prevention programs like the diabetes prevention program that even when there is good evidence of benefit, patient uptake and retention remains low.  So it may be challenging to figure out how exactly to implement this approach–and what exactly the “special sauce” is to take away from this specific exercise intervention.  

That said, recommending exercise in and around cancer-related treatments (even before surgery, in a “prehab” phase)–and even if the effect size is smaller than what was noted–seems like a simple intervention with possible benefit across multiple disease physiologies, for patients who are trying to maintain fitness and regain fitness going into, during, and after chemotherapy and surgery.  

Bottom line (Is this practice changing?):  It seems recommendation-affirming, but not practice-changing–with significant barriers to actually implementing the program described in the trial. This study took a huge amount of effort to design, implement, and complete, and lends some of the first randomized, long-term data to this question.  But limitations with the slow accrual, external generalizability to more frail populations, possible measurement bias and reverse causality leading to large observed effect sizes, and adherence to the protocol give me pause as to how to interpret these seemingly substantial improvements in DFS and OS. That said, I already recommend exercise to my patients with cancer as a general way to improve health, tolerate therapy better, and possibly reduce cancer recurrence (colorectal, breast)–acknowledging the limitations of the data at hand. 

Additional Reading: 

Sensible Medicine (Substack) commentary by John Mandrola. Here’s one quote, “While I want this story to be true, there are at least seven reasons to be cautious. “

DIGEST #4: Cytisinicline for Smoking Cessation (Alex)

Rigotti NA, et al. Cytisinicline for Smoking Cessation: The ORCA Phase 3 Replication Randomized Clinical Trial. JAMA Intern Med. 2025 Jun 1;185(6):648-655. doi: 10.1001/jamainternmed.2025.0628. PMID: 40257755; PMCID: PMC12012700. 

High-yield Summary by Laura Glick (DIGEST #65): 

A new smoking cessation medication! The ORCA-3 phase III clinical trial was a double-blind, randomized, placebo-controlled trial evaluating the efficacy and tolerability of cytisinicline for smoking cessation. Just published in JAMA Intern Med, this study randomized 792 adults who smoked at least 10 cigarettes daily and sought to quit smoking to 12 weeks of cytisinicline, 6 weeks of cytisinicline followed by 6 weeks of placebo, or 12 weeks of placebo. All groups received behavioral support. The primary outcome was biochemically verified continuous smoking abstinence (verified by weekly carbon monoxide levels <10ppm) during the last 4 weeks of treatment. Cytisinicline led to smoking abstinence more frequently than placebo for both the 6- and 12-week cytisinicline groups (15% with cytisinicline versus 6% with placebo for the 6-week treatment group comparison, p<0.001, and 30% vs. 9% for the 12-week treatment comparison, p<0.001). Participants who received cytisinicline had reduced cravings and were also more likely to be abstinent at 24 weeks. The drug was well-tolerated with no serious adverse events in the treatment group. Following these results and a separate randomized trial from May 2023, cytisinicline is expected to be submitted for FDA approval in June 2025. 

Additional Details, Cohost Comments, and Limitations:

One question that remains is the long-term effect of this agent, and what the optimal treatment duration will be (typically, with varenicline, it’s 12 weeks). The abstinence rate went up from 6 to 12 weeks, and they only published data to 24 weeks.  This medication does seem to work, and we now have multiple trials showing it. So, on the one hand, it would be great to have a new agent in our toolbox.  And this agent is cheap in European countries, but it’s unclear how cheap this drug will be in the United States. Even though varenicline is no longer on-patent and there are generic versions of varenicline available, it is still pretty costly for a single course (over 600 per month without insurance and still hundreds if you use Medicare Part D or Medicare Advantage Drug Plans). But keep in mind there are pharmacy discount coupons that decrease the cost of many of these agents. 

One limitation of this study is that the comparison was placebo, not an active comparator such as varenicline or bupropion (which have demonstrated similar efficacy).  It would have been interesting to see this agent tested against something with a different mechanism of action (or against varenicline, which has a similar mechanism of action, in a blinded study) to tell us whether cytisinicline should be the go-to choice for smoking cessation.  It also remains unclear how any of these agents work for vaping cessation, which is the new frontier of smoking/tobacco cessation. 

Abnormal dreams and insomnia occurred in a small minority of patients for both varenicline and with this novel agent – so those side effects should be discussed. It’s also worth noting that the dosing for this agent is 3 times daily, which may be more burdensome to patients (though down from 6 times a day in prior trials).  But overall, even varenicline is still under-offered to patients, so having a new agent may serve as a good reminder that there are smoking cessation tools available besides nicotine replacement therapy.  

Bottom line (Is this practice changing?): Is the addition of rosuvastatin vs atorvastatin or esomeprazole vs omeprazole to the formulary practice changing? I suppose so by definition (all these medications are widely used despite being the same mechanism of action), and so I suppose this may be too. But the medication is likely just another version of varenicline, not a new top performer. The bottom line is really just get somebody on smoking cessation medication. If the idea that this is “natural” helps patients, or if they like the reminder to take it three times a day as a ritual, great. But there isn’t evidence this is a drug that is somehow more effective than what we already have. 

Additional Reading: 

-The FDA initially wanted more safety data, which is why this hasn’t been approved yet. 

Links

Links are included in the show notes above.

Goals

Listeners will review recent practice-changing articles and medical news.

Learning objectives

After listening to this episode listeners will…

1. State the study design of the latest clinical trial comparing cytisinicline to placebo for smoking cessation
2. Identify limitations of the study comparing exercise to health-education materials alone in reducing colon cancer recurrence risk
3. Discuss the evidence supporting the use of moderate-intensity statin and ezetimibe compared to high-intensity statin in older adults with ASCVD. 

Disclosures

Dr Wiliams  reports financial relationship with Merck for grant or research support. Dr Chaitoff  reports financial relationship with  Alosa Health for Consulting. Other Curbsiders members report no relevant financial disclosures. 

Citation

Taranto N, Chaitoff A, Williams PN, Watto MF. “#488 DIGEST: Cytisinicline for smoking cessation, partner-treatment for BV, combination therapy with statins and ezetimibe, and exercise and survival in colon cancer ”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list Final publishing date, June 23, 2025.