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#418 DIGEST (Tofurkey Edition): Semaglutide for HFpEF,  TCAs for IBS, Aspirin vs Clopidogrel after PCI, Pitavastatin for HIV, Starchy Vegetables & Weight Gain, Heavy Metals in Cannabis

November 27, 2023 | By

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Join us as we review recent articles and news featured in The DIGEST #45 and #46, including semaglutide in HFpEF and obesity (STEP HFpEF), TCAs for irritable bowel syndrome (ATLANTIS), clopidogrel versus aspirin as long-term secondary prevention after PCI (HOST-EXAM), statins in HIV (REPRIEVE), weight changes and diet, and heavy metal exposure in cannabis users. Fill your brain hole with a delicious stack of hotcakes! Featuring Drs. Paul Williams (@PaulNWilliamz), Nora Taranto (@norataranto), and Matt Watto (@doctorwatto).

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Show Segments

  • Intro, disclaimer
  • STEP HFpEF: semaglutide for HFpEF in obesity 
  • TCAs for IBS 
  • HOST-EXAM and post-PCI  clopidogrel versus aspirin after DAPT 
  • REPRIEVE and pitavastatin in HIV
  • Starchy vegetables and weight changes 
  • Cannabis and heavy metal content 
  • Outro

This show is based on articles and news featured in The DIGEST #45 and #46

Hot Cake #1 Semaglutide in HFpEF and obesity (Nora)

Covered by: Dr. Alyssa Mancini in Issue 46 of The Digest.

Kosiborod et al. STEP-HFpEF Trialists. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. NEJM. 2023; 389:1069-1084. https://www.nejm.org/doi/full/10.1056/NEJMoa2306963   

Recommended Reading: 

Summary: There are limited tools in our arsenal in the HFpEF space, with the heterogeneity of HFpEF thought to contribute to the lack of multiple evidence-based, effective drugs for the whole class of patients as in HFrEF. In 2021, EMPEROR Preserved demonstrated an improvement in CV death/hospitalization from heart failure with empagliflozin (an SGLT2 inhibitor), with or without diabetes. With data linking obesity and metabolic syndrome to HFpEF, and greater symptom burden among patients with HF who are obese, we have another drug entering the game–the GLP-1 receptor agonists. STEP-HFpEF was a randomized double blind placebo-controlled trial studying weekly subcutaneous semaglutide or placebo in 529 participants (56% women, 96% white, median age 69, BMI 37, median KCCQ-CSS of 59, median nt-probnp of 450) over a year. Primary endpoints were change in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) and change in body weight. The mean change in KCCQ-CSS at week 52 was an improvement of 16.6 points with semaglutide and 8.7 points with placebo (estimated difference 7.8 points, 95% CI 4.8-10.9, P<0.001). The other primary endpoint, mean percentage change in body weight at week 52, was -13.3% for semaglutide and -2.6% for placebo (estimated difference -10.7%, 95% CI -11.9 to -9.4, P<0.001).  

  • Significant improvement in symptom-focused trial endpoints with semaglutide compared to placebo, with regards to both KCCQ-CSS and 6 minute walk test.    
  • Secondary endpoints: Mean change in 6-minute walk distance at week 52 was 21.5 meters with semaglutide (with a clinically meaningful difference thought to be around 25m) and 1.2 meters with placebo (estimated difference 20.3 m, P<0.001). Also a reduced risk of hospitalization for heart failure (HR 0.08, 95% CI 0-0.42). 
  • Serious adverse events in 13.3% with semaglutide and 26.7% receiving placebo–with an increase in cardiac events with placebo, such as arrhythmia (atrial fibrillation, flutter) or cardiac/heart failure. GI side effects were the most common AEs with semaglutide. 
  • Notes/Limitations: 
    • Only 3.6% received SGLT2 inhibitors 
    • Very few non-white participants (though 23% in US, more in alignment with trials) 
    • Lack of power to statistically evaluate differences in clinical events such as hospitalizations for heart failure
  • SELECT preliminary data: This follows the August SELECT trial announcement by Novo Nordisk that Semaglutide reduces risk of major adverse cardiovascular events by 20% in those with prior CVD and overweight/obesity. Hot off the press, the results of this trial were just published in NEJM. Look out for further coverage going forward.  

Bottom line (Is this practice changing?):  Semaglutide is going to become a tool to employ for patients with obesity and HFpEF, as it had multiple benefits, both metabolic and symptom-related, in this randomized control trial, and no unanticipated adverse events. In STEP-HFpEF, semaglutide compared to placebo improved symptoms and exercise capacity, as well as weight loss, in patients with HFpEF and obesity.  Remember, the trial wasn’t powered to look at other important clinical outcomes (such as hospitalizations and death)–though there was a signal towards decreased hospitalization with semaglutide.  It’s currently unclear how to employ GLP1 agonism in relation to SGLT2 inhibition in HFpEF, but it seems likely that GLP1s have a role in the obesity + heart failure space for their multiple beneficial effects. And for those patients with diabetes, there’s trial data to come–with significant optimism at present about the results.  

Hot Cake #2 TCAs for IBS (Watto)

Originally covered by Watto (to be covered in Digest Edition #47) 

Ford AC, et al; ATLANTIS trialists. Amitriptyline at Low-Dose and Titrated for Irritable Bowel Syndrome as Second-Line Treatment in primary care (ATLANTIS): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2023 Oct 16:S0140-6736(23)01523-4. doi: 10.1016/S0140-6736(23)01523-4. Epub ahead of print. PMID: 37858323. 

Recommended Reading: Accompanying editorial by de Wit, 2023, IBS Food Fact Sheet Associated of UK Dieticians, IBS-SSS questionnaire

Summary: This was a randomized, double-blind, placebo-controlled trial of 463 patients age 18 or older with IBS (mostly IBS-D and mixed types; median duration of IBS 9-10 years) despite first-line treatments (dietary changes, fiber, laxatives, antispasmodics, peppermint oil). Participants were recruited from 55 general practices in England and randomized 1:1 to receive either low-dose amitriptyline (up to 30 mg) or placebo. Baseline IBS Severity Scoring System (IBS-SSS) scores were in the 270s (with higher scores indicating increasing severity with a maximum score of 500) and over 80 percent of patients had moderate to severe IBS. They found a statistically significant between-group difference in the primary outcome IBS-SSS at 6 months which favored amitriptyline, –27·0, 95% CI –46·9 to –7·10; p=0·0079). There may have been an issue with blinding because more patients discontinued placebo, and it was not because of adverse events. Interestingly, despite our traditional thinking about TCAs as anti-depressants and centrally acting medications, there was no significant improvement in somatoform or mood symptoms in the amitriptyline group compared to the placebo group–suggesting that perhaps the TCA neuromodulatory effects are happening more predominantly in the periphery at this dose. 

Bottom line (Is this practice changing?):  TCAs are commonly used by specialists to treat IBS. This trial affirms their safety and efficacy in the primary care setting. Readers should be aware that low-dose amitriptyline did not meet the predefined 35-point clinically meaningful difference on the IBS-SSS owing to a strong placebo effect, which has been previously observed in IBS. Nevertheless, it’s reasonable to reach for a low dose TCA as a 2nd or 3rd line treatment in IBS as a neuromodulator, which may help reduce visceral sensitivity and pain modulation.

Hot Cake #3 ASA versus clopidogrel after PCI (Paul)

Covered by: Dr. Jen Desalvo in Issue 46 of The Digest.

Yang S et al. 2023. Comparison of antiplatelet monotherapies after percutaneous coronary intervention according to clinical, ischemic, and bleeding risks. Journal of the American College of Cardiology 82(16): 1565-1578.

Recommended Reading: Aspirin versus clopidogrel for chronic maintenance monotherapy after percutaneous coronary intervention (HOST-EXAM): an investigator-initiated, prospective, randomised, open-label, multicentre trial – PubMed (nih.gov)

Summary: Before we talk about the update, we should probably talk about the HOST-EXAM trial itself.  HOST-EXAM enrolled 5530 patients aged at least 20 years who maintained DAPT for 6-18 months after percutaneous coronary intervention with drug-eluting stent.  These patients were randomized 1:1 to either monotherapy with clopidogrel 75 mg daily or aspirin 100 mg daily for 24 months, looking at a primary composite endpoint of all-cause death, non-fatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and Bleeding Academic Research Consortium (BARC) type 3 or greater (overt bleeding with a drop in Hgb > 3 g).  At the end of the trial, the primary outcome occurred in 5.7% of patients in the clopidogrel group and 7.7% in the aspirin group (HR 0.73 [95% CI 0.59-0.90]; p=0.0035.  The HOST-EXAM Extended trial extended follow-up to over 5 years after randomization. Clopidogrel monotherapy compared with aspirin monotherapy remained associated with lower rates of the composite net clinical outcome (HR, 0.74 [95% CI, 0.63–0.86]; P<0.001).  This effect was attributable to both the thrombotic and bleeding components of the primary outcome

This post-hoc analysis of the HOST-EXAM trial published in JACC evaluated the benefits of clopidogrel across high-risk subgroups, with the same primary composite endpoint.  The authors hoped to see how clopidogrel performed in the context of high thrombotic and high ischemic risk, based on two clinical risk scores for stratification: the DAPT score and the Thrombolysis in Myocardial Infarction Risk Score for Secondary Prevention (TRS 2 P).  The TRS 2 P score is based on 9 variables–age ≥ 75 years, diabetes, HTN, current smoking, PAD, prior CVA, prior CABG, history of heart failure, and renal dysfunction.  This score is used to predict recurrence of cardiovascular events.  The DAPT score estimates risk of both ischemic events and bleeding, with a high DAPT score suggesting increased ischemic risk and decreased bleeding risk, and a low DAPT score suggesting higher bleeding risk and lower ischemic risk.

The reduction in primary composite outcome was seen across all the various strata of risk, and the gap between aspirin and clopidogrel widened after 9 months of treatment, suggesting an ongoing benefit of clopidogrel.  Also, notably, 9 hemorrhagic stroke events occurred in the aspirin and high TRS 2 P group, whereas there was no event in the clopidogrel and high TRS 2 P group.  “Favorable clinical outcomes of clopidogrel over aspirin monotherapy can be expected in high clinical, ischemic, or bleeding risk patients.”

Limitations: The current analysis was not powered to compare outcomes according to risk scores and was also a post-hoc analysis, so the results “should be…considered hypothesis-generating at best.”  The HOST-EXAM study was also performed with a Korean population, and so may not be generalizable.

Bottom line (Is this practice changing?):  I think so! There has been a similar signal in other trials, but practice wasn’t changed due to cost and overall small benefit seen with clopidogrel, compared to aspirin. The authors will be extending this study to a median of 10-year follow up, and we’ll see if that moves the needle.


Hot Take #1 Pitavastatin in HIV (Nora) 

Covered by:  Dr. Alyssa Mancini covered the REPRIEVE trial in Digests 41/45

Grinspoon et al. REPRIEVE Trialists. Pitavastatin to Prevent Cardiovascular Disease in HIV infection. NEJM. 2023;389:687-699. https://www.nejm.org/doi/full/10.1056/NEJMoa2304146 

Recommended Reading: 

Paul Sax Blog (JWatch 2023) 

Editorial (NEJM 2023) 

Summary:  HIV increases risk of cardiovascular disease via mechanisms that are incompletely understood–with some thought recently that individuals with HIV may benefit from a different or earlier primary prevention strategy.  REPRIEVE looked at pitavastatin–which does not interact with antiretroviral therapy–in individuals with HIV and low to moderate ASCVD risk. In REPRIEVE, 7769 adults aged 40-75 who were taking antiretroviral therapy with preserved CD4 counts and who had low to moderate cardiovascular disease risk were randomized to either pitavastatin (4 mg) or placebo. Fasting LDL had to be below 190, with specific criteria depending on the 10-year ASCVD risk score (if < 7.5%, had to be < 190; if 7.5 – 10% LDL had to be < 160, and so forth).  

The trial was stopped early for efficacy after a median follow-up of 5.1 years. Median LDL was 108,  with a median 10-year ASCVD of 4.5% in the study population. The incidence of the primary outcome, major adverse cardiovascular event, was 4.81/1000 person-years with pitavastatin and 7.32/1000 person-years with placebo (HR 0.65, 95% CI 0.48 – 0.9, p=0.002), a 35% risk reduction–with greater reduction in those with higher ASCVD risk. The effect size in men and women appeared to be similar in subgroup analyses, similar across region, and similar across CD4 count. This data translated to a 5-year number needed to treat (NNT) of 106 (95% CI 64 – 303). Muscle related symptoms occurred in 2.1% of pitavastatin patients and 1.4% of placebo. 

Limitations: Remember that studies stopped early for benefit may overestimate the effect size.   It remains unclear whether this is an effect unique to pitavastatin (keeping in mind that there are often significant interactions between protease inhibitors and other statins such as atorvastatin and simvastatin).  Pitavastatin may not be available, or affordable, to everyone (though the patent expires on it in November 2023). 

Bottom line: Prior to REPRIEVE, statins would not typically have been prescribed for the population with low to moderate risk of heart disease and HIV, and CVD prevention guidelines did not make any specific recommendations for individuals living with HIV. REPRIEVE will likely be incorporated into guidelines very shortly for the low to moderate risk population, though access to affordable statins that don’t interact with ART remains an issue. 

Hot take #2 Starchy Vegetables (Watto)

Covered by:  Dr. Hannah Smith covered this article in Issue 46 of The Digest. 

Wan Y, et al. Association between changes in carbohydrate intake and long term weight changes: prospective cohort study. BMJ. 2023 Sep 27;382:e073939. doi: 10.1136/bmj-2022-073939. PMID: 37758268; PMCID: PMC10523278. 

Recommended Reading: BMJ Rapid Responses https://www.bmj.com/content/382/bmj-2022-073939/rapid-responses 

Summary: In healthy middle-aged adults, increasing intake of fiber, natural sugars, whole grains, fruit, and non-starchy vegetables was associated with less weight gain. Replacing refined grains, potatoes and other starchy vegetables, and sugar-sweetened beverages with equal servings of whole grains, fruit, or non-starchy vegetables was associated with less weight gain. These associations were particularly strong among participants with overweight and obesity at baseline. This study supports and reinforces what we all know about avoiding sugar and refined carbohydrates. 

Critics caution the authors that we shouldn’t vilify all starchy vegetables pointing out for example, that fried potatoes and non-fried potatoes are not equivalent, and we should consider multicultural eating patterns when making dietary recommendations (e.g. potatoes, peas, corn, yams), especially since these foods can be good sources of fiber, potassium, etc.

Limitations: Reliance on self-reported measures; we cannot rule out reverse causation (i.e. did they change their diet because of a weight change or did weight change because of a change in their diet); 

Bottom line (Is this practice changing?): Non-fried peas, corn, and potatoes are not the cause of the obesity epidemic. The type of preparation of food probably matters a great deal as well, and may also be worth talking to patients about in the context of dietary advising. Patients might ask about this article so we must be familiar with its strengths and limitations.  

Hot take #3 Heavy Metals and Cannabis (Paul) 

Originally covered by: Dr. Beth “Garbs” Garbitelli covered this article in Issue 45 of The Digest. 

McGraw KE et al. 2023 Blood and Urinary Metal Levels among Exclusive Marijuana Users in NHANES (2005–2018).  Environmental Health Perspectives 131(8): https://doi.org/10.1289/EHP12074

Summary: Cannabis is the third most commonly used drug worldwide behind tobacco and alcohol, and has become legal at the state level in the U.S in over 20 states, but remains illegal at the federal level. This means there is little federal guidance or oversight regarding regulation of contaminants. Cannabis is also evidently a known hyperaccumulator of heavy metals present in soil, water, and fertilizers.  Because this is not well regulated, it is likely that consumers of cannabis are exposed to metal levels that have previously been associated with cardiopulmonary disease, neurodevelopmental effects, and malignancy.

Researchers performed a secondary data analysis in NHANES data from 2005 to 2018, looking at metal levels in blood and urine by categories of tobacco and cannabis use.  The researchers looked at blood levels of cadmium, lead, mercury, manganese and selenium, as well as 15 elements in urine.  They looked at these levels among those with 1) non-tobacco and non-cannabis use 2) cannabis use without tobacco use 3) exclusive tobacco use and 4) dual use.  They found that cadmium and lead levels were higher among those with exclusive cannabis use compared to participants who used neither tobacco or cannabis.  Levels were higher among those who had used cannabis more recently.  Those who used tobacco had higher cadmium levels than other groups, and blood lead levels were comparable among exclusive tobacco use and exclusive cannabis use.  In summary, cannabis is a source of lead and cadmium exposure. 

Limitations: The clinical impact of these metal exposures is unclear, as symptoms and health consequences related to lead or cadmium exposure were not assessed in this study (Itai Itai Disease, anyone?) –nor was the modality by which individuals were exposed (smoking, ingestion, etc.). 

Bottom line: This will be added to my counseling around both therapeutic and recreational cannabis use.  As use becomes more normalized, I think it will be easier to study downstream effects, and we will see more data like this.


Links

Links are included in the show notes above.


Goals

Listeners will review recent practice-changing articles and medical news featured in The DIGEST.

Learning objectives

After listening to this episode listeners will…

  1. Discuss the use of the GLP1 agonist, semaglutide, in patients with HFpEF
  2. Review the use of tricyclic antidepressants for treatment of IBS in primary care
  3. Discuss whether or not clopidogrel monotherapy is preferred to aspirin after dual antiplatelet therapy finishes post-PCI in high-risk groups. 

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Taranto N, Williams PN, Watto MF. “#418 DIGEST: (Tofurkey Edition): Semaglutide for HFpEF,  TCAs for IBS, Aspirin vs Clopidogrel after PCI, Pitivastatin for HIV, Starchy Vegetables & Weight Gain, Heavy Metals in Cannabis”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list Final publishing date, November 27, 2023.

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Episode Credits

Written and Hosted by: Nora Taranto MD; Paul Williams, MD, FACP, Matthew Watto MD, FACP
Cover Art: Matthew Watto MD, FACP
Reviewers: Nora Taranto MD; Paul Williams, MD, FACP; Matthew Watto MD, FACP; Sai Achi, MD MBA
Technical Production: Pod Paste
Showrunners: Matthew Watto MD, FACP; Paul Williams MD, FACP

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