#407 DIGEST: Bempedoic acid and cardiac risk, Alpha-Gal Syndrome, Orforglipron, Zuranolone, DOACs for VTE of Malignancy, mAbs for Dementia, New Med for Smoking Cessation, Kiwis and Constipation

September 11, 2023 | By Nora Taranto

Audio

Video

Join us as we review recent articles and news featured in The DIGEST #43 and #44, including bempedoic acid to lower cardiovascular risk, Alpha-Gal Syndrome, tick bites and meat allergy, orforglipron an oral GLP1 agonist for weight loss, zuranolone for postpartum depression, DOACs for VTE of malignancy, monoclonal antibodies (mAbs) for Dementia, cytisinicline for smoking cessation, and two kiwis a day for constipation. Fill your brain hole with a delicious stack of hotcakes! Featuring Drs. Paul Williams (@PaulNWilliamz), Nora Taranto (@norataranto), and Matt Watto (@doctorwatto).

Claim free CME for this episode at curbsiders.vcuhealth.org!

Episodes | Subscribe | Spotify | Swag! |Mailing List | Contact | Free CME!

Show Segments

• Intro, disclaimer
• Bempedoic Acid for CV risk reduction
• DOACs to prevent recurrent VTE of malignancy
• Cytisinicline for smoking cessation
• Alpha-Gal Syndrome, tick bites, and meat allergy
• Zuranolone for postpartum depression
• Orforglipron, an oral GLP1 agonist, for weight management
• mAbs for Alzheimer’s dementia
• Kiwis to prevent constipation
• Outro

This show is based on articles and news featured in The DIGEST #43 and #44.

Hot take #1 Bempedoic Acid (Watto)

Originally covered by Jen DeSalvo in DIGEST #44

Nissen SE, et al; CLEAR Outcomes Investigators. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients. N Engl J Med. 2023 Apr 13;388(15):1353-1364. doi: 10.1056/NEJMoa2215024. Epub 2023 Mar 4. PMID: 36876740. 

Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR)

• Editorial (Alexander, 2023)
• Editorial (Keaney, 2023)

Summary: Bempedoic acid provided a 13% relative risk reduction (1.6% absolute risk reduction, 11.7 vs 13.3%) for the primary composite endpoint (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization). A reduction in the need for coronary revascularization and incidence of fatal or nonfatal myocardial infarction accounted for the between-group differences and drove the composite endpoint. They did not observe a significant reduction in the incidence of stroke, CV death, or all-cause mortality. The number needed to treat was 71 to prevent one revascularization, 91 to prevent one myocardial infarction and the number needed to harm (for serious adverse events) was 333 after a median treatment of 40.6 months. 

• Bempedoic acid (BA) lowers LDL up to 28% as monotherapy and 16% if added to maximum tolerated statin (Keaney, 2023)
• BA lowers CRP
• BA had a greater benefit in the primary prevention group, which could be due to chance or because it was given earlier in the course of CVD (Alexander, 2023)
• Overall, serious adverse events were about 25% in both groups. 
• Patients receiving bempedoic acid had an increased risk for gout, renal impairment, and hepatic enzyme elevation but a decreased risk for myalgia and diabetes.
• The incidence of muscle symptoms was higher in patients cotreated with statins and BA in prior studies. Do not use BA in patients on more than 20 mg simvastatin or 40 mg pravastatin because it increases their levels. (Keaney, 2023)
• Do not use BA with fibrates because of concerns for cholelithiasis (Keaney, 2023)
• Average retail price per GoodRx.com $465 as of 29 Aug 2023.

Nissen SE, et al. Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients. JAMA. 2023 Jul 11;330(2):131-140. doi: 10.1001/jama.2023.9696. PMID: 37354546; PMCID: PMC10336623. 

• Editorial (Kazi, 2023)

Coverage by Jen DeSalvo: “Now, hot off the press–a prespecified subgroup analysis of the effects of bempedoic acid on major adverse cardiovascular outcomes in this primary prevention population from CLEAR, just published in JAMA in July 2023, has found that in the primary prevention subgroup at high risk of cardiovascular disease, there was a significant reduction from bempedoic acid compared to placebo in MACE, in cardiovascular death, and in all-cause mortality.”

• Follow-up for a median of 39.9 months was associated with a significant risk reduction for the primary composite endpoint (111 events [5.3%] vs 161 events [7.6%] = NNT 43, equivalent to an absolute reduction of 0.8 events per 100 person-years); adjusted hazard ratio [HR], 0.70 [95% CI, 0.55-0.89]; P = .002
• An editorialist notes that primary prevention was one of 38 prespecified subgroups, each with two prespecified endpoints and ten post hoc secondary endpoints with no adjustment for multiple testing, making the possibility of at least one false positive across all subgroups 99.9%, especially with post hoc endpoints like all-cause mortality and CV death, neither of which was prespecified. Clinical trials are powered for the overall population enrolled, not to detect differences in subgroups.
• Watto’s comments: These results should be interpreted cautiously because the original trial was not powered to study the primary prevention population. The composite endpoint of MACE was a prespecified outcome that the researchers planned to explore. However, all-cause mortality and cardiovascular death were each post hoc secondary outcomes assessed in this subgroup. It is possible that the observed reduction in all-cause and cardiovascular death was due to chance.

Bottom line: Statins should still be the first-line treatment for patients with known or at high risk for cardiovascular events, but bempedoic acid is a reasonable alternative for those who cannot or will not take statins. It remains unclear whether BA has an effect on mortality and why it seems to have more benefits when used as primary prevention. Further, the CLEAR trial was not designed to assess how adjunctive bempedoic acid affects cardiovascular outcomes when used as adjunctive therapy so we don’t recommend adding bempedoic acid for patients already on a statin.

Hot take #2 Alpha-Gal (Watto)

Originally covered by Beth Garbitelli in DIGEST #44

Geographic Distribution of Suspected Alpha-gal Syndrome Cases — United States, January 2017–December 2022.https://www.cdc.gov/mmwr/volumes/72/wr/mm7230a2.htm Accessed 22 Aug 2023.

• Macdougall JD, Thomas KO, Iweala OI. The Meat of the Matter: Understanding and Managing Alpha-Gal Syndrome. Immunotargets Ther. 2022 Sep 15;11:37-54. doi: 10.2147/ITT.S276872. PMID: 36134173; PMCID: PMC9484563. 

Summary: The CDC estimates 96,000 to 450,000 patients may have been affected by alpha-gal syndrome since 2010. Alpha-gal syndrome (aka red meat allergy) is an immune-mediated hypersensitivity reaction to an oligosaccharide found in non-primate mammalian meats (cows, pigs, sheep), and various products derived from those animals (dairy, innards, pharmaceuticals, medications, supplements). Sensitization to alpha-gal often occurs after tick bites and might be related to exposure to tick saliva. Unlike other food allergies, symptoms often appear in hours (range 2-8 hours), not minutes after ingestion so a delay in diagnosis is common (estimated up to 7.1 years). Consider alpha-gal in the patient with unexplained hives, swelling, or spontaneous allergic reactions, including angioedema, and anaphylaxis. Hives and gastrointestinal symptoms (emesis, reflux, diarrhea, and abdominal pain) are more common than respiratory symptoms or anaphylaxis. Detection of serum alpha-gal specific IgE is supportive, but not diagnostic without the appropriate clinical history. According to the group at UNC Chapel Hill, about 80% of patients improve with avoidance of mammalian meat products alone, another 15% with dairy avoidance, and approximately 5% must avoid gelatin-containing foods. No medical treatments are officially approved, but steroids, and antihistamines are often tried. Researchers have tried producing alpha-gal knockout pigs since pharmaceuticals (cetuximab), bioprosthetic valves, and supplements may be derived from mammalian animals.

Bottom line: Healthcare providers should be familiar with alpha-gal syndrome, especially in the southern, midwestern, and mid-Atlantic United States. Testing for alpha-gal serum IgE ordered by clinicians with knowledge of alpha-gal and a high index of suspicion has 98% sensitivity and 92% specificity. Don’t miss this diagnosis in the patient with unexplained allergic or even isolated recurrent GI symptoms!

Hot take #3 Alzheimer’s mAbs (Watto)

Originally covered by Alexander Chaitoff in DIGEST #44

Sims JR, et al; TRAILBLAZER-ALZ 2 Investigators. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023 Aug 8;330(6):512-527. doi: 10.1001/jama.2023.13239. PMID: 37459141; PMCID: PMC10352931. 

• CMS – Coverage with Evidence Development https://www.cms.gov/Medicare/Coverage/Coverage-with-Evidence-Development Accessed 22 Aug 2023.
• Enroll in the Alzheimer’s mAb registry https://qualitynet.cms.gov/alzheimers-ced-registry/resources Accessed 22 Aug 2023.

Summary by Alexander Chaitoff: In the past few months, CMS announced that they will cover lecanemab, the monoclonal antibody in the CLARITY-AD trial that reduced memory decline by 27% compared to placebo (though that relative difference represented only a clinically questionable 2.5% absolute difference). However, this approval did come with some strings attached. The drug received the designation of coverage with evidence development. With this relatively rare approval type, CMS is saying they will pay for a drug, but there are still significant questions about the drug’s safety or efficacy. As such, patients prescribed the medication must in effect be research subjects. Sometimes this determination means CMS will only cover the drug for patients enrolled in active clinical trials, which is the case for aducanumab (which demonstrated even less evidence of benefit in trials than lecanemab). But for lecanemab, CMS is only requiring that patients receiving the drug be enrolled into an online registry.

These registries were created because, despite enough evidence for a black box warning about lecanemab’s risks of brain swelling and hemorrhage, there is still more to be learned about the safety and efficacy of the drug. Unfortunately, these registries have made just about everyone mad. Drug proponents, such as patient advocacy groups, worry that the extra administrative burden of online registry enrollment to prescribe the drug will lead to decreased availability.  And researchers argue that the registries, which require only a few pieces of information, have almost no research value and won’t adequately answer safety or efficacy questions. Until the registries mature, lecanemab will have full FDA approval and significant CMS coverage. Expect to see it running in an infusion center near you soon.

Just as this chapter of the lecanemab saga ended, the TRAILBLAZER-ALZ 2 trial was published in JAMA. This trial randomized 1736 patients with mild cognitive impairment or mild dementia to receive donanemab or placebo. Those that received the drug, another monoclonal antibody designed to clear amyloid plaque, had 22.3% less memory decline than with placebo–but with several other notable features. At one year, 47% of patients with low/medium tau who received donanemab had no cognitive function decline, compared to 29% with placebo. Moreover, whereas lecanemab was studied with indefinite treatment duration, 75% of trial participants were able to stop donanemab based on imaging demonstration of adequate amyloid reduction. This latter finding of effect even with limited-duration dosing is important given the huge expense of monoclonal antibodies and the logistic challenges of attending regular infusion appointments.  Now, much like lecanemab one year before, donanemab awaits the regulatory process. Whether there will be stipulations attached to a CMS approval remains to be seen–but the newest entrant nonetheless leaves something to be excited about.

Bottom line: The TRAILBLAZER-2 trial studied a highly selected group of patients using a per-protocol analysis (8240 screened, 1736 randomized, and 1320 analyzed –622 in the treatment arm and 698 in the placebo arm). The absolute change in scores between the donanemab and placebo groups was small, about 3 points on a 144-point scale, compared to the 5-point individual patient difference considered to be clinically meaningful. However, an additional 18% of patients (47% vs 29%) treated with donanemab had no clinical progression after one year even without indefinite treatment. Patients and families interested in clinical trials and specialized care for dementia might reasonably pursue monoclonal antibody therapy to decrease the amyloid burden and slow disease progression, but the logistics, cost, and potentially severe adverse events remain prohibitive for most patients.

Hot take #4 DOACS for VTE in Cancer (Nora)  

Originally covered by Dr. Alyssa Mancini in DIGEST #43 

Schrag D, et al; CANVAS Investigators. Direct Oral Anticoagulants vs Low-Molecular-Weight Heparin and Recurrent VTE in Patients With Cancer: A Randomized Clinical Trial. JAMA. 2023 Jun 13;329(22):1924-1933. doi: 10.1001/jama.2023.7843. PMID: 37266947; PMCID: PMC10265290.

• ASCO Updated Recommendations for VTE (2023) https://ascopubs.org/doi/full/10.1200/JCO.23.00294 
• ASH 2021 VTE in cancer guidelines https://ashpublications.org/bloodadvances/article/5/4/927/475194/American-Society-of-Hematology-2021-guidelines-for 

Summary: CANVAS was a pragmatic, noninferiority, randomized clinical trial randomizing patients with cancer and a new VTE to DOACs or LMWH.  This latest trial addressed the question in the real world, leaving the exact choice of agent up to the provider and patient.  Within 14 days of randomization, physicians chose and prescribed any DOAC or LMWH based on availability, formulary preference, insurance coverage, and drug-drug interactions.  This real world trial included patients with advanced cancer and brain metastases, impaired performance status, and reduced liver and kidney function, and lower platelet counts, compared to the prior individual drug trials.  

Within the DOAC group, 58.5% chose apixaban, 37.0% chose rivaroxaban, 2.7% chose dabigatran, and 1.8% chose edoxaban. Within the LMWH group, 89.9% chose enoxaparin, 7.5% chose fondaparinux, and 2.6% chose dalteparin. Participants were followed up for 6 months or until death.  The primary outcome was recurrent VTE rate at 6 months, with a prespecified noninferiority margin of 3%.  Rates of recurrent VTE were 6.1% in the DOAC group and 8.8% in the LMWH group (difference -2.7%), meeting the noninferiority margin, with the secondary outcome of major bleeding (5.2% with DOAC vs 5.6% with LMWH, difference -0.4), also meeting its 2.5% noninferiority margin.  It’s worth noting that in the DOAC arm, a majority of patients used apixaban, which may have a lower bleeding rate than other DOACs based on prior trial data (especially in GI malignancy it seems) and which may have pushed towards the non-inferiority result in comparisons of bleeding rates.  There were no significant differences in health-related quality of life, but adherence to DOACs was significantly greater compared to LMWH at 6 months (71% with DOACs vs 60% with LMWH). 

Some other background background: Low molecular weight heparin replaced warfarin as the anticoagulant of choice for patients with cancer in the early 2010s (following trials that demonstrated its superiority, most notably the 2003 CLOT trial), at around the same time as Direct Oral Anticoagulants (DOACs) made their way onto the market for the treatment of clots generally speaking. However, many of the initial trials testing DOACs did not include patients with cancer. Now we have a series of randomized trials comparing individual DOACs with low molecular weight heparins (see below), upon which ASCO guidelines have adapted to include DOACs as therapeutic options for both acute treatment and long-term prevention of VTE.  

•  Prior Trials comparing individual DOACs and low molecular weight heparins: Caravaggio (2020) comparing Apixaban to LMWH in cancer demonstrating non-inferiority, ADAM VTE trial (2020) looking at bleeding risk found non-inferiority in major bleeding and VTE recurrence,  2018 Hokusai VTE trial looking at edoxaban vs dalteparin found noninferiority (bleeding + VTE risk), though did have increased major bleeding risk. SELECT-D (2018) which was multicenter randomized, pilot with PE or DVT comparing dalteparin or rivaroxaban, with lower DVT recurrence on rivaroxaban but slightly higher clinically relevant non-major bleeding). 

Bottom line:  This real-world data confirms what we’ve seen in individual trials the last few years–that DOACs can be used safely and effectively in patients with cancer and clots–and bolsters the ASCO guideline inclusion of DOACs for treatment of VTE that DOACs can be used in the context of cancer-associated VTE.  There’s still potential for differences in bleeding risk across agents and types of cancer–and this may be worth considering in prescribing practices.

Hot take #5 Zuranolone (Nora) 

Originally covered by Dr. Laura Glick in DIGEST #44

• SKYLARK: https://pubmed.ncbi.nlm.nih.gov/37491938/  
• ROBIN: https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2781385 

Summary:  There’s a new oral drug, zuranolone, for postpartum depression.  The U.S Food and Drug Administration (FDA) just approved the first oral treatment–Zuranolone–for postpartum depression (PPD).  Postpartum Depression is underdiagnosed and undertreated, occurring among 17.2% of women during pregnancy or following delivery. 

Zuranolone is a progesterone analog with GABA receptor modulation properties with substantially quicker onset than the SSRIs.  A similar drug, Brexanalone, was approved a few years ago but required a 60 hour hospitalization and infusion (because of the risk of sedation and drowsiness).  The FDA approval of zuranolone followed the publication of two phase III, randomized, double-blind, placebo-controlled studies.   SKYLARK randomized 200 women with PPD to 50 mg zuranolone or placebo once daily for 14 days, and ROBIN randomized > 150 women with PPD to 30 mg daily or placebo for 14 days.  Though there was a significant placebo effect across studies, both trials found a statistically significant–and significant absolute–reduction in the HAMD-17 (Hamilton Rating Scale for Depression) score in the group receiving zuranolone compared to placebo at day 15, and significant improvements that persisted beyond day 40.  Adverse events (≥10%) occurring with zuranolone were somnolence, dizziness, and sedation, and some of these did require dose reductions. No loss of consciousness, withdrawal symptoms, or increased suicidal ideation or behavior were observed in SKYLARK.  

In SKYARK, a subset were on SSRIs as well (approximately 15% in each group) at the time of trial initiation. There was a similar discontinuation of therapy rate (around 10%) between placebo and zuranolone, with approximately 16% patients requiring dose reductions on zuranolone.   This drug appeared to work more quickly than other antidepressants in the post-partum population, with a median time to response of 9 days.  Remission rates increased with time, 27% vs 17% at day 15, and 44% vs 29% at day 45.   Notably, there was no breastfeeding allowed from day 1 of study drug through last study drug dose.  There is no drug pricing available yet.  

Bottom line: This is the only oral drug for postpartum depression with FDA approval.  While ROBIN and SKYLARK did find significant clinical benefit from zuranolone, there was a significant placebo effect, both were small trials, and this was also occurring in the context of a larger negative trial of zuranolone in Major Depressive Disorder (MOUNTAIN) this year which did not meet its primary endpoint.  But given the lack of other proven and effective, quick-acting options in this population, this seems like it may very well be practice changing–and soon.  Long-term safety data is largely unknown at this point, and breastfeeding was not allowed in the trial.  Cost is also unclear (drug companies expected to set the cost in the last quarter of 2023). 

Hot take #6 Kiwis for Constipation (Nora) 

Originally covered by Dr. Laura Glick in DIGEST #43

Gearry R, et al. Consumption of 2 Green Kiwifruits Daily Improves Constipation and Abdominal Comfort-Results of an International Multicenter Randomized Controlled Trial. Am J Gastroenterol. 2023 Jun 1;118(6):1058-1068. doi: 10.14309/ajg.0000000000002124. Epub 2022 Dec 20. PMID: 36537785; PMCID: PMC10226473. 

Summary:  A recent international multicenter randomized trial published in the American Journal of Gastroenterology by Ansell et al. found that eating daily GREEN kiwi improves constipation and gastrointestinal discomfort. This was a large, multicenter, randomized crossover trial of healthy controls (HC (n=63)), patients with functional constipation (FC (n=61)), and patients with constipation-predominant irritable bowel syndrome (IBS-C (n=61). Patients were randomized to consume 2 green kiwifruits or 7.5g of psyllium daily for four weeks–with a 4-week washout and then treatment crossover (for 16 weeks).  The type of kiwi was a “Hayward”  kiwi, with the recommendation not to eat the skin (approx 6 g dietary fiber).   Patients with severe IBS or significant GI disorders, and patients with kiwi and latex allergies were excluded.  

Consuming green kiwifruit was associated with a clinically significant increase in complete spontaneous bowel movements (CSBM, the primary outcome, increase of > 1.5 BM per week) in the functional constipation and IBS-C groups, compared to 7.5 g psyllium–which achieved this only in the IBS-C group.  In combined FC + IBS-C group, kiwis had significantly greater effect than psyllium.  Eating kiwifruits also improved gastrointestinal comfort and symptoms without any adverse events, compared to psyllium, across all groups.  More women were in the study than men, and this was an industry sponsored trial (by Zespri).  But it builds on smaller prior studies which have noted similar effects in gold kiwis. 

Bottom line: I will recommend kiwi as a “natural” way to increase dietary fiber and help with constipation, which may work better than psyllium (and or for folks who don’t like psyllium–which is a lot of folks).  Not sure which kiwi to recommend…..and avoid if latex allergy? 

Hot take #7 Cytisinicline for Smoking Cessation (Paul)

Originally covered by Laura Glick in Issue #43

Rigotti NA, et al. Cytisinicline for Smoking Cessation: A Randomized Clinical Trial. JAMA. 2023 Jul 11;330(2):152-160. doi: 10.1001/jama.2023.10042. PMID: 37432430; PMCID: PMC10336611.

Summary: The authors of this study examined the efficacy and tolerability of cytisinicline, a plant-based alkaloid, for tobacco cessation.  This is a substance that has evidently been used for decades in Europe but has not been approved for use outside of certain regions there.  Cytisinicline binds selectively to the ɑ4β2 nicotinic acetylcholine receptor subtype that mediates nicotine dependence.  It acts as a partial agonist to prevent nicotine withdrawal while blocking the reinforcement generated from nicotine use.  The suggested dosing is burdensome – 1.5 mg tablets taken six times a day, reduced over the course of 25-day treatment.  This dosing is not backed by pharmacokinetics, as it has a half-life of 4.8 hours.  This suggested dose failed to meet noninferiority in prior trials.  The authors studied 3 times daily administration versus placebo for six weeks or twelve weeks.

The authors were just looking at cigarettes and excluded individuals with non-cigarette tobacco use.  Patients with certain mental health issues and substance use were also excluded.  The outcomes were whether cytisincline produced biochemical abstinence during the last four weeks of the 6-week or 12-week treatment.

Participants smoked an average of about a pack per day at baseline.  Abstinence rates with the 6-week course of cytisinicline were high during weeks 3-6 (25.3% vs 4.4% with placebo, P < .001), but then dropped during weeks 3-24 (8.9% vs 2.6% with placebo, p=0.002).  Continuous abstinence rates with the 12-week treatment were high (32.6% vs 7.0%, p<0.001) during weeks 9-12 and dropped slightly during weeks 9-24 (21.1% vs 4.8%, P < .001). Participants taking cytisinicline had reduced cravings, and under 10% of participants experienced nausea or insomnia.  Abnormal dreams and insomnia were higher in the cytisinicline groups.

Bottom line: This will eventually be practice-changing.  The more tools in the armamentarium, the better.  Three times daily dosing is somewhat burdensome, but some folks may prefer the more “natural” product, and given that tobacco use is the number one modifiable risk factor for early mortality, it’s great to have another effective option.

Hot Take #8 Orforglipron for Adults with Obesity (Paul)

Originally covered by Alyssa Mancini in Issue #44

Wharton S, et al; GZGI Investigators. Daily Oral GLP-1 Receptor Agonist Orforglipron for Adults with Obesity. N Engl J Med. 2023 Jun 23. doi: 10.1056/NEJMoa2302392. Epub ahead of print. PMID: 37351564.

Summary: We love GLP-1 agonists.  However, a limiting factor for many patients is the prospect of injections.  Presently, only semaglutide is available in an oral formulation, and this has proven less effective than its injectable version at effecting weight loss.  Orforglipron is a once-daily oral nonpeptide GLP-1 receptor agonist.  It has a half-life of 29 to 49 hours, which supports once-daily administration.  In a trial recently published in NEJM, investigators evaluated the efficacy and safety of orforglipron in patients with obesity or overweight plus one weight-related condition (hypertension, dyslipidemia, cardiovascular disease, or obstructive sleep apnea).  Patients with diabetes were excluded.

Men and women aged 18 to 75 were enrolled and were required to have a stable body weight for at least 3 months before randomization.  They were randomized to receive a dose of 12 mg, 24 mg, 36 mg, 45 mg, or placebo once daily for 36 weeks.  Dose escalation occurred in all of the orforglipron cohorts.  The primary endpoint was percentage change from body weight at week 26.  It was deemed adequately powered at 270 patients and 272 underwent randomization.  At week 26, the mean body weight change ranged from -8.6% to -12.6% across dose cohorts compared with -2.0% with placebo. The weight loss achieved was dose-dependent, occurred in a continuous fashion through week 36, and did not appear to reach a plateau.  Additionally, there was a clinically meaningful reduction in systolic blood pressure in the orforglipron group, up to a mean reduction of 10.5 mm Hg at week 36.  There were positive changes in the lipid profiles of the experimental group as well.  The most common adverse events were gastrointestinal-related, occurred during dose escalation, and led to drug discontinuation in 10-20% of participants across cohorts.  The authors will be adjusting the starting dose and dose escalation protocol in phase 3.

Bottom line: Orforglipron is not yet available, but again, it obviously will be.  This will be a game-changer once it’s available, although it may be years before it’s broadly available.  The impact on cardiometabolic risk is significant, and to have demonstrated benefit in patients without diabetes obviously immediately broadens its potential use.

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. Recognize alpha-gal syndrome
2. Discuss monoclonal antibody treatment of Alzheimer’s dementia
3. Consider bempedoic acid for patients with statin intolerance
4. Choose the appropriate therapy to prevent recurrent venous thromboembolism in patients with cancer
5. Consider zuranolone for treatment of postpartum depression
6. Discuss cytisinicline for smoking cessation
7. Recognize orforglipron as a future oral GLP1 agonist for weight management
8. Recall that kiwis can prevent constipation

Disclosures

The Curbsiders report no relevant financial disclosures. 

Citation

Taranto N, Williams PN, Watto MF. “#407 DIGEST: Bempedoic acid and cardiac risk, Alpha-Gal Syndrome, Orforglipron, Zuranolone, DOACs for VTE of malignancy, mAbs for Dementia, New Med for Smoking Cessation, Kiwis and Constipation”. The Curbsiders Internal Medicine Podcast. https://thecurbsiders.com/episode-list Final publishing date, September 11, 2023.