#44 Top Hits Of The Summer, From A(Lpha Gal) To Z(Uranolone)

August 18, 2023 | By Nora Taranto

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Issue 44

08/18/2023

Appetizers (to whet your appetite) 

Palate Cleanser (aka the melon part of the meal) 

The Main Course

A Digestif or two

Appetizers

Brought to you hot off the stove, from a variety of specialties. Delivered in super tasty, bite-sized morsels. 
Beth Garbitelli MD; Laura Glick MD; Alyssa Mancini MD 

• An oral GLP-1 receptor agonist for weight reduction? NEJM recently published results of a phase 2, randomized, double-blind trial looking at the efficacy and safety of orforglipron, a nonpeptide GLP-1 receptor agonist. In this study, 272 adults with obesity or overweight and >1 weight-related comorbidity (but no diabetes) were randomized to receive orforglipron at one of four doses or placebo once daily for 36 weeks. 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 most common adverse events were gastrointestinal-related, occurred during dose escalation, and led to drug discontinuation in 10-20% of participants across cohorts. (AM)
• Once-weekly basal insulin may outperform once-daily basal insulin in insulin-naive individuals with type 2 diabetes (T2DM). In this randomized, open-label, phase 3 trial just published in NEJM, 984 adults with T2DM who had not previously received insulin were randomized 1:1 to receive once-weekly insulin icodec (an investigational once-weekly basal insulin) or once-daily insulin glargine U100.  At 52 weeks, mean hemoglobin A1c measures decreased from 8.5% to 6.93% with icodec, compared with a decrease from 8.44% to 7.12% with glargine, with a between-group difference of -0.19%, demonstrating both noninferiority (p<0.001) and superiority (p=0.02) of icodec.  Additionally, a significantly greater percentage of time was spent in glycemic range with icodec compared to glargine–with slightly more severe hypoglycemia as well. (AM) 
• The U.S Food and Drug Administration (FDA) just approved the first oral treatment–Zuranolone–for postpartum depression (PPD).  The approval followed the publication of two phase III, randomized, double-blind, placebo-controlled, multicenter studies.  SKYLARK randomized 200 women with PPD to 50 mg zuranolone or placebo 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 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 beyond day 40. The medication was generally well tolerated, with drowsiness as a major side effect. (LG)
• New data on low-level HIV viremia and transmission risk. A systematic review in The Lancet evaluated 244 studies, of which 8 were ultimately included for analysis, of serodiscordant HIV couples to assess the risk of HIV transmission based on available data of quantitative viral load.  Studies were excluded if they did not specify viral load thresholds or define low-level viremia. Of the 7,762 total couples and 323 transmission events ultimately included in the review, there were only two cases of transmission at a viral load less than 1,000 copies per ml–with interpretation of those cases clouded by a long interval (over 50 days) between transmission date and most recent prior viral load measurement. (BG)
• Alpha-Gal: New Tick-borne Illness on the Block?! The CDC just published a report on the emerging threat of Alpha-gal syndrome (AGS), an IgE-driven meat allergy that develops after a tick bite.  Researchers reviewed testing results for the specific protein allergy test (sIgE tests) from 2017-2022 and looked at patient age, sex, and residence. Over 90,000 positive cases occurred nationwide during that period, with a substantial increase over the five years. The highest number of AGS cases occurred in Suffolk County, New York and Bedford County, Virginia, with the highest disease prevalence in a swath of southern, midwestern, and mid-Atlantic states spanning from Oklahoma to Delaware. Severity of cases was not assessed. (BG)

Palate Cleanser

The melon part. To get rid of the taste of those pesky apps.  And to fill your brain with some fun facts.

The Health Policy Corner with Alexander Chaitoff MD MPH 

• The Rapidly Evolving Landscape of Dementia Treatment When we covered aducanumab and lecanemab in previous Digest issues, we figured that was going to be it for dementia drugs for a while. Then came new regulations from the Centers for Medicare & Medicaid Services (CMS) and yet another anti-amyloid monoclonal antibody trial. It’s time for an update, and a discussion of cost and drug coverage. 
• New Regulations 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 warningabout 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 todecreased 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.
•  New Kid on the Block 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.

The Main Course

Jen DeSalvo MD

Cardiovascular Outcomes in the Age of Bempedoic Acid 

• Primary and secondary prevention of major adverse cardiovascular events can be challenging, especially in patients with statin intolerance, with a prevalence of approximately 9% commonly attributed to adverse musculoskeletal effects. While there are other non-statin agents including injectable PCSK9 inhibitors and ezetimibe, these drugs can be quite costly–and sometimes still work better when added to statin medications.  More recently, bempedoic acid has emerged as another lipid-lowering therapy that inhibits an enzyme within cholesterol synthesis–that is, within the same pathway but upstream from the activity of statins. As a prodrug activated in the liver not in skeletal muscles, it has been associated with a lower incidence of adverse musculoskeletal effects.  Prior studies have demonstrated the effectiveness of bempedoic acid in reducing LDL cholesterol by >17%. However, to this point, the effect of bempedoic acid on cardiovascular outcomes has been unknown. 
  
  
• Breaking it down: The Cholesterol Lowering via Bempedoic Acid Regimen (CLEAR) Outcomes trial, the results of which were published in NEJM in April 2023, enrolled nearly 14,000 patients aged 18-85 years (mean age 66 years, 48% female, 46% with diabetes, baseline LDL 139 mg/dL). Individuals had to have both statin intolerance and either a history of a prior cardiovascular event (approximately 70%) or a high risk of cardiovascular disease (30%). This double-blind study randomized individuals to receive oral bempedoic acid 180 mg daily or placebo and followed them for a median of 40 months. After 6 months of therapy, the reduction in LDL was 29.2 mg/dL greater with bempedoic acid compared to placebo. The incidence of the primary outcome–major adverse cardiovascular events (MACE) defined as death from cardiovascular causes, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization–was significantly lower for those taking bempedoic acid (11.7%) compared to placebo (13.3%), with a HR 0.87 (95% CI 0.79 to 0.96; P=0.004).  Secondary outcomes including the composite of death from CVD or nonfatal MI/stroke; fatal or nonfatal MI; and coronary revascularization also occurred significantly less for those taking bempedoic acid.  Notably, bempedoic acid had no significant effect on rates of fatal or nonfatal stroke, death from cardiovascular cause, or death from any cause. There were higher rates of gout and cholelithiasis among those taking bempedoic acid, but rates of myalgias–and treatment-discontinuation–were similar across arms. 
  
  
• What does this mean? Among adults with statin intolerance requiring primary or secondary cardiovascular prevention, bempedoic acid was associated with a 13% lower risk of major adverse cardiovascular event–but no significant difference in cardiovascular or all-cause mortality–compared to placebo.  Now, hot off the press–a secondary analysis of 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.
  
  The CLEAR study was limited by low non-white enrollment, self-reported statin-intolerance, and some concomitant lipid-lowering therapy administration while on study (including low-dose statins).  Moreover, the cost of bempedoic acid (around 400$ for a monthly supply on GoodRx) likely remains prohibitive for many, for now.  However, the results of CLEAR suggest that for high-risk patients who truly cannot tolerate statins, bempedoic acid may be worth considering–if one can get it. 
  
  Read The Trial Results HERE

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The Curbsiders Digest

Issue 44

Editor in Chief: Nora Taranto MD

Banner: Kate Grant  MBChB, DipGUMed

Disclosures: Beth Garbitelli, Laura Glick,  Alyssa Mancini, Jennifer Desalvo, and Nora Taranto report no disclosures. 

Alexander Chaitoff reports consultancy for Alosa health 

Kate Grant reports no disclosures

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