Find out how tirzepatide might revolutionize weight loss, pharmacogenomics might improve antidepressant prescribing, seasonal edema affects Google searches, and whether nirmatrelvir/ritonavir helps standard-risk patients with COVID-19, and patient-centered recommendations for inpatient care from SHM/Choosing Wisely! Time to fill your plate with a fresh stack of hotcakes! Drs. Paul Williams (@PaulNWilliamz), Rahul Ganatra (@rbganatra), Nora Taranto (@NoraTaranto), and Matt Watto (@doctorwatto) catch us up on recent practice-changing articles and guidelines!
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Deep dives on practice-changing articles.
Jastreboff AM et al; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022 Jul 21;387(3):205-216. doi: 10.1056/NEJMoa2206038. Epub 2022 Jun 4. PMID: 35658024.
Question: Does the glucose-dependent insulinotropic polypeptide/glucagon-like peptide-1 (GIP/GLP1) receptor agonist tirzepatide afford a meaningful reduction in body weight for adults without diabetes who have obesity or who are overweight with weight-related complications?
Comparison: This was a phase 3 multicenter, double-blind, randomized, placebo-controlled trial conducted at 119 sites in nine countries. They assigned 2539 adults in a 1:1:1:1 ratio to receive dietary counseling plus tirzepatide 5 mg, 10 mg, 15 mg, or placebo for 72 weeks (which included a 20-week dose-escalation) with the co-primary endpoints of a) percent change in weight from baseline and b) weight reduction of 5% or more.
Results: This was a positive trial. In the intention-to-treat analysis, tirzepatide achieved a significant dose-dependent mean weight reduction of 15-20.9% vs 3.1% with placebo, an absolute difference of 11.9-17.8%! NNT to achieve at least 10 percent wt reduction was 1.5-2! They lost 4-6 inches of waist circumference compared to placebo. Fifty percent in the 10 mg group and 57% in the 15 mg achieved over 20% weight reduction vs only 3% in the placebo group. The authors excluded patients they did not believe could adhere to the protocol and patients who had used cannabis in the past three months or were unwilling to quit during the study. Both these decisions can bias in favor of the treatment group. Excluding patients with uncontrolled HTN, recent cardiovascular events, cancer, or advanced CKD may have influenced safety outcomes.
Bottom Line: Tirzepatide provides meaningful, impressive weight loss at 72 weeks that approaches outcomes from metabolic surgery! GI side effects accounted for most adverse events, but we need long-term safety data if this is to become a chronic medication used to treat obesity. The cost will continue to limit access for the foreseeable future.
Hotcakes rating: 4 of 5
Additional Info: #264: Semaglutide 2.4 mg weekly plus usual care achieved nearly 15% weight loss at 68 weeks vs. ~2.5% with usual care plus placebo (Wilding, 2021). Unfortunately, weight gain may occur once semaglutide is stopped (Rubino, 2021). Interestingly, semaglutide 2.4 mg weekly provided significantly more weight loss than the 1 mg dose (max dose approved for diabetes) but with similar hemoglobin A1C lowering effects (Davies, 2021).
A brief discussion of recent articles, medical news, guidelines
Oslin DW, et al. Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial. JAMA. 2022 Jul 12;328(2):151-161. doi: 10.1001/jama.2022.9805. PMID: 35819423.
Summary: Selecting effective therapies is challenging in the management of depression, in which we often have to try different medications before we land on the one that works. Are there biomarkers we can use to predict a patient’s response to, or the likelihood of side effects from, antidepressants? Data from the VA’s PRIME study, just published in JAMA, suggests that pharmacogenomic testing could be helpful in selecting antidepressant medications and predicting responders in a subset of patients–but this approach is not yet ready for PRIME time.
Question: Can pharmacogenomic testing for drug-gene interactions in antidepressant selection affect drug choice and remission rates?
Comparison: The PRIME randomized clinical trial enrolled 1944 patients with major depressive disorder (MDD) when they were starting or switching single antidepressant treatment, randomizing patients to either usual care or pharmacogenomic testing for drug-gene interactions. This trial was performed at 22 VA medical centers and was a pragmatic effectiveness study. The pharmacogenomic test was commercially available (Myriad’s GeneSight panel of 12 genes involved in drug metabolism, including CYP2D6, CYP3A4, and CYP2C19), and the primary outcomes measured were the proportion of prescriptions with a predicted drug-gene interaction in 30 days after randomization, and the remission of depressive symptoms on PHQ-9–at both 12 and 24 weeks.
Result: In this trial, utilization of pharmacogenomic tests to identify variation in drug metabolism compared with usual care resulted in a significantly lower likelihood of receiving a medication with a predicted drug-gene interaction (45% versus 18% chance of a prescription with no predicted drug-gene interactions). There was more remission of symptoms in the pharmacogenomic testing group than the standard of care group at 12 weeks (16.5% versus 11.2%), but the rates of remission were similar at 24 weeks (estimated risk difference 1.5, p = 0.45). Response to treatment and reduction in symptom severity (secondary outcomes) also slightly favored the pharmacogenomic group.
Bottom line: This trial was a technically positive trial but of unclear clinical relevance. It builds on several prior studies which have shown similar modest improvements with pharmacogenomic guidance–though effect size in remitting symptoms in PRIME was small, and one that didn’t persist over time. It was also unclear how clinicians used the “predicted drug-gene interaction” information–and what exactly this surrogate outcome is a measure of since the study did not look at adverse effects or dosing adjustment. Given that a majority of patients in this trial had either no or moderate drug interactions noted on pharmacogenomic testing, the clinical relevance of getting this data before prescribing an antidepressant is unclear.
Summary: Anecdotally, we see more lower extremity edema in the primary care office in the summertime. The majority of these patients are not subsequently diagnosed with cardiovascular disease, DVT, or other major health concerns. The authors of this study used Google trends to evaluate seasonal trends in searches for lower extremity edema to determine if edema was indeed “seasonally modulated.” Sure enough, searches for “ankle swelling” are highest in the summer and lowest in the winter, which is true in both the northern and summer hemisphere.
Question: Is there objective evidence that the symptom burden of ankle swelling is seasonally modulated?
Comparison: The authors plotted search volume against two models–a linear “null model” and a sinusoidal model that accounted for seasonal variation.
Result: The seasonal model provided a significantly better fit than the null model, with seasonality accounting for 86% of the variability in search. Searches peaked in June and had a trough in December in the United States. Interestingly, heart failure admissions demonstrate an opposite trend. Australia’s reversed seasons followed the same pattern of searches for edema. An important limitation is that the authors assume that Google searches for terms related to ankle edema are a reasonable surrogate for patients seeking care for this problem. Though this may be imprecise for measuring the prevalence of edema, as long as the relationship between Google searches and care-seeking behavior doesn’t change substantially throughout the year, it should still allow estimation of seasonal trends.
Bottom line: This is an extraordinarily clever and straightforward study using existing data to show large patterns in disease epidemiology. There are obvious limitations here, but this not only helps confirm my own personal biases but is also a neat demonstration of how to evaluate data.
ClinicalTrials.gov protocol: https://clinicaltrials.gov/ct2/show/NCT05011513
Summary: Ever since the FDA granted authorization to ritonavir-boosted-nirmatrelvir (nirmatrelvir/r, brand name Paxloid) for the treatment of high-risk outpatients with COVID19, the benefit of which was established convincingly by the EPIC-HR trial, many questions have been raised about which patients benefit most from it and what the true downsides are. Well, thanks to a press release from Pfizer last month, we now have a little more information to guide practice: nirmatrelvir/r did not hasten time to symptom resolution among low-risk patients (including vaccinated and boosted patients).
Question: Does nirmatrelvir/r reduce time to symptom resolution among low-risk outpatients with COVID19 (including vaccinated patients)?
Comparison: Patients with symptomatic COVID19 diagnosed within five days were randomized to receive nirmatrelvir/r or placebo for five days. Patients were excluded if they had any high-risk conditions, prior hospitalization for, or prior infection with COVID.
Result: Though the manuscript is not available, the press release reports that patients who received nirmatrelvir/r did not experience a reduction in time to sustained alleviation of symptoms (the primary outcome). That is to say, this was a negative study. Secondary analysis suggested benefit in terms of a reduction in COVID19-related medical visits in the nirmatrelvir/r group, but the details needed to evaluate this are not provided. Due to low event rates, enrollment in the study was stopped in July 2022.
There were two clues that EPIC-SR would be a negative study. The first is that the sample size was increased from 1140 to 1440 patients, and the second was that in EPIC-HR, patients who were seropositive on enrollment had a markedly attenuated benefit of nirmatrelvir/r in comparison with patients who were seronegative. This suggests that patients who have already started to mount their own immune response benefit less from an antiviral, which is essentially what happens during infection in a vaccinated host.
Bottom line: Nirmatrelvir/r, which markedly reduces risk of hospitalization and death among high-risk unvaccinated outpatients with COVID19, has not been shown to improve symptoms or other outcomes in low-risk and vaccinated outpatients. NIH guidelines recommend prioritizing patients at the highest risk for morbidity and mortality from COVID19 for treatment with nirmatrelvir/r: unvaccinated patients, those with advanced age, or immunocompromise.
Summary: Patient-centered recommendations from SHM. Here’s a few of my favorite
Bottom line: Common sense and common decency should be incorporated into the hospitalized patient’s care. These recommendations are low-cost, and patient-centered, which is a win-win.
Listeners will review recent practice-changing articles and medical news.
After listening to this episode listeners will…
The Curbsiders report no relevant financial disclosures.
Taranto NP, Ganatra RB, Williams PN, Watto MF. “#349 Hotcakes: Tirzepatide for weight loss, Personalized Antidepressants, Seasonal Edema, Nirmatrelvir for low-risk COVID-19”. The Curbsiders Internal Medicine Podcast. http://thecurbsiders.com/episode-list Final publishing date August 8, 2022.
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