Primecuts – This Week in the Journals

July 23, 2021

Erin Bresnahan, MD
Peer Reviewed

With medicine advancing at such a rapid pace, it is crucial for physicians to keep up with the medical literature. This can quickly become an overwhelming endeavor given the sheer quantity and breadth of literature released on a daily basis. Primecuts helps you stay current by taking a shallow dive into recently released articles that should be on your radar. Our goal is for you to slow down and take a few small sips from the medical literature firehose.

Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomized, phase 3 trial [1]

Some of the most successful insulin-sparing glycemic control agents used in type 2 diabetes mellitus (DMII) manipulate gastrointestinal peptide signaling. In particular, GLP-1 analogues have proven effective for HgbA1C reduction and weight loss. Targeting the incretin molecular pathway at two different points, with both a GLP-1 agonist as well as an agonist of incretin hormone GIP (glucose-dependent insulinotropic polypeptide), has been shown in preclinical studies to have a more robust effect on glycemic and weight control than either agent alone. A synthetic peptide dual GIP- and GLP-1- agonist, tirzepatide showed promising results in phase 1 and 2 clinical trials with purported benefit over single agent GLP-1 agonists. SURPASS-1 was a subsequent Phase 3 randomized, double-blinded, multicenter international clinical trial with over 450 patients investigating tirzepatide at 3 different doses (5 mg, 10 mg, and 15 mg weekly) compared with placebo for 40 weeks of treatment. Inclusion criteria included patients with DMII naïve to injectable therapy, with HgbA1C between 7.0-9.5%, BMI >23, EGFR >30, and no history of pancreatitis. All groups were permitted only diet/exercise-based diabetic control aside from their assigned blinded intervention; however, patients demonstrating persistent severe hyperglycemia were permitted to initiate rescue therapy, with metformin as first line antihyperglycemic agent. Only 2-3% of the patients in the tirzepatide groups required rescue therapy, compared with 25% of the placebo group.

Results showed significant improvement in HgbA1C at 40 weeks (primary endpoint) compared with placebo in all dosing groups, and significant weight loss (7-9.5 kg) in a dose-dependent manner. Main side effects included nausea, vomiting, and diarrhea, at higher frequency with escalating doses. These side effects diminished with time in all groups. There were no episodes of clinically significant hypoglycemia. Tirzepatide is a promising agent for glycemic and weight control in DMII; an additional phase 3 trial, SURPASS-2, is currently underway to compare tirzepatide directly to semaglutide (rather than placebo, as evaluated in SURPASS-1) to evaluate its comparative efficacy, which was a limitation of this trial.

Mortality Benefit of Rivaroxaban Plus Aspirin in Patients with Chronic Coronary or Peripheral Artery Disease [2]

Patients with chronic atherosclerotic vascular disease have high rates of recurrent cardiovascular events, even with the use of multiple approved mortality-reducing agents. The optimal anti-thrombotic strategy for these patients has been the subject of much investigation in recent years. The COMPASS trial, a multicenter international randomized trial which enrolled 27,395 patients, compared use of aspirin alone, aspirin+low dose rivaroxaban, and full-dose rivaroxaban alone for patients with stable cardiovascular disease [7]. The results, published in 2017, noted significantly lower major adverse cardiac events (primary outcome), significantly increased rates of major bleeding, but no difference in intracranial or fatal bleeds when comparing the aspirin+rivaroxaban group to aspirin alone [8]. The current paper used data from the aspirin+rivaroxaban and aspirin alone groups of this study and focused on analyzing all-cause mortality.

The rivaroxaban+aspirin group demonstrated a significantly lower mortality rate of 3.4%, compared with 4.1% in the aspirin only group (HR of 0.82 (0.71-0.96)). However, the authors of this paper acknowledge as a main limitation of their study that they did not apply statistical adjustments to account for multiple exploratory analyses. In the original data analysis of the COMPASS Trial, mortality outcomes had already been analyzed by the investigators with the same differences noted, but these differences did not meet the statistical significance standards pre-specified in the clinical trial plan [8].

The current paper highlights some of the issues with extracting data from large clinical trials that were designed and powered to analyze a specific research question and using that data to explore other clinical questions. Although initially the conclusions of this paper seemed promising, this was diminished when reviewing the initial trial and discovering that mortality differences did not meet pre-specified significance thresholds on the initial study. In particular, with the use of very large sample sizes in studies conducted over a relatively short period of time (compared with the time course over which atherosclerotic vascular disease kills) with a low event rate, the risk of finding statistically significant but clinically insignificant differences is high. Although adding low-dose rivaroxaban to aspirin may have promise for secondary prevention in patients with chronic CAD or PAD, conclusions about mortality benefit would need to be further explored in a more rigorously controlled trial with mortality as a primary endpoint.

CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis [3]

Transthyretin amyloidosis (ATTR) is a disease in which abnormal aggregates of fibrils of the transthyretin (TTR) protein deposit in various organs, most commonly causing polyneuropathy and cardiomyopathy. There are numerous heritable nucleotide variants in the gene encoding TTR which can lead to this progressive, often fatal disease. Current medications targeting the underlying disease process in ATTR either stabilize the tetrameric form of TTR to prevent amyloid formation (tafamidis, diflunisal) or reduce hepatic production of TTR by targeting the protein’s RNA (antisense oligonucleotide inotersen, small interfering RNA patisiran) [9-11].

This study reports initial findings of an ongoing phase 1 trial of investigational agent NTLA-2001, a guide RNA targeting the TTR gene with the CRISPR-cas9 system, packaged in a nanoparticle targeted to the liver (where transthyretin is produced). Participants had a diagnosis of hereditary ATTR amyloidosis with polyneuropathy (+/- cardiac involvement) and were not previously treated with patisiran or inotersen (prior tafamidis or diflunisal use was permitted with adequate washout period).

Six patients were enrolled, with three given a one-time dose of 0.1 mg/kg of the investigational agent, and three receiving a one-time dose of 0.3 mg/kg. The concentration of TTR protein in serum at 28 days after drug administration underwent a mean reduction of 52% in the 0.1 mg/kg dosing group (range 47-56) and 87% (range 80-96) in the 0.3 mg/kg group. The treatment was well-tolerated, with only mild-grade adverse events noted in 3 patients. These patients will continue to be monitored moving forward to evaluate long-term effects and efficacy of TTR knockdown. Despite the small sample size, the tolerability of this agent and initial success of TTR knockdown in humans at low doses is a promising step towards more robust amyloid suppression.


First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial [4]

This study looked at the usage of PD-1 inhibitor nivolumab in combination with chemotherapy as a first-line treatment for unresectable HER2-negative gastric and gastroesophageal cancers.1581 patients were randomized in 1:1:1 fashion to receive nivolumab+chemotherapy, chemotherapy alone, or nivolumab+ipilimumab. The nivolumab+chemotherapy group showed significantly longer overall survival (OS) and progression free survival (PFS) compared with chemotherapy alone (HR 0.71 OS, HR 0.68 PFS), for patients with high PD-L1 expression. There was a higher incidence of grade 3-4 adverse events in the nivolumab+chemotherapy group (59 vs 44%), however this was considered an acceptable/manageable safety profile. This is the first study to show significant improvement in both OS and PFS with nivolumab+chemotherapy as first-line treatment for advanced esophageal and gastric cancers, which has implications for changes in the standard of care for this patient population.

Bedside Abdominal Ultrasound in Evaluating Nasogastric Tube Placement: A Multicenter, Prospective, Cohort Study [5]

After taking a 10-hour course on ultrasound protocol, physicians analyzed bedside ultrasounds of 526 patients to determine correct NGT placement, and these reads were compared with a gold-standard of chest radiography. Ultrasound was inconclusive in 7.6% of cases, but in the cases of a conclusive interpretation, ultrasound showed a sensitivity of 99.8%, specificity of 91.0%, PPV of 98.3%, and NPV of 98.6% for concluding correct NGT placement. This prospective, multicenter study suggests good potential for ultrasound as a tool for NGT placement assessment; however a specificity of 91% in a study that is mainly done to identify improper placement (and avoid its negative consequences) leaves room for improvement prior to more widespread safe implementation.

Withholding Primary Pneumocystis Pneumonia Prophylaxis in Virologically Suppressed Patients With Human Immunodeficiency Virus: An Emulation of a Pragmatic Trial in COHERE [6]

It is standard practice in many clinical settings to prescribe PCP prophylaxis to HIV-positive patients until their CD4 count rises above a specified threshold for 3 months (100 cells/ul based on EACS guidelines, or 200 based on NIH guidelines). This study used a simulated trial to evaluate risk of PCP infection if prophylaxis was discontinued when viral load fell below 400 RNA copies/ml plasma, compared with discontinuation after CD4 count improved above 200. Based on this trial simulation including 4813 patients from the COHERE database of HIV cohorts, incidence rates of PCP were not significantly different between the two strategies; thus, stopping prophylaxis after viral suppression to <400 appears safe. Risk of adverse antibiotic side effects and promotion of antibiotic resistance could theoretically be decreased with implementation of this strategy as virologic suppression occurs more rapidly than recovery of CD4 count.

Dr. Erin Bresnahan, 2nd year resident, Internal Medicine, NYU Langone Health

Peer reviewed by Neha Nagpal, MD, Chief Resident, Internal Medicine, NYU Langone Health

Image courtesy of Wikimedia Commons – Source:
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1. Rosenstock J, Wysham C, et al. Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): a double-blind, randomised, phase 3 trial. Lancet. 2021 Jul 10;398(10295):143-155. doi: 10.1016/S0140-6736(21)01324-6. Epub 2021 Jun 27. Erratum in: Lancet. 2021 Jul 17;398(10296):212. PMID: 34186022.
2. Eikelboom JW, Bhatt DL, et al. Mortality Benefit of Rivaroxaban Plus Aspirin in Patients With Chronic Coronary or Peripheral Artery Disease. J Am Coll Cardiol. 2021 Jul 6;78(1):14-23. doi: 10.1016/j.jacc.2021.04.083. PMID: 34210409.
3. Gillmore JD, Gane E, et al. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis. N Engl J Med. 2021 Jun 26. doi: 10.1056/NEJMoa2107454. Epub ahead of print. PMID: 34215024.   
4. Janjigian YY, Shitara K, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021 Jul 3;398(10294):27-40. doi: 10.1016/S0140-6736(21)00797-2. Epub 2021 Jun 5. PMID: 34102137.
5. Mumoli N, Vitale J, et al. Bedside Abdominal Ultrasound in Evaluating Nasogastric Tube Placement: A Multicenter, Prospective, Cohort Study. Chest. 2021 Jun;159(6):2366-2372. doi: 10.1016/j.chest.2021.01.058. Epub 2021 Feb 2. PMID: 33545162. 
6. Atkinson A, Zwahlen M, et al. Withholding Primary Pneumocystis Pneumonia Prophylaxis in Virologically Suppressed Patients With Human Immunodeficiency Virus: An Emulation of a Pragmatic Trial in COHERE. Clin Infect Dis. 2021 Jul 15;73(2):195-202. doi: 10.1093/cid/ciaa615. PMID: 32448894.
7. Bosch J, Eikelboom JW, et al. Rationale, Design and Baseline Characteristics of Participants in the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) Trial. Can J Cardiol. 2017 Aug;33(8):1027-1035. doi: 10.1016/j.cjca.2017.06.001. Epub 2017 Jun 8. PMID: 28754388.
8. Eikelboom JW, Connolly SJ, et al. Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease. N Engl J Med. 2017 Oct 5;377(14):1319-1330. doi: 10.1056/NEJMoa1709118. Epub 2017 Aug 27. PMID: 28844192.
9. Benson MD, Waddington-Cruz M, et al. Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):22-31. doi: 10.1056/NEJMoa1716793. PMID: 29972757.
10. Adams D, Gonzalez-Duarte A, et al. Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis. N Engl J Med. 2018 Jul 5;379(1):11-21. doi: 10.1056/NEJMoa1716153. PMID: 29972753.
11. Maurer MS, Schwartz JH, et al. Tafamidis Treatment for Patients with Transthyretin Amyloid Cardiomyopathy. N Engl J Med. 2018 Sep 13;379(11):1007-1016. doi: 10.1056/NEJMoa1805689. Epub 2018 Aug 27. PMID: 30145929.