Primecuts – This Week in the Journals

October 8, 2021

PrimeCuts Uncategorized 8 min read

By Hannah Kopinsky, 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. 

Association Between Cumulative Low-Density Lipoprotein Cholesterol Exposure During Young Adulthood and Middle Age and Risk of Cardiovascular Events [1] https://jamanetwork.com/journals/jamacardiology/article-abstract/2784038

 This cohort study evaluated the associations of cumulative exposure to LDL-C, time-weighted average (TWA) LDL-C (cumulative exposure to LDL-C divided by duration of exposure), and the LDL-C slope change (how rapidly LDL-C accumulates) during young adulthood and middle age to the incidence of cardiovascular events later in life. The investigators analyzed data from 4 prospective cohort studies with a total sample size of 18,288 subjects. Participants were included in the study if they had 2 or more LDL-C measures that were at least 2 years apart between ages 18 and 60, with at least one measure taking place between ages 40 and 60. Participants were excluded if they had an existing cardiovascular episode or if they had missing covariate data (BMI, blood pressure, smoking status). To make up for the difference in age ranges across the four studies, the investigators modeled LDL-C trajectories from 18 years of age to the end of follow-up for all participants and used those trajectories to estimate cumulative exposure to LDL-C, the TWA LDL-C, and the LDL-C slope. The investigators found a hazard ratio for coronary heart disease of 1.57 for cumulative LDL-C level (95% CI, 1.10-2.23; p for trend =.01), 1.69 for TWA LDL-C level (95% CI, 1.23-2.31; p for trend <.001), and 0.88 for LDL-C slope (95% CI, 0.69-1.12; p for trend =0.28). There were no associations between any LDL-C variables and ischemic stroke or heart failure. Overall, this study showed that there is an association between cumulative LDL-C exposure and coronary heart disease, independent of midlife LDL-C level. It suggests that physicians should consider performing cholesterol screening measures starting in early adulthood for patients who are high risk for developing coronary heart disease. This could permit early intervention and prevention of adverse cardiac events in the future. A primary limitation of this study is the variability in age range among all 4 studies. Notably, one study had participants aged 45-64, while another had individuals aged 18-30. The investigators modeled the LDL-C trajectories to compensate, though this is subject to error.

New Creatinine- and Cystatin C–Based Equations to Estimate GFR without Race [2]
https://www.nejm.org/doi/full/10.1056/NEJMoa2102953?query=featured_home

Creatinine and cystatin C are two serum markers that are used to estimate GFR and kidney function. The standard equation that estimates GFR also includes race as a variable (black vs. non-black), based on prior studies showing that black participants had a higher average serum creatinine level [3-5]. The inclusion of race in the GFR estimation has faced scrutiny in recent years, given that race is not a biologically rooted concept and that characterizing a patient as “black” or “non-black” ignores the ethnic and geographical differences seen within racial groups. The investigators of this study created new eGFR equations that exclude race and compared them to measured GFR to test for accuracy. They developed the new equations using two separate data sets, one with 8254 participants (31.5% black) for serum creatinine and one with 5352 participants (39.7% black) for creatinine and cystatin C. They then tested the validity of their equations with the measured GFR from a third data set that had 4050 participants (14.3% black) and compared this to the standard eGFR equation that includes race. The investigators also evaluated the effect of their equations on the prevalence estimates for CKD. Participants needed to be at least 18 years of age to be included in the study. The results revealed that the standard creatinine equation that utilizes race overestimated the measured GFR in black patients (median, 3.7 ml per minute 1.73 m2 of body-surface area; 95% CI, 1.8 to 5.4), and that using the same creatinine equation but omitting race as a variable underestimated the measured GFR in black patients (median, 7.1 ml per minute per 1.73 m2; 95% CI, 5.9 to 8.8). The GFR for black patients was also underestimated when utilizing their new equation that omitted race but only considered serum creatinine and not cystatin C. However, the new eGFR equations created by the investigators that utilized both creatinine and cystatin C was most accurate to the measured GFR and exhibited smaller differences between racial groups. This study demonstrates that including race in the estimation of GFR can lead to undertreatment in black patients, given that the standard creatinine equation that utilizes race resulted in an overestimation of GFR in black patients. This would indicate that CKD has been under-diagnosed in this population and as a result, black patients likely have not been receiving optimum treatment for their disease. However, the authors also note that their equation lead to an under estimation of the prevalence of CKD in non-black populations, which would be counter-productive in their attempt to mitigate discrepancies in health care among different racial groups. Further studies are needed to find an optimal equation, or set of equations, to estimate GFR in different populations that most accurately reflects the measured GFR and prevalence of CKD.

Cardiovascular and Renal Outcomes with Efpeglenatide in Type 2 Diabetes [6]
https://www.nejm.org/doi/full/10.1056/NEJMoa2108269

Prior studies have shown that GLP-1 receptor agonists reduce the risk of cardiovascular and adverse renal events in diabetic patients [7]. Efpeglenatide is a long-acting medication that acts similarly to GLP-1 receptor agonists but has an exendin based structure and a lower risk of hypoglycemia [8, 9]. However, the effects of Efpeglenatide on adverse cardiovascular and renal events in diabetic patients is unknown. Additionally, the effect of these outcomes when GLP-1 agonists are taken alone or in combination with SGLT2 inhibitors is still being studied [10]. This study was a randomized, controlled trial with 4076 participants. All participants had type 2 diabetes mellitus and a glycated hemoglobin > 7%. Of those enrolled, 15.2% of patients were using an SGLT2 inhibitor at baseline. Inclusion criteria required participants to be at least 18 years of age with a history of cardiovascular disease, or to be at least 50 (if male) or 55 (if female) with kidney disease and at least one additional cardiovascular risk factor. Patients were excluded if they had GI symptoms at baseline (such as gastroparesis or uncontrolled reflux), severe retinal disease, or use of GLP-1 receptor agonists or DPP-4 inhibitors in the past 3 months. Participants were randomized into 3 groups who received weekly injections of Efpeglenatide at a dose of 4mg, 6mg, or a placebo. When patients were followed up at a median of 1.81 years after the study, an adverse cardiac event occurred in 7% of patients who received Efpeglenatide and in 9.2% of the patients who received placebo (hazard ratio of 0.73; 95% CI 0.58 to 0.92; P<0.001 for noninferiority; P=0.007 for superiority). Worsening renal function occurred in 13% of patients who received Efpeglenatide and in 18.4% of patients who received placebo (hazard ratio of 0.68; 95% CI 0.57 to 0.79; P<0.001). This study demonstrated that Efpeglenatide reduces the risk of adverse cardiovascular and renal outcomes in patients with type 2 diabetes and a high baseline level of cardiovascular or renal disease. Additionally, it is important to note that the results of this study showed that the cardiovascular benefits from Efpeglenatide occurred independent of the use of an SGLT2 inhibitor at baseline, as there were overlapping confidence intervals for the cardiovascular effects with or without SGLT2 inhibitors. This study is useful for clinicians as this drug is only a once-weekly injection and it also has low risk of hypoglycemia while also promoting weight loss and strong glycemic control. Further studies are needed to determine the effect of GLP-1 receptor agonists in combination with SGLT2 inhibitors on cardiovascular and renal outcomes in diabetic patients.

Minicuts:

Safety and Immunogenicity of an Anti–Zika Virus DNA Vaccine [11]
https://www.nejm.org/doi/full/10.1056/NEJMoa1708120

There are currently no approved vaccines against Zika virus infection. This study tested the safety and immunogenicity of a synthetic, consensus DNA vaccine. It was a phase 1, open-label clinical trial that took place across three locations: Philadelphia, Miami, and Quebec. A total of 40 participants were enrolled and received 3 doses of the vaccine, four weeks apart. Serum samples were collected throughout the study and analyzed on ELISA to measure binding-antibody responses to the recombinant vaccine-matched Zika virus envelope protein. Two weeks after the final dose, there was a 70-95% antibody response in all participants. There were no major adverse events reported. The most frequently reported adverse effects included injection-site pain (50% of participants), and more uncommonly headache, myalgias, fatigue, and nausea.

Prospective, Multicenter, Controlled Trial of Mobile Stroke Units [12]
https://www.nejm.org/doi/full/10.1056/NEJMoa2103879

Mobile stroke units (MSUs) are specialized ambulances that are equipped with staff and a CT scanner to reduce the time to diagnosis and treatment of acute strokes. This prospective, observational study investigated whether MSUs have improved patient outcomes compared to EMS by utilizing a designated alternating weekly schedule of either modality. 1515 patients were enrolled in the study, of whom 1047 were eligible for t-PA. Of the patients who were eligible to receive t-PA, 97.1% of patients in the MSU group received t-PA and 79.5% of patients in the EMS group received t-PA. The median time from onset of stroke symptoms to administration of t-PA was 72 minutes in the MSU group and 108 minutes in the EMS group. Patients who were in the MSU group had less disability indicated by the modified Rankin scale at 90 days post stroke compared to the EMS group. Additionally, mortality at 90 days was 8.9% in the MSU group and 11.9% in the EMS group.

 Effect of Salt Substitution on Cardiovascular Events and Death [13] https://www.nejm.org/doi/full/10.1056/NEJMoa2105675

Salt substitutes with reduced sodium and added potassium have shown to be effective at reducing blood pressure, but their effects on CAD have never been investigated. This study was an open-label, cluster-randomized trial from 600 villages in rural China. A total of 20,995 participants were enrolled in the trial. The results showed that patients who were high risk for CAD had lower rates of stroke, major cardiovascular events, and death of all causes when using salt substitutes rather than regular salt. Sodium reduction and potassium supplementation have been shown to independently lower blood pressure and have additive benefits; the effects observed may be due to enhanced blood pressure control [14-17].

Dr. Hannah Kopinsky is a 1st year resident at NYU Langone Health

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

Image courtesy of Wikimedia Commons, source: Neideck Ruine Pano-20191020-RM-110644.jpg, author: Neideck Ruine Pano-20191020-RM-110644

References

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  1. Inker LA, Eneanya ND, Coresh J, et al. New Creatinine- and Cystatin C–Based Equations to Estimate GFR without Race. N Engl J Med. 2021. DOI: 10.1056/NEJMoa2102953
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  1. Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol 2019;7:776-785.
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  1. Tebas P, Roberts CC, Muthumani K, Reuschel EL, Kudchodkar SB, Zaidi FI, et al. Safety and Immunogenicity of an Anti–Zika Virus DNA Vaccine. New England Journal of Medicine. 2017;385(12):e35.
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