Primecuts – This Week in the Journals

August 5, 2020

By Marcus Anthony, 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 fire hose.

[1] Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis: A Multicenter Cohort Study;

In this population-based cohort study, sodium-glucose cotransporter-2 (SGLT-2) inhibitors were evaluated for their risk of causing diabetic ketoacidosis (DKA) compared to dipeptidyl peptidase-4 (DPP-4) inhibitors in patients with type 2 diabetes. This study comes in the wake of several other studies that presented concerning data regarding the risk of DKA associated with SGLT-2 inhibitors [2,3]. Researchers have speculated that SGLT-2 inhibitors increase the risk of developing DKA in patients with diabetes by indirectly elevating the rates of ketogenesis and lipolysis following increased urinary loss of glucose [4].

Using healthcare databases from seven Canadian Provinces and the Clinical Practice Research Datalink database from the United Kingdom, 208,757 diabetic patients being initiated on SGLT-2 inhibitors were identified between 2013 and 2018. The studied comparison group consisted of a matched cohort of 208,757 diabetics receiving DPP-4 inhibitors. Study participants were 41% female with an average age of 64 years-old and an average diabetes duration of approximately thirteen years. Patients were excluded for no recorded sex, age < 18 years-old, limited healthcare coverage before cohort entry date, and hospitalization for DKA within 365 days of cohort entry date.  The primary outcome was hospitalization with a primary diagnosis of DKA.

During the study period, SGLT-2 inhibitors were observed to have a nearly three-fold increase in risk for DKA (incidence rates, 2.03 versus 0.75 per 1000 person-years; HR, 2.85 [CI, 1.99 to 4.08]). This translated into a low absolute risk of .18% and .07% with an overall number needed to harm of approximately 845. Although modest, the increased risk was consistent across all SGLT-2 molecules observed in the study (dapagliflozin, empagliflozin, and canagliflozin), indicating a likely class effect of SGLT-2 inhibitors. Further subgroup analysis revealed the risk for DKA did not vary based on age and sex in patients receiving SGLT-2 inhibitors.

The study’s findings, though robust and generally applicable to most patient populations, do have several limitations. First the average follow-up period was less than a year, which may have led to an observed incidence of DKA that was inappropriately low. Alternatively, a significant amount of laboratory data was reportedly missing for each cohort. Without this data, it is possible that one of the study groups included more patients with poorly controlled diabetes who could have theoretically been at higher risk of DKA due to inadequate insulin therapy, which could have skewed the observed incidence of DKA. Overall, despite the low absolute risk, the study’s findings still warrant consideration of the risk of DKA when initially prescribing an SGLT-2 inhibitor to a diabetic patient, especially one who may already be high risk for developing DKA.

[5] Nonsteroidal Anti-inflammatory Drugs vs Cognitive Behavioral Therapy for Arthritis Pain: A Randomized Withdrawal Trial;

Investigators in the Veterans Affairs (VA) Healthcare System conducted this study to determine whether placebo and cognitive behavioral therapy (CBT) was noninferior to NSAID therapy for chronic osteoarthritis pain in patients who required NSAIDs for pain management.

To do so, they designed a multi-center withdrawal study that randomized participants to either four then ten weeks of meloxicam (n=184, total 14 weeks meloxicam) or four weeks of placebo followed by a ten week long CBT program (n=180, total 14 weeks placebo and CBT). Noninferiority was pre-specified by the conducting research group as a Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score difference of less than 1 between the two cohorts. Therefore, if the observed delta between WOMAC scores between study groups was found be to greater than 1, the placebo and CBT was to be accepted as inferior to meloxicam.

At four weeks the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score was measured for a first time. At this juncture, the placebo was found to be inferior to meloxicam with an observed difference in WOMAC pain scores of 1.4 (95% CI, 0.8-2.0; noninferiority test P = .92). The investigators then reassessed pain scores after completion of the ten additional weeks of meloxicam and ten weeks of CBT. Again, CBT/placebo was inferior to meloxicam with an observed difference in WOMAC pain scores of 0.8 (95% CI, 0.2-1.4; noninferiority P = .28). Finally, it was observed that there was no significant difference in the additional secondary outcomes that assessed global impression of change and lower extremity disability at fourteen weeks.

Interestingly, although the differences in WOMAC pain scores at four and fourteen weeks were lower than those considered to be clinically significant, because the confidence intervals crossed the preset noninferiority margin of 1, the effect of placebo and CBT at 4 and 14 weeks was considered inferior. Despite rejecting the noninferior hypothesis, however; the observed impact on pain scores was trending towards noninferiority by the end of the study.

Of note, several limitations of the study may have limited the observed impact of CBT. First, the vast majority of study participants were white men ( > 80%) with an average age of 58 year-old. This limits the applicability of the study’s findings and may not accurately represent the potential impact of CBT on the general population with OA. Furthermore, considering the significant cardiovascular, gastrointestinal, and renal side effects associated with chronic NSAID use and rather limited side effect profile of CBT, it may have been appropriate to set a higher noninferiority margin to better weigh both clinical impact and side effects of each therapy. In all, when establishing a treatment course for a patient with chronic OA pain, providers may want to strongly consider CBT after discussing the side effects of potential therapies and after exploring the patient’s individual preferences and perceptions of CBT.

[6] Clinical presentation and outcomes of acute pericarditis in a large urban hospital in the United States of America;

Despite being a relatively common cause of acute chest pain and the most common presentation of pericardial disease, there is currently limited epidemiological data that describers the prognostic value of the clinical features associated with acute pericarditis [7]. As a result, researchers at Virginia Commonwealth University Medical Center recently conducted a retrospective analysis of patient’s initially diagnosed with acute pericarditis in both the inpatient and outpatient settings to determine which clinical findings of acute pericarditis were associated with adverse outcomes.

Using their medical centers data warehouse, the investigators were able to gather clinical data on patients with an initial diagnosis of acute pericarditis using ICD-10 and ICD-9 between January 2009 and November 2018. A total of 240 patients were identified with a first diagnosis of acute pericarditis who also met the European Society of Cardiology diagnostic criteria for acute pericarditis (at least two of the following (1) pericardial chest pain (2) pericardial rub (3) new widespread ST-elevation or PR depression on EKG (4) new or worsening pericardial effusion on imaging) on chart review. The primary outcome of the study was a composite adverse outcome which included recurrent pericarditis, constrictive pericarditis, cardiac tamponade, failure of treatment, and death.

Within the study group, a total of 82 adverse events were recorded in the median follow up time of 179 days (34% of patients). Recurrent pericarditis was the most common adverse event, which occurred in 15.8% of participants. In regards to clinical features, subacute presentation, defined as a presentation developing over a six week to three month interval, was associated with increased odds of the composite adverse outcome (OR 10.69, 95% CI 2.28–50.07, P=.003). Interestingly, an elevated troponin I was associated with a reduced occurrence of the adverse composite outcome (OR 0.27, 95% CI 0.11-0.69, P=.004). The etiology of the acute pericarditis (either idiopathic or post cardiac injury) and baseline demographics were, however, not reported to have significant influence of the rate of adverse outcomes.

Given the findings in this study, a clinical provider must consider the presentation of a patient’s acute pericarditis when assessing the future risk of adverse outcomes, especially when symptoms have been present for an extended amount of time. Interestingly, elevated troponin, which may indicate the clinical syndrome is being driven by a primary process injuring the myocardium (for example: myocardial infarction, acute myocarditis, Takotsubo cardiomyopathy, pulmonary embolism with right heart failure, trauma, etc.) may help providers ascertain the underlying etiology and educate patients on their apparently decreased risk of adverse outcomes.


[8] Trends and Predictors of Use of Digital Health Technology in the United States;

Given the near ubiquitous use of mobile devices by a large percentage of the United States population, there is unprecedented opportunity for healthcare providers to engage and treat patients through remote channels. Despite the promise of digital technologies to improve patient outcomes and experience, measures need to be taken to ensure these new technologies are developed and deployed in an equitable fashion. Here, data from the National Health Interview Survey is used to elucidate the adoption patterns of subpopulations across the United States between 2011 and 2018. The findings described show that despite an overall increase in utilization of digital healthcare platforms, adoption between groups based on race/ethnic background, education status, and family income differ significantly, raising concern that mobile health technologies may not inherently reduce disparities in access to care.

[9] Renin–Angiotensin–Aldosterone System Inhibitors and Risk of Covid-19;

It has been reported that Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) likely causes Coronavirus Disease 2019 (COVID-19) by gaining access to respiratory epithelium via the angiotensin-converting enzyme 2 receptor [10]. In this study, researchers sought to determine whether prior exposure to renin-angiotensin-aldosterone system inhibitors increases patients’ risk of COVID-19. The findings from their retrospective analysis showed no significant association between prior ACE inhibitor, angiotensin receptor blocker, beta-blocker, calcium-channel blocker, or thiazide diuretic use and likelihood of testing positive for COVID-19. They also reported no increased risk of severe COVID-19 illness in patients previously treated with any agent belonging to the aforementioned medication classes.

[11] A Randomized Controlled Trial of an Electronic Clinical Decision Support Tool for Inpatient Antimicrobial Stewardship

In this randomized controlled study, use of an inpatient antibiotic stewardship and antibiogram tool developed by NorthShore University Health System was evaluated across four hospitals to determine if its utilization would  impact length of hospital stay for patients with urinary tract infection (UTI), abdominal-biliary infection (ABI), pneumonia, or non-purulent cellulitis. After enrolling over 6,800 participants, the researchers reported no significant overall difference in length of stay and several secondary outcomes (including 30-day mortality, readmission rates, and costs, among others) when comparing the intervention group and control group. However, subgroup analysis did show significant decrease in hospital length of stay in patient’s treated for cellulitis and significant decrease in 30-day mortality in patients with community acquired pneumonia.

[12] Serial Bone Density Measurement and Incident Fracture Risk Discrimination in Postmenopausal Women

Using data collected during the Women’s Health Initiative (WHI) Study on 7419 women between 1993 and 2010, this study aimed to retrospectively determine whether or not repeated bone mineral density (BMD) measurements in postmenopausal women approximately three years after initial assessment (baseline BMD) was associated with decreased risk of fracture. Upon analysis of the collected data, it was concluded that changes in BMD based on repeated BMD measurements were no more predictive of increased risk of fracture compared to baseline BMD measurements alone, indicating that repeat BMD measurements are likely not clinically useful for evaluating risk of fracture in postmenopausal women.

Dr. Marcus Anthony is a first year resident at NYU Langone Health

Peer reviewed by Neil Shapiro, Editor-in-Chief, Clinical Correlations

Image courtesy of Wikimedia Commons


  1. Douros A, Lix LM, Fralick M, et al. Sodium-Glucose Cotransporter-2 Inhibitors and the Risk for Diabetic Ketoacidosis: A Multicenter Cohort Study [published online ahead of print, 2020 Jul 28]. Ann Intern Med. 2020;10.7326/M20-0289. doi:10.7326/M20-0289
  2. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644-657. doi:10.1056/NEJMoa1611925
  3. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2019;380(4):347-357. doi:10.1056/NEJMoa1812389
  4. Ferrannini E, Baldi S, Frascerra S, et al. Shift to Fatty Substrate Utilization in Response to Sodium-Glucose Cotransporter 2 Inhibition in Subjects Without Diabetes and Patients With Type 2 Diabetes. Diabetes. 2016;65(5):1190-1195. doi:10.2337/db15-1356
  5. Fraenkel L, Buta E, Suter L, et al. Nonsteroidal Anti-inflammatory Drugs vs Cognitive Behavioral Therapy for Arthritis Pain: A Randomized Withdrawal Trial [published online ahead of print, 2020 Jul 20]. JAMA Intern Med. 2020;e202821. doi:10.1001/jamainternmed.2020.2821
  6. Vecchié A, Chiabrando JG, Dell MS, et al. Clinical presentation and outcomes of acute pericarditis in a large urban hospital in the United States of America [published online ahead of print, 2020 Jul 24]. Chest. 2020;S0012-3692(20)32058-4. doi:10.1016/j.chest.2020.07.039
  7. Chiabrando JG, Bonaventura A, Vecchie A, et al. Management of Acute and Recurrent Pericarditis: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75(1):76-92
  8. Mahajan S, Lu Y, Spatz ES, Nasir K, Krumholz HM. Trends and Predictors of Use of Digital Health Technology in the United States [published online ahead of print, 2020 Jul 24]. Am J Med. 2020;S0002-9343(20)30617-3. doi:10.1016/j.amjmed.2020.06.033
  9. Reynolds HR, Adhikari S, Pulgarin C, et al. Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19. N Engl J Med. 2020;382(25):2441-2448. doi:10.1056/NEJMoa2008975
  10. Li W,Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-454.
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  12. Crandall CJ, Larson J, Wright NC, et al. Serial Bone Density Measurement and Incident Fracture Risk Discrimination in Postmenopausal Women. JAMA Intern Med.Published online July 27, 2020. doi:10.1001/jamainternmed.2020.2986