Primecuts – This Week In The Journals

November 18, 2013

By Karin Katz, MD

Faculty Peer Reviewed

Last week Typhoon Haiyan took a devastating hit on the Philippines. According to UNICEF, 13 million people have been affected, and the death toll is estimated to be close to 4,000. In the aftermath of this disaster, with hundreds of thousands of people homeless, there is a concern that crowded living spaces with contaminated drinking water and unsanitary conditions could lead to the spread of communicable diseases. International relief efforts have been working to provide people with food, shelter and clean water, but the struggle to provide aid to the Filipino people is ongoing. While the relief efforts were being initiated, in our own clinics, we have been rethinking our disease management and preventative strategies for atherosclerotic cardiovascular disease with the new ACC/AHA lipid management guidelines. Let’s look to the journals to see what else is new this week.

A study published in the New England Journal of Medicine examined the efficacy of combination therapy with ACE inhibitors and angiotension II receptor blockers for preventing the progression of renal disease in diabetics with proteinuria [1]. It is well established that ACE inhibitors and ARBs individually are renoprotective for diabetics with diabetic nephropathy, and previous studies have shown that combination therapy produced a greater reduction in urinary protein excretion in these patients. Combining an ACE inhibitor with and ARB has also been associated with adverse events, however, most commonly hyperkalemia and acute kidney injury [2]. The recent Veterans Affairs Nephropathy in Diabetes study compared the combination of losartan with lisinopril to losartan alone in diabetics with proteinuria in a double-blind, randomized controlled trial[1].

Participants in this study were veterans with type 2 diabetes, a GFR of 30-89.9 mL/min/1.73 m2 of body surface area, and a urinary albumin-to-creatinine ratio of at least 300 in a random sample (albumin measured in milligrams, creatinine in grams). A total of 1,448 participants were initiated on 50mg of losartan, and the dose was uptitrated to 100mg daily, as tolerated. Once patients were on a stable dose for 30 days, they were randomly assigned to receive either lisinopril (up to 40mg daily) or placebo in a 1:1 ratio. The primary, combined end point measured was the occurrence of a decline in the estimated GFR (defined as an absolute decrease of greater than or equal to 30), end-stage renal disease (the initiation of maintenance dialysis or estimated GFR <15), or death. In total there were 152 primary endpoint events in the monotherapy group and 132 in the combination-therapy group (HR, 0.88; 95% CI 0.70 to 1.12, p=0.30). Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, compared to 2.6 events per 100 person-years in the monotherapy group, P<0.001). Combination therapy also increased the risk of acute kidney injury (12.2 events per 100 person-years, compared to 6.7 in the monotherapy group, P<0.001). There was no demonstrated mortality benefit with combination therapy, and the study was ultimately stopped early due to safety issues given the results of the combination therapy group.

This study has a number of limitations, including a lack of diversity (participants were predominantly white males). In addition, the participants were not naïve to ACE inhibitor or ARB therapy, and this may have contributed to the time course and progression of kidney disease that the authors could not account for. Overall, however, it demonstrates that the lack of benefit along with significant adverse effects of combined therapy do not justify its use in diabetic patients with proteinuria.

Another look at chronic disease in our nation’s veteran population was published in JAMA this week, which examined testosterone therapy and the associated risk of cardiovascular events[3]. This retrospective study included 8,700 veterans who underwent coronary angiography and had a total testosterone levels of less than 300 ng/mL. Of note, the cohort had a high prevalence of co-morbidities, including 20% with a prior history of MI, 50% with diabetes, and more than 80% with coronary artery disease, demonstrated by coronary angiography. Within the cohort, 14% of patients had initiated testosterone therapy, usually via patch or an injection, at a median of 1.5 years following angiography. The primary outcome studied was a composite of all-cause mortality, myocardial infarction and ischemic stroke. At baseline, there were no significant differences in systolic blood pressure, LDL levels, or the use of beta-blockers and statins between the groups. After 3 years, the Kaplan-Meier estimated cumulative frequency of events was 26% in the testosterone group and 20% in the group without testosterone therapy (AR 5.8%; 95% CI, -1.4 to 13.1). Cox proportional hazards models adjusting for the presence of CAD demonstrated testosterone therapy use was associated with a statistically signifciant increased risk of adverse outcomes (HR 1.29, 95% CI, 1.04 to 1.58).

Interestingly, in epidemiologic studies, low serum testosterone levels have been associated with the development of obesity, high insulin levels, the metabolic syndrome and diabetes[4-6]. A meta-analysis previously showed that testosterone replacement in hypogonadal men is not associated with increased cardiovascular risk[7]. Clearly, there has been conflicting literature on this topic. Another earlier study demonstrated that cardiovascular disease was associated with testosterone therapy[8]. There are several limitations with the present study, as the patients were not randomized, and there may be a component of selection bias introduced by including only patients who had a testosterone level checked in clinic. Furthermore, the time of day serum testosterone levels were measured was unknown. This may have greatly influenced the specificity in diagnosing hypogonadism, and therefore not only altered the cohort of patient’s included in the study but weakens the strength of the authors’ conclusions.


The Lancet this week examines a more established risk factor for coronary artery disease, smoking. A study conducted in Auckland, New Zealand compared the use of electronic cigarettes (containing nicotine) to nicotine patches as therapy for smoking cessation [9]. This randomized controlled trial included 657 individuals 18 years or older who had smoked 10 or more cigarettes per day during the previous year, and were also interested in quitting. The primary outcome was continuous smoking abstinence, initially self-reported and then verified 6 months after quit day with an exhaled breath carbon monoxide test. The study included three groups: 289 participants were assigned use to nicotine e-cigarettes, 295 to nicotine patches, and 73 to placebo e-cigarettes that did not contain nicotine. At 6 months following quit day, smoking cessation was highest in the nicotine e-cigarettes group (7.3%) followed by the patches group (5.8%) and placebo (4.1%), with the absolute risk difference for nicotine e-cigarette versus patches 1.51 (95% CI, -2.49 to 5.51). The absolute risk difference for nicotine e-cigarettes versus placebo e-cigarettes was 3.16 (95% CI, -2.29 to 8.61).

The authors note that the study was not powered to conclude superiority of nicotine e-cigarettes to patches, however they conducted post-hoc analyses using a 5% non-inferiority limit, and from this analysis concluded that nicotine e-cigarettes were at least as effective as patches. The study had many limitations, however, including but not limited to the fact that many participants were lost to follow-up. Also of note, the amount of nicotine differs between e-cigarettes and patches, and smokers have varying needs for nicotine replacement. There is also concern about inconsistent ingredients in e-cigarettes, including impure nicotine. This study shows potential for e-cigarettes to assist with smoking cessation in some individuals, however further investigation is required, including an evaluation of the safety of e-cigarettes.

In Chest this month, Pedrosa et al. published a randomized trial of a small group of patients with resistant hypertension [10]. Resistant hypertension is defined as uncontrolled blood pressure, despite the use of three antihypertensive agents, or the need for more than three medications to control blood pressure. In these patients it is important to perform a diagnostic workup of secondary causes of hypertension such as obstructive sleep apnea. Participants of this study, who had no previous diagnoses of sleep disorders, underwent a sleep study. Patients found to have moderate to severe obstructive sleep apnea were included in the therapy portion of the trial. These participants were randomly assigned to standard medical treatment with anti-hypertensive therapy, or standard treatment plus OSA treatment with continuous positive airway pressure (CPAP) for 6 months. The study was small, and ultimately included 35 middle-aged obese men with similar glucose and lipid profiles, and similar ambulatory blood pressure. Patients with arrhythmias, heart failure, valvular heart disease, renal failure, smoking, regular alcohol intake, or taking any medication that increased blood pressure were excluded.

The investigators monitored medication compliance with frequent pill counts, and CPAP compliance was monitored as well. In the CPAP group, awake systolic and diastolic blood pressures decreased significantly after 6 months, with a mean reduction of 6.5 mm Hg and 4.5 mm Hg for systolic and diastolic blood pressure, respectively (p<0.05). When evaluating how this study impacts practice, it is important to highlight that obese patients may not always complain of the typical symptoms of obstructive sleep apnea. All patients with resistant hypertension should be evaluated for secondary causes of hypertension, with a sleep study as a part of this workup.

Other interesting articles of note this week:

The American Heart Association/American College of Cardiology published updated guidelines on the management of overweight and obesity in adults [11]. The authors describe dietary and lifestyle modifications, however there is still insufficient evidence to recommend bariatric surgery to patients with a body mass index less than 35 kg/m2.

In a systematic review of pharmacotherapy for obesity by Yanovski et al. in JAMA, the authors describe the efficacy and side effects of current FDA-approved medications for weight loss[12], with the proportion of patients achieving clinically meaningful weight loss ranging from 37-47% for lorcaserin, 35 to 73% for orlistat, and 67% to 70% for phentermine-topiramate. No obesity medication has been shown to reduce CV morbidity or mortality.

Also in BMJ, investigators examined a cohort in Sweden of women with a history of bariatric surgery, and found that they were at increased risk of having preterm and small for gestational age births [13].

Dr. Karin Katz is a 2nd year resident, internal medicine, at NYU Langone Medical Center

Peer reviewed by Gregory Schrank, MD, Contributing Editor, Clinical Correlations

Image courtesy of Wikimedia Commons


1. Fried LF, Emanuele N, Zhang JH, et al. Combined Angiotensin inhibition for the treatment of diabetic nephropathy. N Engl J Med. Nov 14 2013;369(20):1892-1903.

2. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. Aug 16 2008;372(9638):547-553.

3. Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. Nov 6 2013;310(17):1829-1836.

4. Kupelian V, Page ST, Araujo AB, Travison TG, Bremner WJ, McKinlay JB. Low sex hormone-binding globulin, total testosterone, and symptomatic androgen deficiency are associated with development of the metabolic syndrome in nonobese men. J Clin Endocrinol Metab. Mar 2006;91(3):843-850.

5. Laaksonen DE, Niskanen L, Punnonen K, et al. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care. May 2004;27(5):1036-1041.

6. Oh JY, Barrett-Connor E, Wedick NM, Wingard DL. Endogenous sex hormones and the development of type 2 diabetes in older men and women: the Rancho Bernardo study. Diabetes Care. Jan 2002;25(1):55-60.

7. Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. Jun 2010;95(6):2560-2575.

8. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl J Med. Jul 8 2010;363(2):109-122.

9. Bullen C, Howe C, Laugesen M, et al. Electronic cigarettes for smoking cessation: a randomised controlled trial. Lancet. Sep 9 2013.

10. Pedrosa RP, Drager LF, de Paula LK, Amaro AC, Bortolotto LA, Lorenzi-Filho G. Effects of OSA Treatment on BP in Patients With Resistant Hypertension: A Randomized Trial. Chest. Nov 1 2013;144(5):1487-1494.

11. Jensen MD, Ryan DH, Apovian CM, et al. 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. Circulation. Nov 12 2013.

12. Yanovski SZ, Yanovski JA. Long-term Drug Treatment for Obesity: A Systematic and Clinical Review. JAMA. Nov 14 2013.

13. Roos N, Neovius M, Cnattingius S, et al. Perinatal outcomes after bariatric surgery: nationwide population based matched cohort study. BMJ. 2013;347:f6460.