Clinical Briefs in Primary Care

A Relationship Between Nocturia and Hypertension

Source: Feldstein CA. J Am Soc Hypertens 2013;7:75-84.

Nocturia could easily be misconstrued as a "nuisance" symptom since, after all, nobody dies from nocturia … or do they? Indeed, urinary frequency and nocturia have been associated with greater risk for nocturnal falls and hip fracture; hence, nocturia can be much more than just a nuisance.

Clinicians are used to identifying nocturia as a symptom associated with benign prostatic hyperplasia, overactive bladder, uncontrolled diabetes, uncontrolled congestive heart failure, use of diuretics, and (less commonly) interstitial cystitis. What is only minimally recognized, however, is the emerging observation that hypertension is associated with nocturia.

Several plausible mechanisms can explain the nocturia/hypertension relationship: hypertension-induced alterations in glomerular filtration or tubular transport, activation of atrial natriuretic peptide from ventricular wall stress induced by hypertension, and resetting of the pressure-natriuresis relationship in the kidney, to name a few.

Feldstein indicates that the prevalence of nocturia in untreated hypertension patients may be as high as 33%. Since nocturia can be both a burdensome symptom and lead to significant morbidity (and mortality), clinicians may wish to specifically inquire about nocturia when encountering hypertension patients.

Peripheral Artery Disease: Helping Patients to Walk the Walk

Source: Ahimastos AA, et al. JAMA 2013; 309:453-460.

Currently available treatments for peripheral artery disease (PAD) are only modestly effective. PAD portends increased risk of cardiovascular disease; hence, most PAD patients should be receiving pharmacotherapy with a statin and an antiplatelet agent (usually clopidogrel).

Because one of the quality-of-life limiting factors in advanced PAD is disease-mediated diminution in walking distance and walking time, incorporation of pharmacotherapy to improve these limitations is also considered important. Unfortunately, the two FDA-approved treatments (pentoxifylline and cilostazol) for symptoms of PAD provide only a modest increase in walking distance (25% or less). Smoking cessation and exercise advice remain critically important, but are too often not heeded.

Ramipril is an angiotensin-converting enzyme (ACE) inhibitor that has been used in numerous major clinical trials, including the HOPE trial, ONTARGET trial, REIN trial, and others. Use of ramipril is usually predicated on 1) its ability to lower blood pressure, 2) its ability to improve outcomes in congestive heart failure, or 3) its ability to improve albuminuria.

Based on results seen in a small pilot trial that suggested favorable results of ramipril on treadmill time in subjects with PAD, Ahimastos et al performed a larger randomized clinical trial (n = 212).

At the conclusion of the 6-month trial of ramipril 10 mg/day vs placebo, pain-free walking time had increased by more than 50% in the ramipril group, but only 10% in the placebo group.

Although the mechanism for improved function is speculative, it has been noted that ACE inhibitors increase skeletal muscle blood flow; indeed, this has been the mechanism to which improved insulin sensitivity in diabetics has been attributed. Ramipril may offer a new avenue to improve functionality in patients with PAD.

Long-Term Functional Outcomes After Localized Prostate Cancer Treatment

Source: Resnick MJ, et al. N Engl J Med 2013;368:436-445.

When prostate cancer is localized, either radical prostatectomy (RPT) or external beam radiation (EBR) can often be curative. The adverse effect profile of these two interventions, however, may be meaningfully different and such differences might also be time-dependent.

Resnick et al studied men (n = 1164) from the Prostate Cancer Outcomes Study who had been enrolled between the ages of 55-74 and had localized prostate cancer. More than 80% of the men had a Gleason score of 7 or less. The prevalence of urinary incontinence (UI) and erectile dysfunction (ED) were compared among these men at years 2, 5, and 15.

Prostatectomy subjects were five to six times more likely to have incontinence at 2 years and 5 years than EBR subjects. Similar disadvantage was seen in the prevalence of ED (two- to four-fold increased incidence in the RPT group). At the 15-year conclusion of their observations, no differences between groups remained. However, one would anticipate, for instance, a substantial incremental increase in ED as men age with or without intervention; hence, the fact that between-group differences are eliminated by 15 years provides little solace for the men who suffer the adverse effects in the interim!

The Word 'GPR40 Modulator’ May Soon be Entering Our Vocabulary

Source: Basu A, et al. Diabetes Care 2013;36:185-187.

The search for safe and effective agents to treat type 2 diabetes (DM2) continues, with hypoglycemia often being a limiting adverse effect of otherwise highly efficacious agents.

It has been observed that free fatty acids (FFA) play a role in glucose homeostasis, although the story line is complex. Acutely, elevations of FFA stimulate beta cell secretion of insulin. Chronic FFA elevations result in an impaired insulin response to high glucose levels, a phenomenon known as lipotoxicity.

The mechanism by which FFA impacts insulin secretion has been elegantly worked out and includes the G-protein-coupled receptor (GPR40). Because GPR is involved not only in insulin secretion, but also plays a role in obesity and dyslipidemia, its potential as a multimodal intervention has looked promising.

Studies in humans have shown that GPR40 agonists live up to the expectation that they lower glucose, with a very low risk of hypoglycemia. For instance, a head-to-head comparison with the sulfonylurea glimepiride found hypoglycemic episodes to be six-fold lower with the GRP40 agonist.

In an era of a burgeoning population of DM2 patients, we look forward to the addition of pharmacotherapies that safely complement our current options.

A More Effective Regimen for H. pylori Eradication

Source: Liou JM, et al. Lancet 2013;381: 205-213.

In the United States, peptic ulcer disease is caused primarily by two culprits: nonsteroidal anti-inflammatory drugs and Helicobacter pylori (and their combination). Evolution of pharmacotherapy for H. pylori currently employs combinations of amoxicillin (AMOX), metronidazole (METR), clarithromycin (CLAR), and a proton pump inhibitor (PPI). Unfortunately, over time H. pylori eradication rates with such regimens have fallen to as low as 80% or less. Is there a better way?

Liou at al randomized H. pylori-positive Taiwanese adults (n = 900) to one of three regimens — 1) Sequential 10 days: PPI + AMOX for 5 days followed by PPI + CLAR + METR for 5 days; 2) Sequential 14 days: PPI + AMOX for 7 days followed by PPI + CLAR + METR for 7 days; or 3) Standard 14 days: PPI + AMOX + CLAR for 14 days. The PPI used in this clinical trial was lansoprazole.

Adverse effect profiles of the three regimens were similar. Eradication rates were statistically significantly higher using sequential regimens (10 days = 87%, 14 days = 91%) than in standard regimens (82%).

Reflecting an increased recognition of problematic CLAR resistance at the end of the initial comparison trial, treatment failures from each regimen were assigned to receive an additional 14-day sequential course of treatment in which levofloxacin was substituted for CLAR. Eradication rates from this "rescue" population (regardless of which initial regimen they had received) were 80%.

Based on this large dataset, the authors suggest that sequential treatment regimens should become first line.

Uric Acid: How Much of a Bad Guy?

Source: Rosendorff C, et al. J Clin Hypertens 2013;15:5-6.

Uric Acid (URA) has become the object of intense scrutiny of late, with more than its share of accusations linking it to hypertension and heart disease. The relationship between URA and gout is incontrovertible, though not necessarily universal. That is, in persons who develop gout, risk of future attacks is definitely related to absolute URA plasma levels. However, among persons without gout, elevations of URA appear to be well tolerated without evident toxicity in most: In asymptomatic adults with URA levels > 9.0 mg/dL, only about 5% per year go on to manifest acute gout.

The association of URA with hypertension, myocardial infarction, and even congestive heart failure is acknowledged. Whether this relationship is causal, and if a causal relationship is determined, whether lowering of URA will be beneficial remains to be determined. Remember the enthusiasm attendant to the recognition that homocysteine was associated with cardiovascular disease, heightened by the assurance that lowering homocysteine was simple and safe (B vitamins and folate), soon thereafter torpedoed by the interventional trials that failed to show improved outcomes in subjects whose homocysteine levels were reduced?

Despite the growing enthusiasm for criminalizing URA, we still do not have a large randomized, controlled trial indicating that modulation of URA improves hard endpoints. Until then, since all medications that reduce URA have their own bundle of potential misadventure to consider, we should watch and wait.