Clinical Briefs in Primary Care

Refining the Relationship Between Thyroid Hormones and Left Ventricular Mass

Source: Iida M, et al. J Am Soc Hypertens 2012;6:261-269.

Animal studies have shown that thyroid hormones (T3 and T4) induce hypertrophy of cardiac myocytes through stimulation of both structural and regulatory myocyte genes, which can be prevented by ACE inhibitors or beta-blockers. Such observations have led to the question of whether there might be a relationship between cardiac mass and thyroid hormones, even within the range currently defined as normal.

Hypothyroidism and hyperthyroidism are each considered a potential secondary cause of hypertension: the former through endothelial dysfunction that leads to vasoconstrictor hyperresponsiveness and subsequent increased peripheral resistance, and the latter through increased sympathetic tone. Iida et al investigated hypertensive subjects (n = 293) who had no known thyroid disease and whose thyroid function tests (T3, T4, and TSH) were within normal limits.

Among these euthyroid hypertensive study subjects, multiple linear regression found a positive relationship between T3 and T4 and ventricular mass (the higher the thyroid hormones, the greater the ventricular mass), and an inverse relationship between TSH and ventricular mass. When compared with normotensive controls, no such relationship could be identified. This would lead to consideration that in persons with hypertension, higher levels of thyroid hormone — even within the normal range — may be related to the development of left ventricular hypertrophy.

The ORIGIN Trial: Basal Insulin vs Standard Care for Early Type 2 Diabetes

Source: The ORIGIN Trial Investigators. N Engl J Med 2012;367:319-328.

Type 2 diabetes reflects insulin insufficiency. Early in the disease process, plasma insulin levels may actually be higher than normal, but insufficient to maintain euglycemia. By the time of formal diagnosis, approximately half of beta cell mass has been lost, and as the disease progresses, insulin levels continue to fall.

The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial randomized subjects with prediabetes or early diabetes (n = 12,537) to insulin glargine (GLAR) or standard treatment (STND) for 6.2 years (mean). The objective of the trial was to determine whether early institution of basal insulin, as compared to STND, improves cardiovascular outcomes. Standard treatment was simply treatment of diabetes as per the treating clinician's choice; by the end of the trial, only 11% of the STND group was receiving insulin. Eighty percent of the GLAR group was on insulin at the end of the trial.

There was no difference in cardiovascular outcomes between the two treatment groups. One notable difference between treatments was the likelihood of progression from prediabetes to diabetes. The GLAR group was 28% less likely to progress than the STND group; however, there was also more hypoglycemia and weight gain in the GLAR group.

Increased incidence of cancer — a concern generated by earlier insulin trial data — was not seen in this large trial, and hence should be very reassuring.

Bronchodilators in COPD and Arrhythmias

Source: Wilchesky M, et al. Chest 2012; 142:298-304.

For chronic obstructive pulmonary disease (COPD), except for the provision of oxygen in late-stage disease, no pharmacologic intervention has been confirmed to save lives. Nonetheless, since bronchodilators improve symptoms, quality of life, and exercise capacity, and reduce acute exacerbations of COPD, they play an important role in routine care. Concerns about the potential capacity for arrhythmogenicity of bronchodilators has arisen from clinical COPD trials such as the Lung Health Study (n = 5887), in which short-acting ipratropium bromide was associated with a three-fold greater incidence of arrhythmia than comparator groups. Other smaller trials have not confirmed these findings, hence clarification is needed.

Wilchesky et al analyzed data from the province of Saskatchewan, Canada, to identify COPD subjects (n = 6018) and compare the incidence of arrhythmia in new users of ipratropium, beta-agonists (short- and long-acting), and methyhlxanthines to non-users.

Short-acting anticholinergics were associated with a 2.4 relative risk of arrhythmia, and long-acting beta-agonists with a 4.5 relative risk. No statistically significant increased risk was seen with short-acting beta-agonists or methylxanthines. Despite these concerns, the authors remind us that the absolute risk increase was very small, and "in most cases would be outweighed by the therapeutic benefit accrued through symptomatic relief and consequent improvements to quality of life."

Reversible Dementia from Corticosteroid Therapy

Source: Cipriani G, et al. Clin Geriatrics 2012;20:38-41.

Although there are many clinical situations in which corticosteroids (CTS) are disease modifying and life saving, one aspect of CTS that has not received much attention is the potential for central nervous system (CNS) adverse effects. CTS may be largely subgrouped into mineralocorticoids exemplified by aldosterone, and glucocorticoids (GLC) like prednisone, the latter of which is the object of this case report.

There are at least two types of CTS receptors in the brain: type I (mineralocorticoid receptors) and type II (glucocorticoid receptors). Type II receptors are found in the hippocampus as well as diffuse other sites throughout the brain. The hippocampus is required for voluntary recollection of learned information, such as recalling what you had for dinner last night. Even low doses of GLC have been shown to impair hippocampal function, despite being used for short time periods: doses of prednisone of 80 mg/day have been shown to alter cognitive function within 4-5 days.

The authors include discussion of a report detailing six cases of dementia-like cognitive decline (distinct from steroid psychosis) in patients whose cognitive function was restored upon GLC discontinuation.

Clinicians should be vigilant for decline in cognitive function in persons receiving GLC treatment, even over the short-term.

Could Thinner be Worse for Newly Diagnosed Diabetics?

Source: Carnethon MR, et al. JAMA 2012;308:581-590.

Usually, we anticipate a direct relationship between overweight and cardiovascular adversity, attributed to increases in blood pressure, lipids, glucose, insulin resistance, and sympathetic tone that are associated with obesity. There appears to be some exception to this general rule in reference to diabetes. For instance, in the TRIAD study, diabetics who were normal weight at entry to the study had a higher mortality than overweight/obese study subjects; similarly, in the PROactive trial, normal weight subjects or those who lost weight had higher mortality than overweight subjects. Because these two studies included confounding issues such as diabetes of varying duration and pre-existing cardiovascular disease, a more clear-cut relationship between body mass index (BMI) and outcome in diabetes could be discerned by selecting newly diagnosed diabetics.

Carnethon et al performed a pooled analysis of five longitudinal cohort studies (n = 2625) to examine the relationship between mortality and BMI for persons with newly diagnosed diabetes. Overall, only 12% of study subjects had a BMI < 25 at the time of diagnosis, but the relative risk for total mortality during follow-up (up to 15 years) was essentially doubled in this population compared to overweight individuals.

The mechanism(s) by which lower BMI increases mortality risk are unknown. Clinicians must not be falsely reassured that this lower-BMI phenotype, which is commonly seen in Asian-Americans, portends a favorable future.

The Impact of Exercise on Depression in Heart Failure

Source: Blumenthal JA, et al. JAMA 2012;308:465-474.

It is estimated that 5 million Americans have chronic heart failure (CHF), and almost half of these patients fulfill diagnostic criteria for depression. Subsyndromal depression is present in as many as 75%. Notwithstanding the burden of depression on quality of life, a direct impact on mortality has been shown in post-myocardial infarction patients, and even in patients with hypertension in the Systolic Hypertension in the Elderly Program. Unfortunately, to date the information on the impact of treating depression is both limited and generally disappointing. For instance, a clinical trial of sertraline in depressed patients with CHF found no cardiovascular event outcomes benefit.

Exercise is a treatment for depression, and exercise has been shown to provide event reduction in CHF patients. Whether it might improve depression and cardiovascular events in CHF patients was the object of the HF-ACTION trial (Heart Failure-A Controlled Trial Investigating Outcomes of Exercise Training).

More than 2000 patients with stable CHF were randomized to an aerobic exercise program. The exercise subjects enjoyed a statistically significant 11% reduction in mortality over the next 30 months. Although the mean score on the Beck Depression Inventory was statistically significantly lower in the exercise group, the improvement was sufficiently modest to be of uncertain clinical impact. Exercise in CHF reduces mortality and may have a modest effect on depression.