Pioglitazone and Secondary Cardiovascular Prevention

SOURCE: Kernan WN, Viscoli CM, Furie KL, et al. Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374:1321-1331.

In addition to traditional risk factors for cardiovascular (CV) events (e.g., hyperlipidemia, hypertension, cigarette smoking), it has not gone unnoticed that insulin resistance, even in the absence of frank diabetes, also is associated with stroke and myocardial infarction (MI). Might a pharmacologic agent that improves insulin resistance be effective in secondary prevention of CV events?

Kernan et al performed a randomized, double-blind, placebo-controlled trial of adults who had sustained a stroke or transient ischemic attack (n = 3,876) to compare pioglitazone, an agent that improves insulin sensitivity, to placebo. Diabetic patients were excluded; rather, inclusion criteria required that patients demonstrate insulin resistance (as measured by the HOMA-IR metric), but did not meet criteria for diabetes. The primary outcome was fatal or nonfatal stroke or MI.

At 4.8 years, subjects who had been treated with pioglitazone experienced a 24% relative risk reduction in the primary endpoint (9% vs. 11.8%). Additionally, pioglitazone served well as a tool to prevent progression to diabetes by reducing incident diabetes more than 50% (3.8% vs. 7.7%). There was a trend toward lower mortality in the pioglitazone group that did not achieve statistical significance.

Before making an abrupt practice change based on this study, it is important to note that the incidence of fracture requiring surgery or hospitalization statistically significantly increased in the pioglitazone treatment arm (5.1% vs. 3.2%). Hence, the absolute reduction in CV events (almost 3%) is nearly offset by the increase in fractures (nearly 2%). Arguably, elimination of a major CV event substantially outweighs a new bone event, but clinicians should consider such adverse events in their therapeutic decision process, especially in patients acknowledged to be at high risk for fracture.


Subclinical Thyroid Disease Associated with Increased Mortality in Seniors

SOURCE: Grossman A, Weiss A, Koren-Morag N, et al. Subclinical thyroid disease and mortality in the elderly: A retrospective cohort study. Am J Med 2016;129:423-430.

Subclinical thyroid disease is defined as altered thyroid stimulating hormone (TSH) level in the presence of normal thyroid hormone (T4, T3) levels. Hence, subclinical hypothyroidism exists when TSH levels are elevated but T4 is normal, and subclinical hyperthyroidism exists when TSH levels are reduced, but T3 and T4 levels are normal. Since a substantial number of cases of overt hyperthyroidism and hypothyroidism are immediately preceded by a period of subclinical status, it probably should not be surprising that subclinical thyroid disease status (both hyper and hypo) is associated with mortality in elders.

Grossman et al performed a retrospective analysis on patients > 65 years of age (n = 17,440), comprised of individuals with normal thyroid status (n = 14,946), subclinical hyperthyroidism (n = 538), and subclinical hypothyroidism (n = 1,956) who were followed for as long as 10 years.

Both subclinical hypo- and hyperthyroidism were associated with increased risk for mortality (hazard ratio = 1.53 and 2.33, respectively). In the population of subjects with subclinical hypothyroidism, a TSH > 6.35 mIU/L was the threshold for increasing mortality risk. Subclinical hyperthyroidism has been associated with increased risk for atrial fibrillation, so the increased mortality risk in this population is perhaps less surprising.


An Infectious Disease Causes Pathological Aggression?

SOURCE: Coccaro EF, Lee R, Groer MW, et al. Toxoplasma gondii infection: Relationship with aggression in psychiatric subjects. J Clin Psychiatry 2016;77:334-341.

Many have followed an evolution of medical disorders surprisingly linked to infectious diseases: cervical cancer (human papillomavirus infection), gastric and peptic ulcer disease (Helicobacter pylori), and even obesity (adenovirus 36). Toxoplasma gondii (TXG) is a highly prevalent protozoan reportedly infecting, albeit usually asymptomatically, as many as one-third of U.S. adults. Humans can acquire TXG from household cat feces and less commonly from undercooked meat infected with TXG. In immunocompetent humans, TXG lives in the central nervous system within neurons and glial cells and is generally asymptomatic, although associations between latent TXG and schizophrenia, bipolar disease, and personality disorders have been demonstrated.

Coccaro et al performed sero-analyses on 358 adults comprised of approximately three equally sized groups: healthy controls, psychiatric controls without noteworthy aggression issues, and psychiatric patients with intermittent explosive disorder. A TXG IgG antibody titer > 12 IU was regarded as seropositive.

Positive TXG sero-status was statistically significantly associated with aggression. Prevalence of TXG seropositivity ranged from 9.1% in healthy controls to 16.7% in psychiatric controls (without aggression issues) to 21.8% in subjects with intermittent explosive disorder. These preliminary results do not include any advice about if, how, or when TXG treatment should be considered.