CAN STATINS PROTECT AGAINST DIABETES AND STROKE?

For the first time, a statin has been shown to reduce the risk of type 2 diabetes, according to a post hoc analysis from the West of Scotland Coronary Prevention Study (WOSCOPS). The findings were published in the January 23 issue of Circulation. Pravastatin treatment may prevent or delay the appearance of diabetes by one third in patients with high cholesterol, researchers said.

The researchers identified possible risk factors for diabetes among 5,974 men (mean age, 55.2) who participated in the WOSCOPS. These men had high cholesterol (mean baseline plasma levels of total cholesterol, 7 mmol/L) and no history of diabetes, myocardial infarction, unstable angina, or coronary revascularization. By the end of the study period, 139 men had developed overt diabetes, as defined as two blood glucose levels greater than or equal to 7 mmol/L and one level or greater than or equal to 2 mmol/L than baseline.

Pravastatin therapy, along with body mass index, change in triglyceride levels, and baseline glucose levels were multivariate predictors of the development of diabetes, the researchers reported. They speculated that pravastatin therapy can influence the development of insulin resistance by acting on plasma lipid levels, the inflammatory response, and endothelial function.

These findings need to be confirmed in other trials, such as the ongoing Prospective Study of Pravastatin in the Elderly at Risk (PROSPER), they concluded.

The analysis in WOSCOPS should be repeated, agreed Steven M. Haffner, MD, in an accompanying commentary. An attractive mechanism to explain the protective effect of pravastatin is a reduction in inflammation, he said. This study found that white blood cell count predicted the incidence of type 2 diabetes in some of the statistical models. Previous studies, he added, have shown that pravastatin and simvastatin can lower markers of inflammation such as C-reactive protein. Both cardiovascular interventions and strict glycemic control appear to be necessary in the prevention and management of diabetes, he concluded.

In the same issue, a separate study reported that pravastatin can reduce the risk of stroke. The effect of pravastatin (40 mg/d) on stroke events was investigated in a prospectively defined pooled analysis of three trials that included 19,768 participants from Scotland, United States, Canada, Australia, and New Zealand. By the end of the study, a total of 598 patients had a fatal or nonfatal stroke.

Taken together, data from the Cholesterol and Recurrent Events (CARE) and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) trials demonstrated a 22% reduction in total strokes and a 25% reduction in nonfatal stroke. "Among the people in CARE and LIPID, regardless of what kind of patient we had—older or younger, male or female, moderate or high cholesterol—they benefited from being on pravastatin in terms of having a reduced level of stroke," said Robert P. Byington, PhD. The WOSCOPS study exhibited a similar, although smaller, trend for a reduction in total stroke, the researchers noted.

This study suggests that "pravastatin is more effective than the older, nonstatin lipid-lowering therapies in reducing stroke rates," the researchers concluded.

Suggested Reading
1. Byington RP, Davis, BR, Plehn JF, et al. Reduction of stroke events with pravastatin. The Prospective Pravastatin Pooling (PPP) Project. Circulation. 2001; 103:387-392.
2. Freeman DJ, Norrie J, Sattar N, et al. Pravastatin and the development of diabetes mellitus. Evidence for a protective treatment effect in the West of Scotland Coronary Prevention Study. Circulation. 2001;103:357-362.
3. Haffner SM. Do interventions to reduce coronary heart disease reduce the incidence of type 2 diabetes? A possible role for inflammatory factors. Circulation. 2001; 103:346-347.

GLUTEN SENSITIVITY ASSOCIATED WITH CNS ABNORMALITIES AND HEADACHE

Headache and central nervous system (CNS) white matter abnormalities may be linked to gluten sensitivity, according to British researchers. They described in the February 12 Neurology 10 patients with abnormal magnetic resonance imaging (MRI) results and headache, some of whom also had unsteadiness or gait ataxia, and who responded to a gluten-free diet.

The 10 patients (six female; mean age, 52) were seen at the gluten sensitivity/neurology clinic at the Royal Hallamshire Hospital, Sheffield, United Kingdom. They were selected for the study on the basis of CNS white matter abnormalities on MRI scan.

The entire cohort experienced episodic unilateral headache, which was often associated with visual or sensory disturbance. Four patients reported gait ataxia, and six reported unsteadiness while walking. Two had evidence of distal sensory disturbance in the feet and hands. The authors reported that all of the patients had the HLA DQ2 antigliadin antibodies. In three of the four patients who showed evidence of bowel inflammation, the histology was comparable to celiac disease. All 10 patients showed high T2 signal on MRI. Of the nine patients who agreed to try a gluten-free diet, headaches resolved in seven and partially improved in two.

The authors noted that a previously published study has shown that only 3.1% of patients with celiac disease had migraine, which is a lower prevalence than in the general population. Thus, it is possible that the association between gluten sensitivity and headache in this study is coincidental. However, not only was the gluten-free diet associated with the resolution of headaches, but noncompliance with the diet was associated with headache recurrence and some progression of the white matter abnormalities on MRI.

"Gluten sensitivity can be primarily, and at times exclusively, a neurologic disease," said the authors. Patients with episodic headache, unexplained white matter lesions on MRI, or neurologic dysfunction of obscure cause (particularly ataxia or peripheral neuropathy) should be evaluated for gluten sensitivity. "If the results of the current study are confirmed, removal of the trigger factor by the early introduction of gluten-free diet may be a promising therapeutic intervention," concluded the authors.

Suggested Reading
Hadjivassiliou M, Grünewald RA, Lawden M, et al. Headache and CNS white matter abnormalities associated with gluten sensitivity. Neurology. 2001;56:385-388.

"NEGATIVE" STUDIES ARE ESSENTIAL

The importance of "negative" studies was emphasized by Bruce G. Gellin, MD, MPH, and William Schaffner, MD, coauthors of an editorial in the February 1 New England Journal of Medicine. Negative studies, they said, are essential to dispel certain commonly held misconceptions of risk. "Chief issues of concern do not always reflect the scientific evidence," said Drs. Gellin and Schaffner. "Hypotheses can become 'facts' long before the critical data are in."

Such has been the case with the public perception that hepatitis B vaccinations play a role in the pathogenesis of multiple sclerosis. Despite an excellent safety profile, France dropped hepatitis B from a school-based vaccination program in October 1998, following the development of several cases of multiple sclerosis by recipients of the vaccine. "If the cause of the disease is unknown, it is understandable that recipients of the vaccine and even some physicians may assume that sequence is consequence," noted Drs. Gellin and Schaffner. Moreover, it has been suggested that an immune system stimulus (like a vaccine) might trigger an autoimmune disease, they added.

In the same issue of the New England Journal of Medicine, Alberto Ascherio, MD, and colleagues reported that they had found no evidence of an association between hepatitis B vaccination and the development of multiple sclerosis. They conducted a nested case-control study in two cohorts of American women: the Nurses' Health Study (which has followed 121,700 women since 1976) and the Nurses' Health Study II (which has followed 116,671 women since 1989). Dr. Ascherio and colleagues found that vaccinated women were at a 0.9 age-adjusted relative risk of multiple sclerosis compared to unvaccinated women, and that women vaccinated within two years prior to the index date were at a 0.7 risk of developing multiple sclerosis. "Considering the public health importance of preventing hepatitis B infection, concern about possible increases in the risk of multiple sclerosis does not appear to justify changes in vaccination policy that could compromise or delay the control of the infection," concluded Dr. Ascherio and colleagues.

Further evidence that hepatitis B vaccination is not linked to multiple sclerosis was presented by Christian Confavreux, MD, and colleagues in the same issue of the journal. Dr. Confavreux identified 643 patients in the European Database for Multiple Sclerosis who had had a relapse between 1993 and 1997. The 2.3% of the cohort that had been vaccinated for hepatitis B, tetanus, or influenza within two months preceding relapse were at a 0.71 risk of relapse. "This study suggests that commonly administered vaccinations (specifically, against tetanus, hepatitis B, and influenza) do not increase the risk of relapse in patients with multiple sclerosis," said the authors. "Most vaccinations, especially those against tetanus plus poliomyelitis or diphtheria, were actually associated with a lower risk of relapse, although the difference was not significant."

Public concern over health issues should be addressed through scientific studies and public education, said Drs. Gellin and Schaffner. They noted that it is not clear which concerns should be investigated, who should orchestrate the research, or from where the funding should originate. They added that the public's knowledge about health issues such as the role of immunization in the pathogenesis of multiple sclerosis may be limited. (Twenty-five percent of parents thought that their child's immune system could be weakened by too many immunizations, and a similar proportion believed that their children were "already getting more vaccines than was good for them," according to a recent study.) "If improved education is not successful, the fruits of our investments in immunization—both now and in the future›are likely to be viewed with skepticism, and necessary vaccines may remain on the shelf," predicted Drs. Gellin and Schaffner.

Suggested Reading
1. Ascherio A, Zhang SM, Hernán MA, et al. Hepatitis B vaccination and the risk of multiple sclerosis. N Engl J Med. 2001;344:327-332.
2. Confavreux C, Suissa S, Saddier P, et al. Vaccinations and the risk of relapse in multiple sclerosis. N Engl J Med. 2001;344:319-326.
3. Gellin BG, Schaffner W. The risk of vaccination—the importance of "negative" studies. N Engl J Med. 2001;344:372-373.

NEW STUDY CASTS DOUBT ON MIGRAINE THERAPY

Migraine pain is not necessarily caused by cortical spreading depression, according to an electrophysiologic animal study published in the January Annals of Neurology. Nociceptive neurons within the trigeminal nucleus were not activated by cortical spreading depression, the researchers reported. Furthermore, the researchers failed to find a link between the wave of decreased cortical activity and various markers of inflammation that accompany migraine pain. "We suspect that a still-unidentified stimulus causes spreading depression on the one hand and headache pain on the other," said senior author Frank Richter, PhD.

This study was the first to directly test the relationship between cortical spreading depression and nociceptive activity. In the anesthetized rat, the researchers recorded neuronal activity from secondary sensory neurons in the trigeminal nucleus caudalis with input from the meninges. They also probed for inflammatory markers—such as plasma extravasation and release of calcitonin gene-related peptide (CGRP) and prostaglandin E2—after evoking a cortical depression with either a pinprick or application of potassium chloride to the cortical surface.

No activation of nociceptive neurons was correlated with the peak of cortical spreading depression or in the following 10-minute period, the researchers said. "Even when on average as many as 22.5 ± 8.2 cortical spreading depressions crossed the receptive field of the brainstem neurons, ongoing activity of these neurons was not altered," they reported. Overall, the neurons' heat and mechanical thresholds appeared to increase, suggesting that they were actually desensitized after cortical spreading depressions, the researchers pointed out.

Cortical spreading depressions were not sufficient to cause plasma extravasation in the meninges, the researchers continued. No difference in extravasation was observed when cortical spreading depressions were elicited every 20 minutes for three hours. Stimulation with potassium chloride at levels seen during cortical spreading depression did not enhance release of CGRP and prostaglandin E2 from the dura, they added.

"Collectively, these results do not support the general hypothesis that cortical spreading depression could activate the trigeminovascular system by leading to neurogenic inflammation that ultimately causes migraine headache," the researchers concluded.

This study casts doubt on the view that aura generates the migraine attack and is pivotal to the pain, observed Peter James Goadsby, MD, PhD, in an editorial. He provided additional clinical evidence that questioned the relationship between migraine aura and pain. Only 15% to 20% of migraineurs have aura by standard criteria, he said. Aura, he noted, can appear after a headache or may not accompany a headache at all. Also, there are cases in which unilateral aura is not contralateral to the pain. Finally, he noted that genetic analysis is starting to separate aura and headache.

If aura or vascular changes are ruled out, then what is the source of migraine pain? "A radical possibility is that migraine pain is more to do with the abnormal perception of the normal than the activation of nociceptive pathways in the classical way that pain is generated," Dr. Goadsby suggested. "We must know the answer to this question if we want new preventatives and to provide patients with a coherent explanation for the condition," he concluded.

NR

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