CME Author: Vicki Brower
Study Authors: Guy Fagherazzi, Douae El Fatouhi, et al.
Target Audience and Goal Statement:
Endocrinologists, women’s health specialists, neurologists, internists, and family medicine specialists
The goal is to understand the association between migraine and type 2 diabetes in women, and the possible underlying mechanisms that account for any relationship between the two conditions.
- If there is an association between migraine and type 2 diabetes in women, what is it, and what might account for the connection?
- How does the risk of migraine change in association with the incidence of type 2 diabetes?
Study Synopsis and Perspective:
In a population-based longitudinal study of 74,247 French women, known as the E3N Cohort Study, researchers found that those who suffered with active migraines had a 20% reduction in the risk of developing pharmacologically-treated type 2 diabetes — which rose to a 30% reduction in multivariate modeling — than women without a history of migraine, according to Guy Fagherazzi, PhD, of the Center for Research in Epidemiology and Population Health in Villejuif, France, and coauthors. In addition, among women who developed incident diabetes during the study, the prevalence of active migraine declined in the years leading up to a diabetes diagnosis and plateaued after, they wrote in JAMA Neurology.
In this study, Fagherazzi and colleagues analyzed data from the E3N-EPIC cohort, a French prospective study of women born between 1925 and 1950 who are insured by a health insurance plan that covers mostly teachers. Participants were a mean age of 61 at baseline, and they were followed for 10 years.
In this study, participants completed self-administered biennial questionnaires since 1990, and the health insurance plan provided information about all outpatient reimbursements for health expenditures since 2004, including dosages and dates of drug purchases.
Based on the questionnaire data, the researchers grouped subjects into three main categories: no migraine history, active migraine (women who self-reported migraine on the current questionnaire), and prior migraine (women who reported migraine in at least one past questionnaire but not currently). They defined a type 2 diabetes patient as someone who was treated pharmacologically with type 2 diabetes–specific medications at least twice, with diagnosis date as the date of the first drug reimbursement. Researchers controlled for the use of anti-migraine drugs.
At baseline, the 74,247 women in the analysis had no diabetes diagnosis. From 2004 to 2014, a total of 2,372 women had incident cases of type 2 diabetes: 1,562 of these women had no migraine history; 681 had prior migraine, and 129 had active migraine.
In univariate models, women with active migraine had a lower risk of incident type 2 diabetes than women with no migraine history (HR 0.80, 95% CI 0.60-0.96); in multivariable-adjusted models, this magnitude increased (HR 0.70, 95% CI 0.58-0.85). Prior migraine was not associated with the risk of type 2 diabetes in both univariate models (HR 1.16, 95% CI 1.06-1.27) and multivariable-adjusted models (HR 1.07, 95% CI 0.98-1.17).
The 2-year prevalence of active migraine decreased linearly from 24 months before the type 2 diabetes diagnosis (22%, 95% CI 16%-27%) to the date of diagnosis (11%, 95% CI 10%-12%). After type 2 diabetes diagnosis, prevalence of active migraine stabilized at rates of 10% to 11% that persisted up to 22 years after diagnosis.
Source Reference: JAMA Neurology, online Dec. 17, 2018; DOI:10.001/jamaneurol.2018.3960
Study Highlights: Explanation of Findings
Women in this study who suffered from active migraines had a lower risk of developing type 2 diabetes, the French researchers reported. Conversely, among those who developed incident diabetes during the study, the prevalence of active migraine declined in the years leading up to a diabetes diagnosis, and plateaued after, they wrote.
“The linear decrease of migraine prevalence long before and the plateau long after type 2 diabetes diagnosis is novel,” Fagherazzi added. “The association deserves to be studied in other populations, and in men, as well,” he said.
“Our results may suggest a potential role of both hyperglycemia and hyperinsulinism on migraine occurrence,” Fagherazzi said. “Because plasma glucose concentration rises with time up to type 2 diabetes occurrence, the prevalence of migraine symptoms may decrease. Consequently, tracking the evolution — and especially the decrease — of migraine frequency in migraineurs at high risk of diabetes, such as obese individuals, irrespective of age, could be the sign of emerging increased blood glucose levels, prediabetes, or type 2 diabetes,” he told MedPage Today.
These findings coincide with observations from clinical practice, observed Amy Gelfand, MD, MAS, of the University of California San Francisco, and Elizabeth Loder, MD, MPH, of Brigham and Women’s Hospital and Harvard Medical School in Boston, in an accompanying editorial. “Headache practitioners have long discussed the rarity of patients with type 2 diabetes in headache clinics,” they wrote.
But the reason for the link is uncertain: “One plausible biological explanation involves calcitonin gene-related peptide, which is involved in energy metabolism in animal models,” Gelfand and Loder wrote. “Calcitonin gene-related peptide [CGRP] is also clearly involved in the pathophysiology of migraine. It is possible that the development of insulin resistance and hyperglycemia result in damage to sensory neurons that produce this peptide.” Potential associations exist between CGRP, migraine pathophysiology, and glucose metabolism, authors wrote, but how they fit together is still unclear.
In addition, it is possible that a migraine trigger could be nutritional, hormonal, or metabolic in some people, Fagherazzi and co-authors noted.
When Fagherazzi’s team compared women with no migraine history with those who reported active migraine, women with migraine were younger, had a lower level of physical activity, were more likely to have a family history of diabetes, were more likely to use oral contraceptives, were more likely to have a body mass index less than 20, and were more likely to be former smokers. Interestingly, women with a mixed or ambidextrous handedness had an increased risk of self-reporting migraine during the followup period (2004-2014), compared with right-handed women, whereas left-handed women were not.
Other researchers have shown an association between polymorphisms in the insulin receptor gene and migraine, while an elevation in free fatty acid plasma concentrations and ketone body before a migraine attack, have also been reported. “These biological factors could therefore explain an inverse association between migraine and type 2 diabetes risk,” the authors wrote. This could also support their observation of decreased prevalence of migraine in the years before the diagnosis of type 2 diabetes, “when there is usually a progressively increasing hyperglycemic state.”
They also noted that increased insulin secretion after carbohydrate- and sucrose-laden meals “may promote the occurrence of reactive hypoglycemia in some people, which may trigger migraine.” They recounted that one study reported higher levels of plasma insulin in women with migraines, compared with controls.
Gelfand and Loder muse about whether migraine, with its “strong genetic underpinnings” confers some type of survival advantage, from an evolutionary perspective. “What is it [migraine] good for?” they ask.
Strengths to the study include the prospective design, which reduces a differential bias in reporting of migraine episodes with incident type 2 diabetes, and the long follow-up time.
This study has several limitations, the authors noted. Migraine status was based on self-reports, and no information about self-medication was available. The E3N sample consisted of a somewhat homogeneous swathe of women, mainly white, not obese, post-menopausal, and teachers; because of this, these results may not apply to men or other women. And, because the study was observational, potential residual and unmeasured confounding may exist, they added.
Judy George wrote the original story for MedPage Today
Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner