Migraine May Cut Diabetes Risk in Women

Damian McNamara

December 19, 2018

Having a migraine may mitigate the risk for diabetes development in women, new research suggests.

In a large national cohort study conducted in France, women with active migraine were 30% less likely than women without a history of migraine to develop type 2 diabetes mellitus (T2DM).

When the researchers also looked at prevalence patterns over time, they found "a linear decrease of migraine prevalence long before and a plateau long after type 2 diabetes diagnosis," Guy Fagherazzi, PhD, senior research scientist in digital and diabetes epidemiology, Center for Research in Epidemiology and Population Health, University of Paris-Saclay, France, told Medscape Medical News.

"Both migraine and type 2 diabetes are highly prevalent diseases. Therefore, our results can have substantial implications regarding the understanding of mechanisms underlying these two conditions," Fagherazzi added.

The findings were published online this week in JAMA Neurology.

No Consensus in Literature

Previous studies have pointed to an association between migraine, particularly migraine with aura, and increased risk for hyperlipidemia and hypertension and an elevated Framingham Risk Score for coronary heart disease.

Other researchers found a link between migraine and risk of overall and specific cardiovascular events.

In contrast, Women’s Health Study investigators did not find associations between migraine and incident diabetes.

"Despite the high prevalence of both diseases, the association between migraine and type 2 diabetes is still unclear," the current investigators write.

To address this gap in the literature, they examined data from the Etude Epidémiologique Auprès des Femmes de la Mutuelle Générale de l’Education Nationale (E3N) study. They assessed 74,247 women with complete follow-up data and no diagnosis of diabetes at baseline.

Participants in the ongoing E3N research complete questionnaires every 2 years asking about their health, including migraines since the last survey and development of T2DM. The researchers also accessed health insurance and other data to confirm any self-reported diagnoses.

Participants were a mean age of 61 years when E3N investigators began the follow-up surveys in April 2004. Fagherazzi and colleagues classified the women into three groups: active migraine, history of migraine, and no history of migraine.

They also performed a secondary analysis of women who developed T2DM and then looked at the prevalence of migraine in this group over time.

In both analyses, the researchers controlled for factors such as age, level of education, family history of diabetes, body mass index, smoking status, hypertension, level of recreational physical activity, use of oral contraceptives, menopausal status, menopausal hormone therapy use, and handedness (left-handed, right-handed, or ambidextrous).

Key Findings

Between 2004 and 2014, 2372 women developed an incident case of T2DM.

The likelihood of developing the condition was lower among women with active migraine.

This group had a 20% reduction in the risk of developing pharmacologically treated T2DM compared with those who did not have a history of migraine (hazard ratio [HR], 0.80; 95% confidence interval [CI], 0.67 - 0.96).

The risk was further reduced, to 30%, in multivariate modeling (HR, 0.70; 95% CI, 0.58 - 0.85).

However, the women who reported a history of migraine were not more likely to develop T2DM in univariate analysis (HR, 1.16; 95% CI, 1.06 - 1.27) or in multivariable-adjusted models (HR, 1.07; 95% CI, 0.98 - 1.17).

There were no differences in distribution of handedness and migraine at baseline. However, women with mixed or ambidextrous handedness were at increased risk of self-reporting migraine over time vs right-handed women (odds ratio [OR], 1.13; 95% CI, 1.02 - 1.24). In contrast, the association did not emerge among left-handed women (OR, 1.01; 95% CI, 0.88 - 1.16).

In terms of changes over time, the investigators found "a clear linear decrease" in the 2-year prevalence of active migraine -- from 22% at 24 years to 11% at the date of diagnosis. Thereafter, the prevalence of migraine plateaued, remaining at approximately 10% to 11%.

"Tracking the evolution — and especially the decrease — of migraine frequency in migraineurs at high risk of diabetes, such as obese individuals irrespectively of age, could be the sign of emerging increased blood glucose levels, prediabetes, or type 2 diabetes,” Fagherazzi said.

Possible Mechanisms

Although the exact mechanism(s) behind an association between migraine and lower risk for diabetes remains elusive, the investigators proposed some hypotheses.

Past research has pointed to a link between polymorphisms in the insulin receptor gene and migraine, while other investigators have reported an elevation in free fatty acids in plasma and ketone bodies prior to migraine attacks.

Fasting also could play a role in migraine development because of hypoglycemia and increased ketone bodies production.

"These biological factors could therefore explain an inverse association between migraine and type 2 diabetes risk," the current researchers note.

"They could also support our observed decreased prevalence of migraine in the years before type 2 diabetes diagnosis, when there is usually a progressively increasing hyperglycemic state," they add.

In other words, increasing hyperglycemia could decrease the likelihood for migraine.

Supporting this association is calcitonin gene-related peptide (CGRP), a neuropeptide expressed in sensory nerves. CGRP "seems to play an important role in migraine pathophysiology and is also associated with glucose metabolism," the authors write.

The current study was unable to assess participants who had migraine with aura, a potential limitation. In addition, even though the investigators controlled for many common risk factors for T2DM, "potential residual and unmeasurable confounding cannot be ruled out completely because this study is observational."

Potential advantages that hyperglycemia and/or hyperinsulinism confer on migraine prevalence should be evaluated further, the researchers note.

"Similar studies should be run in men as well and in other populations in the world," Fagherazzi said.

"Moreover, we would like to investigate the potential associations between migraine and other main chronic diseases, including cardiometabolic outcomes other than type 2 diabetes or cancer," he added.

In Line With Clinical Practice

"These findings are in line with observations from clinical practice. Headache practitioners have long discussed the rarity of patients with type 2 diabetes in headache clinics," Amy A. Gelfand, MD, and Elizabeth Loder, MD, write in an accompanying editorial.

The prospective, longitudinal nature is a strength of the study, they add.

The long follow-up allowed the researchers to compare participants who suffer active migraine with those who don't suffer migraine, and to evaluate the evolution of migraine prevalence over time, note Gelfand, Child and Adolescent Headache Program, Benioff Children's Hospital, University of California, San Francisco; and Loder, affiliated with the Division of Headache, Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.

"The study also has several limitations," they write. "Migraine status was based on self-report. However, clinician assessment of migraine would have been optimal but impractical for a study of this size; moreover, those who say they have migraine are usually correct."

In addition, women in the study cohort were principally white, not obese, and mostly employed as teachers, "so it is uncertain whether the results apply to men or those from other ethnic/racial or socioeconomic backgrounds," the editorialists write.

T he E3N cohort is supported by the Mutuelle Generale de l'Education Nationale, European Community, French League against Cancer, Gustave Roussy, and the French Institute of Health and Medical Research. The study was also supported through a grant from The French Research Agency (Agence Nationale de la Recherche). Dr Fagherazzi and Dr Loder have disclosed no relevant financial relationships. Dr Gelfand consults for Eli Lilly, Impax, Zosano, and Biohaven; receives research funding from Amgen and eNeura, and personal compensation for medical-legal consulting; and has received honoraria from UpToDate and JAMA Neurology.

JAMA Neurology. Published online December 17, 2018. Full text. Editorial

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