Kioumourtzoglou MA, Rotem RS, Seals RM, Gredal O, Hansen J, Weisskopf MG. Diabetes Mellitus, Obesity, and Diagnosis of Amyotrophic Lateral Sclerosis: A Population-Based Study. JAMA Neurol. 2015 Aug;72(8):905-11. PubMed.
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Université de Strasbourg
The study by Paganoni is a retrospective analysis of six clinical trials reanalyzed for the influence of diabetes on ALS survival. The authors found no such effect, meaning that the diabetic status did not correlate with either improved or worsened survival. Contrastingly, and consistent with multiple other studies, the authors found that patients with higher initial body mass index (BMI) had increased survival. Paganoni and collaborators also observed lower-than-expected frequency of diabetes in ALS patients in their cohort, and confirmed this observation in two other ALS cohorts. The authors are cautious in their interpretation since multiple biases might be responsible for this lower-than-expected frequency; yet, this latter observation is entirely consistent with previous studies by the Fang group showing decreased risk of ALS in diabetic patients.
Intriguingly, the second study shows the opposite relationship, with increased risk of ALS in younger men with diabetes. The reasons for these discrepancies are not known, but might be related to different genetic backgrounds. Further studies are required to clarify this difference.
In general, both studies are consistent with a role of altered energy metabolism in ALS. Diabetes is, however, a very distant proxy of metabolic health, and it is not surprising that BMI correlates better with survival than diabetes. These studies remain correlative, and a causal relationship between weight loss and ALS remains to be established. The first step in this direction was recently provided by Wills and collaborators, who showed that hypercaloric nutrition protects ALS patients who had needed gastrostomy for survival (Wills et al., 2014). These data suggest we urgently need to perform interventional studies in less-advanced ALS patients to determine whether providing energy-rich diets slows down disease progression.
References:
Wills AM, Hubbard J, Macklin EA, Glass J, Tandan R, Simpson EP, Brooks B, Gelinas D, Mitsumoto H, Mozaffar T, Hanes GP, Ladha SS, Heiman-Patterson T, Katz J, Lou JS, Mahoney K, Grasso D, Lawson R, Yu H, Cudkowicz M, MDA Clinical Research Network. Hypercaloric enteral nutrition in patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled phase 2 trial. Lancet. 2014 Jun 14;383(9934):2065-72. Epub 2014 Feb 28 PubMed.
View all comments by Luc DupuisThere are no obvious methodological flaws in these three studies. However, there are similarities and dissimilarities.
In the age-specific analyses, these three studies all showed a higher relative risk of ALS in relation to diabetes in younger ages than in older ages.
The Swedish study showed a protective effect of diabetes only in those aged 70 years and older; similar findings were noted in those older than 60 in the U.S. study. While the Taiwanese study showed a significant elevated hazard ratio for men younger than 65 with diabetes, it did not show such adverse effect of diabetes in people aged 65 years and older.
The co-morbidities and other socioeconomic factors considered in the analysis were not the same in these three studies. For example, the Swedish study considered education, occupation-based socioeconomic status, age, sex, and area of residence in its analysis. In addition to socioeconomic status, the U.S. study additionally adjusted for chronic obstructive pulmonary disorder, obesity, and marital status. Compared to the U.S. and Swedish studies, the Taiwanese study took more factors into consideration, but I don’t believe this explains why the Taiwanese study arrived at different conclusions.
The other difference in these three studies is the age of study population. The mean age in the Taiwanese study was 60, but it was 66 in the U.S. study and 68 in the Swedish.
All told, there was a tendency in these three studies for diabetes to be a risk factor for ALS in younger ages, but it may pose a protective effect on risk of ALS overall.
Therefore, if we took only a single value showing the overall effect of diabetes on ALS, the Taiwanese study may be overrepresented by younger people, and both the Swedish and U.S. studies tended to show an association of diabetes with ALS in an older people. I believe such a “population mix” is the most likely reason for the dissimilarities in findings between ours and the other two studies.
Based on what I observed. I would make the following three suggestions:
1. Age could significantly modify the relationship between diabetes and ALS. Therefore, future studies should present age-specific relative risk of ALS in relation to diabetes.
2. We need more studies that include diabetics with wider age ranges (e.g., younger than 50 years or older than 70 years) to see if age is truly a significant effect-modifier.
3. For our own Taiwanese study, or other future studies, it would be better to make a more detailed age-stratified analyses (like the Swedish study) to look into the age-specific relationship between diabetes and ALS.
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