Comparative effect of metformin versus sulfonylureas with dementia and Parkinson's disease risk in US patients over 50 with type 2 diabetes mellitus.

BackgroundLean body mass has been identified as a key determinant of left ventricular mass and wall thickness. However, the importance of lean body mass or other body‐size measures as normative determinants of carotid intima‐media thickness (cIMT), a widely used early indicator of atherosclerosis, has not been well established.Methods and ResultsCarotid artery ultrasound measurements of cIMT and carotid artery plaque burden (derived from plaque number and maximum size) and measurements of body size, including height, body mass index, weight, body fat proportion, and lean body mass ([1−body fat proportion]×weight), were recorded in 25 020 participants from 10 regions of China. Analyses were restricted to a healthy younger subset (n=6617) defined as never or long‐term ex‐regular smokers aged <60 years (mean age, 50) without previous ischemic heart disease, stroke, diabetes mellitus, or hypertension and with plasma non‐high‐density lipoprotein cholesterol <4 mmol/L. Among these 6617 participants, 86% were women (because most men smoked) and 9% had carotid artery plaque. In both women and men separately, lean body mass was strongly positively associated with cIMT, but was not associated with plaque burden: overall, each 10 kg higher lean body mass was associated with a 0.03 (95% CI, 0.03–0.04) mm higher cIMT (P=5×10−33). Fat mass, height, and other body‐size measures were more weakly associated with cIMT.ConclusionsThe strong association of lean body mass with cIMT, but not with plaque burden, in healthy adults suggests a normative relationship rather than reflecting atherosclerotic pathology. Common mechanisms may underlie the associations of lean body mass with cIMT and with nonatherosclerotic vascular traits.

Background Taller adult height is associated with lower risks of ischemic heart disease in mendelian randomization (MR) studies, but little is known about the causal relevance of height for different subtypes of ischemic stroke. The present study examined the causal relevance of height for different subtypes of ischemic stroke. Methods and findings Height-associated genetic variants (up to 2,337) from previous genome-wide association studies (GWASs) were used to construct genetic instruments in different ancestral populations. Two-sample MR approaches were used to examine the associations of genetically determined height with ischemic stroke and its subtypes (cardioembolic stroke, large-artery stroke, and small-vessel stroke) in multiple ancestries (the MEGASTROKE consortium, which included genome-wide studies of stroke and stroke subtypes: 60,341 ischemic stroke cases) supported by additional cases in individuals of white British ancestry (UK Biobank [UKB]: 4,055 cases) and Chinese ancestry (China Kadoorie Biobank [CKB]: 10,297 cases). The associations of genetically determined height with established cardiovascular and other risk factors were examined in 336,750 participants from UKB and 58,277 participants from CKB. In MEGASTROKE, genetically determined height was associated with a 4% lower risk (odds ratio [OR] 0.96; 95% confidence interval [CI] 0.94, 0.99; p = 0.007) of ischemic stroke per 1 standard deviation (SD) taller height, but this masked a much stronger positive association of height with cardioembolic stroke (13% higher risk, OR 1.13 [95% CI 1.07, 1.19], p < 0.001) and stronger inverse associations with large-artery stroke (11% lower risk, OR 0.89 [0.84, 0.95], p < 0.001) and small-vessel stroke (13% lower risk, OR 0.87 [0.83, 0.92], p < 0.001). The findings in both UKB and CKB were directionally concordant with those observed in MEGASTROKE, but did not reach statistical significance: For presumed cardioembolic stroke, the ORs were 1.08 (95% CI 0.86, 1.35; p = 0.53) in UKB and 1.20 (0.77, 1.85; p = 0.43) in CKB; for other subtypes of ischemic stroke in UKB, the OR was 0.97 (95% CI 0.90, 1.05; p = 0.49); and for other nonlacunar stroke and lacunar stroke in CKB, the ORs were 0.89 (0.80, 1.00; p = 0.06) and 0.99 (0.88, 1.12; p = 0.85), respectively. In addition, genetically determined height was also positively associated with atrial fibrillation (available only in UKB), and with lean body mass and lung function, and inversely associated with low-density lipoprotein (LDL) cholesterol in both British and Chinese ancestries. Limitations of this study include potential bias from assortative mating or pleiotropic effects of genetic variants and incomplete generalizability of genetic instruments to different populations. Conclusions The findings provide support for a causal association of taller adult height with higher risk of cardioembolic stroke and lower risk of other ischemic stroke subtypes in diverse ancestries. Further research is needed to understand the shared biological and physical pathways underlying the associations between height and stroke risks, which could identify potential targets for treatments to prevent stroke.

Background: Taller adult height is associated with lower risks of ischaemic heart disease in both observational and Mendelian randomisation studies, but little is known about the causal relevance of height for different subtypes of ischaemic stroke and the mechanisms involved. Methods: Height-associated genetic variants (up to 2,931) from previous genome-wide association studies were used to construct genetic instruments in different populations. Two-sample Mendelian randomisation approaches were used to examine the associations of genetically-determined height with ischaemic stroke and its subtypes in multiple ancestries (MEGASTROKE: 60,341 ischaemic stroke cases) supported by additional cases in Europeans (UK Biobank: 4,055 cases) and in Chinese (China Kadoorie Biobank: 10,297 cases). The associations of genetically-determined height with established cardiovascular and other risk factors were also examined in Europeans (UK Biobank: 336,750 participants) and Chinese (China Kadoorie Biobank: 58,277 participants). Results: Genetically-determined height was inversely associated with ischaemic stroke (4% [95% CI: 1-7] lower risk per 1 standard deviation taller height in MEGASTROKE). This masked much stronger opposing associations of height with different subtypes, with a 12% (95% CI: 6-17) higher risk of cardioembolic stroke, 11% (6-16) lower risk of large-artery stroke, and 14% (9-18) lower risk of small-vessel stroke. Genetically-determined height was strongly positively associated with atrial fibrillation, lean body mass and lung function, and inversely associated with levels of LDL cholesterol and blood pressure in both Europeans and Chinese. Conclusions: In multiple ancestries, genetic associations support the causal relevance of taller adult height for higher risk of cardioembolic stroke (in addition to atrial fibrillation) and lower risk of other ischaemic strokes, highlighting the need to properly differentiate subtypes of ischaemic stroke in both clinical practice and research.

Background Taller adult height is associated with lower risks of ischaemic heart disease in both conventional and Mendelian randomisation studies, providing support for a causal association, but the associations of height with ischaemic stroke and ischaemic stroke subtypes are uncertain. Purpose To examine the causal relevance of height for ischaemic stroke and ischaemic stroke subtypes. Methods Two-sample Mendelian randomisation analyses were used to examine the associations of height with: (i) ischaemic stroke and ischaemic stroke subtypes in MEGASTROKE (using summary data from 34 217 ischaemic stroke cases), and with (ii) established cardiovascular and other risk factors using individual data from 336 433 participants in UK Biobank and 57 785 in the China Kadoorie Biobank. Instruments for Mendelian randomisation were constructed from up to 3280 height-associated genetic variants, previously identified as having genome-wide significant effects on height. Results Genetically-determined taller height was inversely associated with ischaemic stroke (3% [95% CI: 1–6] lower risk per 1 standard deviation taller height) in MEGASTROKE but this masked much stronger opposing associations on risks of different ischaemic stroke subtypes: 15% (95% CI: 9–21) higher risk of cardioembolic stroke, 10% (4–15) lower risk of large-artery atherosclerotic stroke, and 15% (10–20) lower risk of small-vessel stroke (Figure). Genetically-determined taller height was strongly associated with atrial fibrillation and higher lean body mass and lung function but more weakly associated with lower levels of LDL cholesterol and blood pressure. Conclusions The findings support a causal association between taller adult height and risk of atrial fibrillation and cardioembolic stroke. The opposing associations of height with other ischaemic stroke subtypes provide further support for considering ischaemic stroke subtypes as distinct diseases in both research and clinical practice. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Medical Research Council, British Heart Foundation