- Email: [email protected]
Cognitive decline in type 2 diabetes
Comment
Ultimately, the goal of any diabetes prevention strategy is to reduce the burden of complications and especially cardiovascular disease, which causes the most morbidity and mortality, and to which south Asian individuals are particularly susceptible. Endpoints should include cardiovascular risk factors and subclinical cardiovascular disease. Consideration of multiple risk factors should be as embedded in prevention trials as it now is in clinical practice.
3
*Therese Tillin, Nish Chaturvedi
7
Institute of Cardiovascular Science, University College London, London, WC1E 6BT, UK [email protected] We declare that we have no conflicts of interest. 1
2
Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011; 94: 311–21. Tillin T, Hughes AD, Godsland IF, et al. Insulin resistance and truncal obesity as important determinants of the greater incidence of diabetes in Indian Asians and African Caribbeans compared with Europeans: the Southall And Brent REvisited (SABRE) cohort. Diabetes Care 2013; 36: 383–93.
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Tillin T, Hughes AD, Mayet J, et al. The relationship between metabolic risk factors and incident cardiovascular disease in Europeans, south Asians, and African Caribbeans: SABRE (Southall and Brent revisited)—a prospective population-based study. J Am Coll Cardiol 2013; 61: 1777–86. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 2006; 49: 289–97. Bhopal RS, Douglas A, Wallia S, et al. Effect of a lifestyle intervention on weight change in south Asian individuals in the UK at high risk of type 2 diabetes: a family-cluster randomised controlled trial. Lancet Diabetes Endocrinol 2013; published online Dec 23. http://dx.doi.org/10.1016/ S2213-8587(13)70204-3. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343–50. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393–403. Dabelea D, Crume T. Maternal environment and the transgenerational cycle of obesity and diabetes. Diabetes 2011; 60: 1849–55. Kuh D, Ben-Shlomo Y. A life course approach to chronic disease epidemiology: tracing the origins of ill-health from early to adult life, 2nd edn. Oxford: Oxford University Press, 2004. Lawlor DA, Chaturvedi N. Treatment and prevention of obesity—are there critical periods for intervention? Int J Epidemiol 2006; 35: 3–9. Srinivasan S, Ambler GR, Baur LA, et al. Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin. J Clin Endocrinol Metab 2006; 91: 2074–80.
Cognitive decline in type 2 diabetes Published Online December 19, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70167-0 See Articles page 228
188
Evidence is accumulating that type 2 diabetes is associated with cognitive impairment and dementia. In individuals older than 60 years, 7–13% of dementia cases are estimated to be attributable to diabetes,1 and the number of cases of diabetes-associated dementia is expected to increase because of the diabetes pandemic and ageing populations worldwide. Dementia is preceded by accelerated cognitive decline, and study of the risk factors for cognitive decline could therefore provide insights into the causes of dementia. However, the natural history of cognitive decline in type 2 diabetes is not well understood. Some researchers have suggested that clinically relevant cognitive decline related to type 2 diabetes does not develop until the neurodegenerative changes in the brain associated with ageing have started to occur (ie, after age 60 years).1 Additionally, in some studies2,3 the extent of cognitive decline in new-onset diabetes was not clearly different from that in individuals without diabetes, suggesting a threshold for diabetes duration in the association between cognitive decline and diabetes. Against this background, Richard Tuligenga and colleagues’ analysis4 from the Whitehall II cohort study in The Lancet Diabetes & Endocrinology addresses the questions of whether type 2 diabetes is associated
with cognitive decline before old age, and whether glycaemic control and disease duration are risk factors for faster cognitive decline. The investigators compared cognitive decline over 10 years between individuals with normoglycaemia, prediabetes, new-onset diabetes, and known diabetes; the known diabetes group had a mean age of 57·4 years—much younger than in previous studies (69–74 years).2,5,6 They report that diabetes was associated with accelerated cognitive decline and that both disease duration and glycaemic control (assessed by HbA1c) were important risk factors. A strength of the present study is that it explicitly compares the effect of diabetes with that of age. Cognitive decline in middle-aged individuals with diabetes was 1·24–1·45 times faster than that in normal ageing (ie, those with known diabetes had a 45% faster decline in memory [10 year difference in decline –0·13 SD, 95% CI –0·26 to –0·00; p=0·046] and a 24% faster decline in global cognitive score [–0·11 SD, –0·21 to –0·02; p=0·014]), which seems less than that in previous studies (1·5–2·0).7 Because most previous studies were done in older individuals with diabetes, these findings suggest that the effect of diabetes on cognitive decline might accelerate with age. Thus, 10 years of diabetes could be calculated to correspond to 2·5–10 years of extra www.thelancet.com/diabetes-endocrinology Vol 2 March 2014
Comment
cognitive ageing, a huge difference that clearly needs to be better understood. In Tuligenga and colleagues’ study,4 longer diabetes duration was associated with faster cognitive decline; however, contrary to the investigators’ claim, this finding is not new.5,6 Notably, individuals with new-onset diabetes in the Whitehall II study did not do worse than normoglycaemic participants on the cognitive tests at baseline, and did not show faster cognitive decline over the 10 year follow-up. This finding contrasts with those from other cross-sectional studies in older individuals8,9 and with results from the Maastricht Aging Study,6 in which a post-hoc analysis showed that individuals with new-onset diabetes had a rate of decline in information-processing speed that was smaller than in individuals with established type 2 diabetes, but significantly greater than in those without diabetes. The mean age of individuals with new-onset diabetes was similar in the Maastricht Aging and Whitehall II studies (60 vs 59 years, respectively), so variables other than age must underlie this difference An alternative explanation lies in the tests of cognitive function used in the Whitehall II study, which might have been insufficiently sensitive10 to pick up subtle differences in cognitive performance between individuals with new-onset diabetes and those with normoglycaemia. In people with type 2 diabetes, cognitive decrements are most consistently reported for measures of verbal memory and information-processing speed,10 although in older individuals with diabetes decrements in executive functioning (ie, higher-order functions that allow for planning, goal-directed behaviour, and attention) can also be seen.3,6 Previous studies2,3,5,6 have included measures of memory storage and retrieval, assessment of information-processing speed with tasks that measure the ability to match digits to letters, or symbols to digits, as quickly as possible (so-called substitution tasks), and assessment of executive functioning with tests for divided (concept-shifting test) or selective attention (Stroop colour-word test). None of these tests were used in the present study, even though they were sensitive to the effects of diabetes in the Maastricht Aging Study6 and the Doetinchem Cohort Study.3 Furthermore, information-processing speed seemed to be most sensitive to the effects of new-onset diabetes in previous studies.6,9 However, the present study did not measure information-processing speed or memory retrieval. Instead, it used only a brief short-term memory test www.thelancet.com/diabetes-endocrinology Vol 2 March 2014
(which does not measure learning rate and retrieval), an intelligence test of inductive reasoning (which measures the ability to identify patterns and infer principles and rules) to measure executive function, and phonemic and semantic fluency tests (which measure the ability to say as many words as possible beginning with a certain letter or within a certain category in 1 min, respectively). Cognitive decline in individuals with type 2 diabetes affects memory, information processing, and executive functioning. It can start in middle age, is affected by diabetes duration and glycaemic control, and can accelerate with age. Whether diabetes-related cognitive decline starts at onset of diabetes or takes some time to develop is unclear, as is the rate of progression. These questions are clearly important for prevention of diabetesrelated dementia, and further longitudinal studies, in which cognitive performance is accurately measured in multiple domains, are needed to provide answers. Peggy J J Spauwen, *Coen D A Stehouwer Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands (PJJS); and Department of Internal Medicine and Cardiovascular Research Institute, Maastricht University Medical Center, 6202 AZ, Maastricht, Netherlands (CDAS) [email protected] We declare that we have no conflicts of interest. 1 2
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Biessels GJ, Deary IJ, Ryan CM. Cognition and diabetes: a lifespan perspective. Lancet Neurol 2008; 7: 184–90. Yaffe K, Falvey C, Hamilton N, et al. Diabetes, glucose control, and 9-year cognitive decline among older adults without dementia. Arch Neurol 2012; 69: 1170–75. Nooyens AC, Baan CA, Spijkerman AM, Verschuren WM. Type 2 diabetes and cognitive decline in middle-aged men and women: the Doetinchem Cohort Study. Diabetes Care 2010; 33: 1964–69. Tuligenga RH, Dugravot A, Tabák AG, et al. Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a prospective analysis of the Whitehall II cohort study. Lancet Diabetes Endocrinol 2013; published online Dec 19. http://dx.doi. org/10.1016/S2213-8587(13)70192-X. Okereke OI, Kang JH, Cook NR, et al. Type 2 diabetes mellitus and cognitive decline in two large cohorts of community-dwelling older adults. J Am Geriatr Soc 2008; 56: 1028–36. Spauwen PJ, Kohler S, Verhey FR, Stehouwer CD, van Boxtel MP. Effects of type 2 diabetes on 12-year cognitive change: results from the Maastricht Aging Study. Diabetes Care 2013; 36: 1554–61. Reijmer YD, van den Berg E, Ruis C, Kappelle LJ, Biessels GJ. Cognitive dysfunction in patients with type 2 diabetes. Diabetes Metab Res Rev 2010; 26: 507–19. Ruis C, Biessels GJ, Gorter KJ, van den Donk M, Kappelle LJ, Rutten GE. Cognition in the early stage of type 2 diabetes. Diabetes Care 2009; 32: 1261–65. Saczynski JS, Jonsdottir MK, Garcia ME, et al. Cognitive impairment: an increasingly important complication of type 2 diabetes: the age, gene/environment susceptibility—Reykjavik study. Am J Epidemiol 2008; 168: 1132–39. Awad N, Gagnon M, Messier C. The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function. J Clin Exp Neuropsychol 2004; 26: 1044–80.
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Ultimately, the goal of any diabetes prevention strategy is to reduce the burden of complications and especially cardiovascular disease, which causes the most morbidity and mortality, and to which south Asian individuals are particularly susceptible. Endpoints should include cardiovascular risk factors and subclinical cardiovascular disease. Consideration of multiple risk factors should be as embedded in prevention trials as it now is in clinical practice.
3
*Therese Tillin, Nish Chaturvedi
7
Institute of Cardiovascular Science, University College London, London, WC1E 6BT, UK [email protected] We declare that we have no conflicts of interest. 1
2
Whiting DR, Guariguata L, Weil C, Shaw J. IDF diabetes atlas: global estimates of the prevalence of diabetes for 2011 and 2030. Diabetes Res Clin Pract 2011; 94: 311–21. Tillin T, Hughes AD, Godsland IF, et al. Insulin resistance and truncal obesity as important determinants of the greater incidence of diabetes in Indian Asians and African Caribbeans compared with Europeans: the Southall And Brent REvisited (SABRE) cohort. Diabetes Care 2013; 36: 383–93.
4
5
6
8 9
10 11
Tillin T, Hughes AD, Mayet J, et al. The relationship between metabolic risk factors and incident cardiovascular disease in Europeans, south Asians, and African Caribbeans: SABRE (Southall and Brent revisited)—a prospective population-based study. J Am Coll Cardiol 2013; 61: 1777–86. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia 2006; 49: 289–97. Bhopal RS, Douglas A, Wallia S, et al. Effect of a lifestyle intervention on weight change in south Asian individuals in the UK at high risk of type 2 diabetes: a family-cluster randomised controlled trial. Lancet Diabetes Endocrinol 2013; published online Dec 23. http://dx.doi.org/10.1016/ S2213-8587(13)70204-3. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343–50. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393–403. Dabelea D, Crume T. Maternal environment and the transgenerational cycle of obesity and diabetes. Diabetes 2011; 60: 1849–55. Kuh D, Ben-Shlomo Y. A life course approach to chronic disease epidemiology: tracing the origins of ill-health from early to adult life, 2nd edn. Oxford: Oxford University Press, 2004. Lawlor DA, Chaturvedi N. Treatment and prevention of obesity—are there critical periods for intervention? Int J Epidemiol 2006; 35: 3–9. Srinivasan S, Ambler GR, Baur LA, et al. Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: improvement in body composition and fasting insulin. J Clin Endocrinol Metab 2006; 91: 2074–80.
Cognitive decline in type 2 diabetes Published Online December 19, 2013 http://dx.doi.org/10.1016/ S2213-8587(13)70167-0 See Articles page 228
188
Evidence is accumulating that type 2 diabetes is associated with cognitive impairment and dementia. In individuals older than 60 years, 7–13% of dementia cases are estimated to be attributable to diabetes,1 and the number of cases of diabetes-associated dementia is expected to increase because of the diabetes pandemic and ageing populations worldwide. Dementia is preceded by accelerated cognitive decline, and study of the risk factors for cognitive decline could therefore provide insights into the causes of dementia. However, the natural history of cognitive decline in type 2 diabetes is not well understood. Some researchers have suggested that clinically relevant cognitive decline related to type 2 diabetes does not develop until the neurodegenerative changes in the brain associated with ageing have started to occur (ie, after age 60 years).1 Additionally, in some studies2,3 the extent of cognitive decline in new-onset diabetes was not clearly different from that in individuals without diabetes, suggesting a threshold for diabetes duration in the association between cognitive decline and diabetes. Against this background, Richard Tuligenga and colleagues’ analysis4 from the Whitehall II cohort study in The Lancet Diabetes & Endocrinology addresses the questions of whether type 2 diabetes is associated
with cognitive decline before old age, and whether glycaemic control and disease duration are risk factors for faster cognitive decline. The investigators compared cognitive decline over 10 years between individuals with normoglycaemia, prediabetes, new-onset diabetes, and known diabetes; the known diabetes group had a mean age of 57·4 years—much younger than in previous studies (69–74 years).2,5,6 They report that diabetes was associated with accelerated cognitive decline and that both disease duration and glycaemic control (assessed by HbA1c) were important risk factors. A strength of the present study is that it explicitly compares the effect of diabetes with that of age. Cognitive decline in middle-aged individuals with diabetes was 1·24–1·45 times faster than that in normal ageing (ie, those with known diabetes had a 45% faster decline in memory [10 year difference in decline –0·13 SD, 95% CI –0·26 to –0·00; p=0·046] and a 24% faster decline in global cognitive score [–0·11 SD, –0·21 to –0·02; p=0·014]), which seems less than that in previous studies (1·5–2·0).7 Because most previous studies were done in older individuals with diabetes, these findings suggest that the effect of diabetes on cognitive decline might accelerate with age. Thus, 10 years of diabetes could be calculated to correspond to 2·5–10 years of extra www.thelancet.com/diabetes-endocrinology Vol 2 March 2014
Comment
cognitive ageing, a huge difference that clearly needs to be better understood. In Tuligenga and colleagues’ study,4 longer diabetes duration was associated with faster cognitive decline; however, contrary to the investigators’ claim, this finding is not new.5,6 Notably, individuals with new-onset diabetes in the Whitehall II study did not do worse than normoglycaemic participants on the cognitive tests at baseline, and did not show faster cognitive decline over the 10 year follow-up. This finding contrasts with those from other cross-sectional studies in older individuals8,9 and with results from the Maastricht Aging Study,6 in which a post-hoc analysis showed that individuals with new-onset diabetes had a rate of decline in information-processing speed that was smaller than in individuals with established type 2 diabetes, but significantly greater than in those without diabetes. The mean age of individuals with new-onset diabetes was similar in the Maastricht Aging and Whitehall II studies (60 vs 59 years, respectively), so variables other than age must underlie this difference An alternative explanation lies in the tests of cognitive function used in the Whitehall II study, which might have been insufficiently sensitive10 to pick up subtle differences in cognitive performance between individuals with new-onset diabetes and those with normoglycaemia. In people with type 2 diabetes, cognitive decrements are most consistently reported for measures of verbal memory and information-processing speed,10 although in older individuals with diabetes decrements in executive functioning (ie, higher-order functions that allow for planning, goal-directed behaviour, and attention) can also be seen.3,6 Previous studies2,3,5,6 have included measures of memory storage and retrieval, assessment of information-processing speed with tasks that measure the ability to match digits to letters, or symbols to digits, as quickly as possible (so-called substitution tasks), and assessment of executive functioning with tests for divided (concept-shifting test) or selective attention (Stroop colour-word test). None of these tests were used in the present study, even though they were sensitive to the effects of diabetes in the Maastricht Aging Study6 and the Doetinchem Cohort Study.3 Furthermore, information-processing speed seemed to be most sensitive to the effects of new-onset diabetes in previous studies.6,9 However, the present study did not measure information-processing speed or memory retrieval. Instead, it used only a brief short-term memory test www.thelancet.com/diabetes-endocrinology Vol 2 March 2014
(which does not measure learning rate and retrieval), an intelligence test of inductive reasoning (which measures the ability to identify patterns and infer principles and rules) to measure executive function, and phonemic and semantic fluency tests (which measure the ability to say as many words as possible beginning with a certain letter or within a certain category in 1 min, respectively). Cognitive decline in individuals with type 2 diabetes affects memory, information processing, and executive functioning. It can start in middle age, is affected by diabetes duration and glycaemic control, and can accelerate with age. Whether diabetes-related cognitive decline starts at onset of diabetes or takes some time to develop is unclear, as is the rate of progression. These questions are clearly important for prevention of diabetesrelated dementia, and further longitudinal studies, in which cognitive performance is accurately measured in multiple domains, are needed to provide answers. Peggy J J Spauwen, *Coen D A Stehouwer Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands (PJJS); and Department of Internal Medicine and Cardiovascular Research Institute, Maastricht University Medical Center, 6202 AZ, Maastricht, Netherlands (CDAS) [email protected] We declare that we have no conflicts of interest. 1 2
3
4
5
6
7
8
9
10
Biessels GJ, Deary IJ, Ryan CM. Cognition and diabetes: a lifespan perspective. Lancet Neurol 2008; 7: 184–90. Yaffe K, Falvey C, Hamilton N, et al. Diabetes, glucose control, and 9-year cognitive decline among older adults without dementia. Arch Neurol 2012; 69: 1170–75. Nooyens AC, Baan CA, Spijkerman AM, Verschuren WM. Type 2 diabetes and cognitive decline in middle-aged men and women: the Doetinchem Cohort Study. Diabetes Care 2010; 33: 1964–69. Tuligenga RH, Dugravot A, Tabák AG, et al. Midlife type 2 diabetes and poor glycaemic control as risk factors for cognitive decline in early old age: a prospective analysis of the Whitehall II cohort study. Lancet Diabetes Endocrinol 2013; published online Dec 19. http://dx.doi. org/10.1016/S2213-8587(13)70192-X. Okereke OI, Kang JH, Cook NR, et al. Type 2 diabetes mellitus and cognitive decline in two large cohorts of community-dwelling older adults. J Am Geriatr Soc 2008; 56: 1028–36. Spauwen PJ, Kohler S, Verhey FR, Stehouwer CD, van Boxtel MP. Effects of type 2 diabetes on 12-year cognitive change: results from the Maastricht Aging Study. Diabetes Care 2013; 36: 1554–61. Reijmer YD, van den Berg E, Ruis C, Kappelle LJ, Biessels GJ. Cognitive dysfunction in patients with type 2 diabetes. Diabetes Metab Res Rev 2010; 26: 507–19. Ruis C, Biessels GJ, Gorter KJ, van den Donk M, Kappelle LJ, Rutten GE. Cognition in the early stage of type 2 diabetes. Diabetes Care 2009; 32: 1261–65. Saczynski JS, Jonsdottir MK, Garcia ME, et al. Cognitive impairment: an increasingly important complication of type 2 diabetes: the age, gene/environment susceptibility—Reykjavik study. Am J Epidemiol 2008; 168: 1132–39. Awad N, Gagnon M, Messier C. The relationship between impaired glucose tolerance, type 2 diabetes, and cognitive function. J Clin Exp Neuropsychol 2004; 26: 1044–80.
189