Comment
People with type 2 diabetes have a 50–100% greater risk of dementia and cognitive impairment than normoglycaemic individuals.1,2 Since almost all patients with type 2 diabetes receive pharmacological treatment at some point during the course of their disease, studies investigating the effects of antidiabetic drugs on cognition are timely. Intranasal insulin has been studied as a potential treatment for mild cognitive impairment and Alzheimer’s disease3 and to enhance cognition in type 2 diabetes.4 Although intranasal insulin has the potential to directly affect the brain, the role of exogenous insulin on brain function is less clear, particularly because whether or how it could permeate the blood–brain barrier is unknown. In some observational studies there was an increased risk of dementia in patients with diabetes using insulin compared with those not using insulin; however, these studies are inherently flawed and represent a classic case of confounding by indication. Compared with patients with diabetes not using insulin, those using insulin are older, have more comorbidities, and have a longer duration of diabetes—all risk factors for dementia.2 Thus, trials that assess the effects on cognition of adding insulin to diabetes care in groups of comparable patients with diabetes are needed. In The Lancet Diabetes & Endocrinology, Tali CukiermanYaffe and colleagues5 report cognitive outcomes from the ORIGIN trial after a median of 6·2 years of follow-up. ORIGIN assessed several outcomes in 11 685 individuals with dysglycaemia (early-stage diabetes or prediabetes) who received exogenous insulin glargine versus standard care, and 1 g omega-3 fatty acid versus placebo, in a factorial design. In the present study,5 Cukierman-Yaffe and colleagues used the Mini-Mental State Examination (MMSE) and the Digit Symbol Substitution (DSS) test to assess cognition and cognitive decline. Results suggest that in this group of patients (mean age 63·4 years), insulin glargine or omega-3 fatty acid was not associated with a different cognitive trajectory versus standard care or placebo (all crude p>0·50). Unlike previous trials of diabetes treatments and glycaemic control in advanced type 2 diabetes (ADVANCE, ACCORD, and VADT), ORIGIN assessed the effects of treatment in early type 2 diabetes and prediabetes. This earlier intervention is what sets the trial apart from earlier work, but also means younger
patients were included, which makes detecting potential cognitive decline, cognitive impairment, and dementia endpoints challenging. The absence of an association between insulin treatment and cognition could be a result of many factors. Basal insulin treatment might not affect cognitive decline because it cannot penetrate the blood– brain barrier, or there might be molecular differences in neuronal uptake of basal insulin compared with intranasal insulin. In ORIGIN, the glycaemic target for the insulin glargine group was a fasting glucose concentration of 5·3 mmol/L or less. Although reaching this target might result in a reduction in cardiovascular complications of type 2 diabetes, it may also increase the likelihood of hypoglycaemic episodes. Indeed, patients in the insulin glargine group experienced more hypoglycaemic episodes than the standard care group. Patients with diabetes who experience hypoglycaemia have a higher risk of dementia and cognitive impairment,6,7 and a recent diabetes-specific prognostic risk score for dementia also underscored the importance of acute metabolic events in increasing dementia risk.2 Thus, a higher rate of hypoglycaemic episodes in the insulin glargine arm could have ameliorated a potential cognitive benefit. Cukierman-Yaffe and colleagues5 also reported no effect of omega-3 fatty acid supplementation on cognitive outcomes. Although a Mediterranean diet rich in omega-3 fatty acids seems to reduce the risk of dementia and progression from mild cognitive impairment to dementia,8 the role of dietary changes on cognition in the context of chronic disease is unknown. A recent Cochrane analysis of trials of omega-3 fatty acids for cognition concluded that there was no evidence of a benefit,9 although a recent observational study found an association between plasma concentrations of omega-3 fatty acid and less decline in executive function.10 In ORIGIN, all patients had diabetes or prediabetes and high cardiovascular risk, and 58% had a history of a major cardiovascular event at baseline. Thus, omega-3 fatty acids could yield cognitive benefits in the general population, but not in patients with prevalent diabetes and cardiovascular disease. The MMSE was originally designed to screen for frank cognitive impairment. In view of the small range of cognition covered by this scale, whether a more
www.thelancet.com/diabetes-endocrinology Published online June 2, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70104-4
Jim Varney/Science Photo Library
Cognitive impairment in ORIGIN: timing is everything
Lancet Diabetes Endocrinol 2014 Published Online June 2, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70104-4 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(14)70062-2
1
Comment
expansive cognitive battery encompassing additional cognitive domains (particularly those affected by diabetes, such as executive function1) would have shown different results is unknown. In a subgroup analysis of patients with dysglycaemia but not overt diabetes, a benefit of insulin glargine was detected with the MMSE, but not the DSS (pinteraction=0·024), which suggests that more stringent glycaemic targets might have cognitive benefits if treatment is started before to the onset of overt diabetes. For cognitive endpoints, intervening after the onset of type 2 diabetes—whether by dietary or glycaemic control—might be too late. Long-term follow-up of ORIGIN, and of other prediabetes and type 2 diabetes cohorts, will hopefully yield crucial answers regarding potential legacy effects of metabolic control on cognitive endpoints. Rachel A Whitmer Dementia Epidemiology Research Group, Kaiser Permanente Division of Research, Behavioral and Mental Health and Aging Section, Oakland, CA 94612, USA [email protected]
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I declare no competing interests. 1
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Biessels GJ, Strachan MW, Visseren FL, Kappelle LJ, Whitmer RA. Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions. Lancet Diabetes Endocrinol 2014; 2: 246–55. Exalto LG, Biessels GJ, Karter AJ, et al. Risk score for prediction of 10 year dementia risk in individuals with type 2 diabetes: a cohort study. Lancet Diabetes Endocrinol 2013; 1: 183–90. Freiherr J, Hallschmid M, Frey WH 2nd, et al. Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs 2013 27: 505–14. Novak V, Milberg W, Hao Y, et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care 2014; 37: 751–59. Cukierman-Yaffe T, Bosch J, Diaz R, et al, for the ORIGIN Investigators. Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial. Lancet Diabetes Endocrinol 2014; published online June 2. http://dx.doi.org/10.1016/S2213-8587(14)70062-2. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 2009; 301: 1565–72. Yaffe K, Falvey CM, Hamilton N, et al. Association between hypoglycemia and dementia in a biracial cohort of older adults with diabetes mellitus. JAMA Intern Med 2013; 173: 1300–06. Psaltopoulou T, Sergentanis TN, Panagiotakos DB, Sergentanis IN, Kosti R, Scarmeas N. Mediterranean diet, stroke, cognitive impairment, and depression: a meta-analysis. Ann Neurol 2013; 74: 580–91. Sydenham E, Dangour AD, Lim WS. Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane Database Syst Rev 2012; 6: CD005379. Bowman GL, Dodge HH, Mattek N, et al. Plasma omega-3 PUFA and white matter mediated executive decline in older adults. Front Aging Neurosci 2013; 5: 92.
www.thelancet.com/diabetes-endocrinology Published online June 2, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70104-4
People with type 2 diabetes have a 50–100% greater risk of dementia and cognitive impairment than normoglycaemic individuals.1,2 Since almost all patients with type 2 diabetes receive pharmacological treatment at some point during the course of their disease, studies investigating the effects of antidiabetic drugs on cognition are timely. Intranasal insulin has been studied as a potential treatment for mild cognitive impairment and Alzheimer’s disease3 and to enhance cognition in type 2 diabetes.4 Although intranasal insulin has the potential to directly affect the brain, the role of exogenous insulin on brain function is less clear, particularly because whether or how it could permeate the blood–brain barrier is unknown. In some observational studies there was an increased risk of dementia in patients with diabetes using insulin compared with those not using insulin; however, these studies are inherently flawed and represent a classic case of confounding by indication. Compared with patients with diabetes not using insulin, those using insulin are older, have more comorbidities, and have a longer duration of diabetes—all risk factors for dementia.2 Thus, trials that assess the effects on cognition of adding insulin to diabetes care in groups of comparable patients with diabetes are needed. In The Lancet Diabetes & Endocrinology, Tali CukiermanYaffe and colleagues5 report cognitive outcomes from the ORIGIN trial after a median of 6·2 years of follow-up. ORIGIN assessed several outcomes in 11 685 individuals with dysglycaemia (early-stage diabetes or prediabetes) who received exogenous insulin glargine versus standard care, and 1 g omega-3 fatty acid versus placebo, in a factorial design. In the present study,5 Cukierman-Yaffe and colleagues used the Mini-Mental State Examination (MMSE) and the Digit Symbol Substitution (DSS) test to assess cognition and cognitive decline. Results suggest that in this group of patients (mean age 63·4 years), insulin glargine or omega-3 fatty acid was not associated with a different cognitive trajectory versus standard care or placebo (all crude p>0·50). Unlike previous trials of diabetes treatments and glycaemic control in advanced type 2 diabetes (ADVANCE, ACCORD, and VADT), ORIGIN assessed the effects of treatment in early type 2 diabetes and prediabetes. This earlier intervention is what sets the trial apart from earlier work, but also means younger
patients were included, which makes detecting potential cognitive decline, cognitive impairment, and dementia endpoints challenging. The absence of an association between insulin treatment and cognition could be a result of many factors. Basal insulin treatment might not affect cognitive decline because it cannot penetrate the blood– brain barrier, or there might be molecular differences in neuronal uptake of basal insulin compared with intranasal insulin. In ORIGIN, the glycaemic target for the insulin glargine group was a fasting glucose concentration of 5·3 mmol/L or less. Although reaching this target might result in a reduction in cardiovascular complications of type 2 diabetes, it may also increase the likelihood of hypoglycaemic episodes. Indeed, patients in the insulin glargine group experienced more hypoglycaemic episodes than the standard care group. Patients with diabetes who experience hypoglycaemia have a higher risk of dementia and cognitive impairment,6,7 and a recent diabetes-specific prognostic risk score for dementia also underscored the importance of acute metabolic events in increasing dementia risk.2 Thus, a higher rate of hypoglycaemic episodes in the insulin glargine arm could have ameliorated a potential cognitive benefit. Cukierman-Yaffe and colleagues5 also reported no effect of omega-3 fatty acid supplementation on cognitive outcomes. Although a Mediterranean diet rich in omega-3 fatty acids seems to reduce the risk of dementia and progression from mild cognitive impairment to dementia,8 the role of dietary changes on cognition in the context of chronic disease is unknown. A recent Cochrane analysis of trials of omega-3 fatty acids for cognition concluded that there was no evidence of a benefit,9 although a recent observational study found an association between plasma concentrations of omega-3 fatty acid and less decline in executive function.10 In ORIGIN, all patients had diabetes or prediabetes and high cardiovascular risk, and 58% had a history of a major cardiovascular event at baseline. Thus, omega-3 fatty acids could yield cognitive benefits in the general population, but not in patients with prevalent diabetes and cardiovascular disease. The MMSE was originally designed to screen for frank cognitive impairment. In view of the small range of cognition covered by this scale, whether a more
www.thelancet.com/diabetes-endocrinology Published online June 2, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70104-4
Jim Varney/Science Photo Library
Cognitive impairment in ORIGIN: timing is everything
Lancet Diabetes Endocrinol 2014 Published Online June 2, 2014 http://dx.doi.org/10.1016/ S2213-8587(14)70104-4 See Online/Articles http://dx.doi.org/10.1016/ S2213-8587(14)70062-2
1
Comment
expansive cognitive battery encompassing additional cognitive domains (particularly those affected by diabetes, such as executive function1) would have shown different results is unknown. In a subgroup analysis of patients with dysglycaemia but not overt diabetes, a benefit of insulin glargine was detected with the MMSE, but not the DSS (pinteraction=0·024), which suggests that more stringent glycaemic targets might have cognitive benefits if treatment is started before to the onset of overt diabetes. For cognitive endpoints, intervening after the onset of type 2 diabetes—whether by dietary or glycaemic control—might be too late. Long-term follow-up of ORIGIN, and of other prediabetes and type 2 diabetes cohorts, will hopefully yield crucial answers regarding potential legacy effects of metabolic control on cognitive endpoints. Rachel A Whitmer Dementia Epidemiology Research Group, Kaiser Permanente Division of Research, Behavioral and Mental Health and Aging Section, Oakland, CA 94612, USA [email protected]
2
I declare no competing interests. 1
2
3
4
5
6
7
8
9
10
Biessels GJ, Strachan MW, Visseren FL, Kappelle LJ, Whitmer RA. Dementia and cognitive decline in type 2 diabetes and prediabetic stages: towards targeted interventions. Lancet Diabetes Endocrinol 2014; 2: 246–55. Exalto LG, Biessels GJ, Karter AJ, et al. Risk score for prediction of 10 year dementia risk in individuals with type 2 diabetes: a cohort study. Lancet Diabetes Endocrinol 2013; 1: 183–90. Freiherr J, Hallschmid M, Frey WH 2nd, et al. Intranasal insulin as a treatment for Alzheimer’s disease: a review of basic research and clinical evidence. CNS Drugs 2013 27: 505–14. Novak V, Milberg W, Hao Y, et al. Enhancement of vasoreactivity and cognition by intranasal insulin in type 2 diabetes. Diabetes Care 2014; 37: 751–59. Cukierman-Yaffe T, Bosch J, Diaz R, et al, for the ORIGIN Investigators. Effects of basal insulin glargine and omega-3 fatty acid on cognitive decline and probable cognitive impairment in people with dysglycaemia: a substudy of the ORIGIN trial. Lancet Diabetes Endocrinol 2014; published online June 2. http://dx.doi.org/10.1016/S2213-8587(14)70062-2. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP Jr, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA 2009; 301: 1565–72. Yaffe K, Falvey CM, Hamilton N, et al. Association between hypoglycemia and dementia in a biracial cohort of older adults with diabetes mellitus. JAMA Intern Med 2013; 173: 1300–06. Psaltopoulou T, Sergentanis TN, Panagiotakos DB, Sergentanis IN, Kosti R, Scarmeas N. Mediterranean diet, stroke, cognitive impairment, and depression: a meta-analysis. Ann Neurol 2013; 74: 580–91. Sydenham E, Dangour AD, Lim WS. Omega 3 fatty acid for the prevention of cognitive decline and dementia. Cochrane Database Syst Rev 2012; 6: CD005379. Bowman GL, Dodge HH, Mattek N, et al. Plasma omega-3 PUFA and white matter mediated executive decline in older adults. Front Aging Neurosci 2013; 5: 92.
www.thelancet.com/diabetes-endocrinology Published online June 2, 2014 http://dx.doi.org/10.1016/S2213-8587(14)70104-4
