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the report by Diana et al.1 can be applied to the routine clinical practice of children and adults with Graves disease.

Apart from some concerns about variabil­ity in the way patient details were inter preted in the different centres, in particular what is meant by ‘euthyroid Graves ophthalmo­pathy’, this retrospective study has been well performed. Single standardized assays for anti­TSH­R antibodies were used and it is clear from the results that the preva­lence of TSI and TBII, as revealed by their respective tests, are impressively high in all groups of patients with Graves dis ease in the study and always negative in con trol groups. The most important point of the study (although not recognized as such by the authors), however, is the relationship of anti­TSH­R antibodies to ophthalmopathy; unfortunately, the findings do not enlighten us about the patho genesis of this complex eye disorder.

University of Sydney, Nepean Hospital, PO Box 63, 68 Derby Street, Penrith, NSW 2751, Australia. jack.wall@sydney.edu.au

Competing interestsThe author declares no competing interests.

1. Diana, T. et al. Clinical relevance of thyroid-stimulating autoantibodies in pediatric patients with Graves’ disease—a multicentre study. J. Clin. Endocrinol. Metab. http://dx.doi.org/ 10.1210/jc.2013-4026.

2. Lytton, S. D., Li, Y., Olivo, P. D., Kohn, L. D. & Kahaly, G. J. Novel chimeric thyroid-stimulating hormone-receptor bioassay for thyroid-stimulating immunoglobulins. Clin. Exp. Immunol. 162, 438–446 (2010).

3. Lytton, S. D. et al. A novel thyroid stimulating immunoglobulin bioassay is a functional indicator of activity and severity of Graves’ orbitopathy. J. Clin. Endocrinol. Metab. 95, 2123–2131 (2010).

4. Tjiang, H., Lahooti, H., McCorquodale, T., Parmar, K. R. & Wall, J. R. Eye and eyelid abnormalities are common in patients with Hashimoto’s thyroiditis. Thyroid 20, 287–290 (2010).

5. Subekti, I., Boedisantoso, A., Moeloek, N. D., Waspadji, S. & Mansyur, M. Association of TSH receptor antibody, thyroid stimulating antibody, and thyroid blocking antibody with clinical activity score and degree of severity of Graves ophthalmopathy. Acta Med. Indones. 44, 114–121 (2012).

6. Uretsky, S., Kennerdell, J. S. & Gutai, J. P. Graves’ ophthalmopathy in children and adolescents. Arch. Ophthalmol. 98, 1963–1964 (1980).

7. Kim, W. B. et al. The prevalence and clinical significance of blocking thyrotropin receptor antibodies in untreated hyperthyroid Graves’ disease. Thyroid 10, 579–586 (2000).

8. Kiljanski, J., Nebes, V., Kennerdell, J. S. & Wall J. R. Graves’ hyperthyroidism, ophthalmopathy and pretibial myxoedema may be components of a multi-system autoimmune disorder. Orbit 15, 129–136 (1996).

DIABETES

Cognitive decline and T2DM —a disconnect in the evidence?Mark W. J. Strachan and Jacqueline F. Price

Type 2 diabetes mellitus is associated with an increased risk of cognitive decline and dementia. Observational data suggest that hyperglycaemia, hypertension and dyslipidaemia might be involved in the causal pathway underlying this link, but data from the ACCORD MIND investigators challenge these findings. Why are the findings of observational and intervention studies so disconnected?Strachan, M. W. J. & Price, J. F. Nat. Rev. Endocrinol. 10, 258–260 (2014); published online 1 April 2014; doi:10.1038/nrendo.2014.38

Unequivocal evidence exists of a link between type 2 diabetes mellitus (T2DM), cognitive decline and dementia.1 This asso­ciation has been the subject of numerous observational investigations and one such study has even suggested that dia betes mellitus is one of the largest potentially modifiable risk factors in the aetiology of demen tia.2 Observational studies have sug­gested potential mechanisms that underlie this association. Given the complexity of the phenotype of T2DM, it is not surpris­ing that multiple factors have been impli­cated (Figure 1); foremost amongst these are the classic vascular risk factors.3 How­ever, few randomised clinical trials have tested interventions that might improve or slow the decline of cognitive function in patients with T2DM. The Memory in Dia betes (MIND) substudy of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial is, therefore, enormously important as it is by some margin the largest intervention study on cognitive impair­ment in diabetes mellitus. The investiga­tors previously reported that intensive glycaemic control had no effect on cogni­tive function4 and have now reported data on the effect of intensive blood pressure and lipid interventions.5

The ACCORD study was a landmark trial investigating the effect of intensive management of blood glucose on cardio­vascular outcomes in people with T2DM who were already at high risk of cardio­vascular events, either because of prevalent cardiovascular disease or because of preva­lent risk factors for cardiovascular disease. The study included 10,251 participants who were randomly assigned to undergo either intensive or less intensive glycaemic control (targets HbA1c <6.0% or HbA1c 6.0–6.9%, respectively). In a double 2 × 2

factorial design, just under half of the par­ticipants (who had a systolic blood pressure of 130–180 mmHg and who were receiving fewer than three antihypertensive agents) were randomly assigned to an intensive blood pressure control strategy (targeting a systolic blood pressure of <120 mmHg) or a less intensive strategy (targeting a sys­tolic blood pressure of <140 mmHg). The remaining par ticipants took part in a trial of blinded administration of fenofibrate versus placebo; all participants in the lipid trial took daily simvastatin and so had levels of LDL cholesterol <2.59 mmol/l. As has been widely reported, the glycaemic control arm of the study was terminated pre maturely because of an increased incidence of cardio­vascular events in the intensive therapy arm.6 The trials investigating blood pres­sure and lipid levels continued to their planned end date. After 4.7 years, neither fenofibrate7 nor intensive blood pressure control8 had a statistically significant effect on the composite primary cardiovascular end point; however, a small reduction in the incidence of stroke was observed in the arm of the trial in which intensive blood pr essure control was performed.

The MIND substudy was established to investigate the effect of the intensive inter­ventions on cognitive function. Recruitment started after the main studies had been established and individuals <55 years old were not eligible. Therefore, 5,575 of the main ACCORD participants were eligible and subsequently 2,977 individuals were recruited.5 Of these par ticipants, 1,439 were enrolled in the blood pressure trial and 1,538 in the lipid trial; baseline charac­teristics were very similar to the overall ACCORD study population. Cognitive function was assessed at baseline and after 20 months and 40 months using a battery

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of cognitive tests that examined verbal memory, pro cessing speed and execu­tive function. MRI scanning of the brain at baseline and after 40 months was also undertaken in 503 participants; the main outcome measure was total brain volume (TBV). The pri mary out come measure of cognitive function (the score in the Digit Symbol Substitu tion Test) was similar in all the base line groups and declined over the period of the study. However, no signifi­cant difference was found in adjusted mean scores after 40 months between either the intensive and standard blood pressure arms or the feno fibrate and placebo arms. No intervention effect was seen in any of the other cognitive tests performed. The group that underwent intensive blood pressure control had a signifi cantly lower TBV than the group that received stand­ard care, whereas no significant difference in TBV was seen between the two arms of the lipid trial. Participants who received the combination of standard blood pressure control and intensive glycaemic control experienced ~50% of the decline in TBV observed in the other groups in the blood pressure trial.

The fact that intensive blood pressure con trol and fibrate therapy do not seem to have an effect on cognitive decline in

patients with T2DM is disappointing, but is perhaps not altogether surprising. A Cochrane review of randomised trials of antihypertensive therapy concluded there was no convincing evidence that any therapy to reduce blood pressure in later life prevented the development of demen­tia or cognitive impairment.9 Similarly, a Cochrane review of randomised trials of statin therapy in people at increased risk of Alzheimer disease or dementia found no effect on prevention of dementia.10 The TBV data in ACCORD MIND imply that intensive control of blood pressure might actually be disadvantageous.5 How ever, these data must be treated with caution, as TBV cannot as yet be regarded as a su rrogate marker of cognitive decline.

We are, therefore, seeing a possible dis­connection between observational data, which suggest that poor glycaemic control, hypertension and dyslipidaemia might con tribute to cognitive decline, and inter­ventional data, which suggest they do not. Which is correct? Given the primacy placed on randomised trials, it certainly does not look good for the observational studies. How ever, ACCORD MIND has some design issues that need to be considered. The follow­up period was ‘only’ 40 months. We know that cognitive function changes

Geneticpredisposition

Cerebralmicrovascular

disease

Dyslipidaemia

HPA axisdysregulation

Acutehyperglycaemia

Advancedglycation end

products

Depression

In�ammatorymediators

Macrovasculardisease

Rheologicalfactors

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Amyloiddeposition

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Drugtherapy

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fairly slowly and so it might simply be that the follow­up period was too short to see any important changes. In addition, the participants in ACCORD MIND were aged ≥55 years and had established cardio­vascular disease or cardio vascular risk fac­tors and so the interventions might have occurred too late in the trajectory of cogni­tive decline, after a pathway of irreversible neu ronal damage had started. Further more, most risk factors probably have a J­curve for effect and so the consider able intensifi­ca tion of therapy to lower blood pressure and reduce hyperglycaemia, in particular, might have been a step too far. In the case of gly ca emic control, the potential benefits of cor recting hyperglycaemia might have been counteracted by the increased inci­dence of hypoglycaemia. Studies of cognitive decline and intensive glucose control that use agents that do not cause hy poglycaemia would be of considerable interest.

Associations seen in observational studies might not necessarily reflect causal relation­ships, as a result of confounding factors. Con versely, we must not be too quick to dis miss the usefulness of findings from obser va tional studies on the basis of the find ings from a limited number of clinical trials. In the medium to long term, observa­tional studies con tinue to be required to guide the develop ment of new interven­tions and the design of more sophisti cated trials. In the imme diate future, trials need to consider ‘novel’ interventions, such as anti­ inflammatory agents, but should also examine interventions aimed at influ encing classic risk factors less inten sively and earlier in the time course of T2DM.

Metabolic Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK (M.W.J.S.). Centre for Population Health Sciences, University of Edinburgh, Teviot Place, Edinburgh EH8 9AG, UK (J.F.P.). Correspondence to: M.W.J.S. mark.strachan@nhs.net

Competing interestsThe authors declare no competing interests.

1. Strachan, M. W. J., Reynolds, R. M., Marioni, R. E. & Price J. F. Cognitive function, dementia and diabetes in the elderly. Nat. Rev. Endocrinol. 7, 108–114 (2011).

2. Ritchie, K. et al. Designing prevention programmes to reduce incidence of dementia: prospective cohort study of modifiable risk factors. BMJ 341, c3885 (2010).

3. Kloppenburg, R. P., van den Berg, E., Kappelle, L. J. & Biessels, G. J. Diabetes and other vascular risk factors for dementia: which factor matters most? A systematic review. Eur. J. Pharmacol. 585, 97–108 (2008).

Figure 1 | Potential mediators of cognitive impairment in patients with type 2 diabetes mellitus. Permission obtained from Nature Publishing Group © Strachan, M. W. J. et al. Nat. Rev. Endocrinol. 7, 108–114 (2011).

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4. Launer, L. J. et al. Effects of intensive glucose lowering on brain structure and function in people with type 2 diabetes (ACCORD MIND): a randomized open-label substudy. Lancet Neurol. 10, 969–977 (2011).

5. Williamson, J. D. et al. Cognitive function and brain structure in persons with type 2 diabetes mellitus after intensive lowering of blood pressure and lipid levels. A randomized clinical trial. JAMA Intern. Med. 174, 324–333 (2014).

6. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive

glucose lowering in type 2 diabetes. N. Engl. J. Med. 358, 2545–2559 (2008).

7. ACCORD Study Group. Effects of combination lipid therapy in type 2 diabetes mellitus. N. Engl. J. Med. 362, 1563–1574 (2011).

8. ACCORD Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N. Engl. J. Med. 362, 1575–1585 (2011).

9. McGuinness, B., Todd, S., Passmore, P. & Bullock, R. Blood pressure lowering in patients

without prior cerebrovascular disease for prevention of cognitive impairment and dementia. Cochrane Database of Systematic Reviews Issue 4. Art. No.: CD004034. http://dx.doi.org/10.1002/14651858.CD004034.pub3.

10. McGuinness, B., Craig, D., Bullock, R. & Passmore, P. Statins for the prevention of dementia. Cochrane Database of Systematic Reviews Issue 2. Art. No.: CD003160. http://dx.doi.org/10.1002/14651858.CD003160.pub2.

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