Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer’s disease: Pooled analysis from 5 cohorts

Weinstein, Galit; Davis‐Plourde, Kendra; Conner, Sarah C.; Himali, Jayandra J.; Beiser, Alexa S.; Lee, Anne; Rawlings, Andreea M.; Sedaghat, Sanaz; Ding, Jie; Moshier, Erin; Duijn, Cornelia M. van; Beeri, Michal Schnaider; Selvin, Elizabeth; Ikram, M. Arfan; Launer, Lenore J.; Haan, Mary N.; Seshadri, Sudha

doi:10.1371/journal.pone.0212293

Cited by 81 publications

(91 citation statements)

References 62 publications

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“…For individual medication, there was no significant association among metformin users (p = 0.12, Table 3B). This result is consistent with a recent study based on pooled analyses from multiple studies [55]. The result for statin was also not significant compared with the reference group (p = 0.07, Table 3B).…”

Section: Discussionsupporting

confidence: 92%

Beneficial association of angiotensin-converting enzyme inhibitors and statins on the occurrence of possible Alzheimer’s disease after traumatic brain injury

Reisman

Morris-Eppolito

et al. 2020

Alz Res Therapy

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Background: Pathological analysis of brain tissue from animals and humans with a history of traumatic brain injury (TBI) suggests that TBI could be one of the risk factors facilitating onset of dementia with possible Alzheimer's disease (AD), but medications to prevent or delay AD onset are not yet available. Methods: This study explores four medication classes (angiotensin-converting enzyme inhibitors (ACEI), beta blockers, metformin, and statins) approved by the Food and Drug Administration (FDA) for other indications and evaluates their influence when used in combination on the risk of possible AD development for patients with a history of TBI. We identified patients with history of TBI from an existing Department of Veterans Affairs (VA) national database. Among 1, 660,151 veterans who used VA services between the ages of 50 to 89 years old, we analyzed 733,920 patients, including 15,450 patients with a history of TBI and 718,470 non-TBI patients. The TBI patients were followed for up to 18.5 years, with an average of 7.7 ± 4.7 years, and onset of dementia with possible AD was recorded based on International Statistical Classification of Diseases (ICD) 9 or 10 codes. The effect of TBI on possible AD development was evaluated by multivariable logistic regression models adjusted by age, gender, race, and other comorbidities. The association of ACEI, beta blockers, metformin, statins, and combinations of these agents over time from the first occurrence of TBI to possible AD onset was assessed using Cox proportional hazard models adjusted for demographics and comorbidities. Results: Veterans with at least two TBI occurrences by claims data were 25% (odds ratio (OR) = 1.25, 95% confidence intervals (CI) (1.13, 1.37)) more likely to develop dementia with possible AD, compared to those with no record of TBI. In multivariable logistic regression models (propensity score weighted or adjusted), veterans taking a combination of ACEI and statins had reduced risk in developing possible AD after suffering TBI, and use of this medication class combination was associated with a longer period between TBI occurring and dementia with possible AD onset, compared to patients who took statins alone or did not take any of the four target drugs after TBI.

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Section: Discussionsupporting

confidence: 92%

Beneficial association of angiotensin-converting enzyme inhibitors and statins on the occurrence of possible Alzheimer’s disease after traumatic brain injury

Reisman

Morris-Eppolito

et al. 2020

Alz Res Therapy

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“…Исследование G. Weinstein еt al. [65], объединившее данные 5 популяционных исследований (Offspring cohort of the Framingham Heart Study (FHS), Rotterdam Study (RS), Atherosclerosis Risk in Communities (ARIC) Study, Aging Gene-Environment Susceptibility-Reykjavik Study (AGES), Sacramento Area Latino Studyon Aging (SALSA)), ставило целью изучить влияние различных сахароснижающих препаратов на когнитивный статус больных с СД и оценить риск развития КН и деменции на фоне сахароснижающей терапии. В FHS был включен 301 пациент (средний возраст 70,1±5,9 года), средняя продолжительность СД составляла 7,5±4,8 года, у 13,8% больных исходно диагностирована деменция.…”

Section: исследования поперечного типаunclassified

“…В результате исследования G. Weinstein еt al. [65] выявлено, что больные, находящиеся на инсулинотерапии, имели повышенный риск развития деменции, равный 50% (ОР 1,58; 95% ДИ 1,18-2,12, р=0,002), независимо от наличия депрессии, уровня гликированного гемоглобина и гликемии, по сравнению с пациентами, не получающими инсулин. Терапия производными сульфонилмочевины и метформином не была ассоциирована с повышенным риском развития деменции или недементных КН.…”

Section: A R T I C L E I N P R E S Sunclassified

Hypoglycemia and the risk of cognitive impairment and dementia in elderly and senile patients with type 2 diabetes

Остроумова¹,

Суркова²,

Васильевна³

et al. 2020

Diabetes mellitus

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Research results show that poor glycemic control and recurrent episodes of severe hypoglycaemia are associated with a decrease in cognitive function in elderly people with type 2 diabetes mellitus (T2DM). On the other hand, patients with diabetes mellitus associated with cognitive impairment/dementia are most at risk of developing hypoglycaemic conditions. It is obvious that the relationship between hypoglycaemia and dementia is very complex and has a mutually aggravating nature. Studies also show that individuals of older age groups with diabetes and cognitive impairment have a high risk of developing hypoglycaemic conditions, such as unwanted side effects from glucose-lowering therapy. In this case, of particular interest is the question that is being actively studied at the present time, which is concerning the effect of different groups of glucose-lowering antidiabetic drugs on the cognitive status and the rate of cognitive decline in diabetic patients with cognitive impairment. In this review, we attempted to summarise, systematise, and present data available in the literature concerning the effect of hypoglycaemia on the risk of cognitive impairment and dementia in elderly and senile patients with type-2 diabetes, as well as the degree of participation in this process of of various groups of sugar-lowering antidiabetic drugs.

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“…The effect of insulin should be put in the context of the underlying condition, which in itself favours neurodegeneration. As insulin is typically prescribed in diabetes cases with severely impacted glucose controls, effects of disease may outweigh the effects of the agent [40,41]. Vasomotor modulators (PDE5 inhibitors) also show enrichment 14 on 3 df.…”

Section: Screening Of Individual Pharmacological Mechanisms For Corrementioning

confidence: 99%

“…On the other side, analgesics (0.45, 46 df), corticosteroids (0.34, 42 df), anti-acid (0.45, 16 df), anti-arrythmic (0.55, 13 df), antibiotics (0.5, 5 df), anti-cancer therapies (0.25, 29 df), statins (0.6, 13 df), antidepressants (0.45, 17 df), antifungals (0.4, 19 df), overall antihypertensives (0.9, 28 df), bronchodilators (0.6, 17 df) display the opposite trend of distributing in favour of the lower Z-score octiles. Thus, PDE5 inhibitors [42], antiplatelet [43,44], vasodilators [43,45], antimigraine [38,39], antivirals [46], probiotics [47], magnesium [48,49], transdermal oestrogen ( Table 2) and possibly metformin [40,41,50,51] are the agents of interest to perhaps combine with the multivitamin-multimineral formulas of Table 2. Conversely, the signals by corticosteroids [52,53], anti-cancer therapies [54,55], anti-acid drugs [56,57], infections underlying use of antibiotics and antifungals [58], the link between dementia and respiratory deficiency [59], between dementia and cardiac arrythmia [44] mostly align with outside evidence of involvement in neurodegeneration.…”

Section: Screening Of Individual Pharmacological Mechanisms For Corrementioning

confidence: 99%

Pharmacological signatures of the reduced incidence and the progression of cognitive decline in ageing populations suggest the protective role of beneficial polypharmacy

Mayburd

Koivogui²,

Baranova

2019

PLoS ONE

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Preventive treatments for dementia are warranted. Here we show that utilization of certain combinations of prescription medications and supplements correlates with reduced rates of cognitive decline. More than 1,900 FDA-approved agents and supplements were collapsed into 53 mechanism-based groups and traced in electronic medical records (EMRs) for >50,000 patients. These mechanistic groups were aligned with the data presented in more than 300 clinical trials, then regression model was built to fit the signals from EMRs to clinical trial performance. While EMR signals of each single agents correlated with clinical performance relatively weakly, the signals produced by combinations of active compounds were highly correlated with the clinical trial performance (R = 0.93, p = 3.8 x10^-8). Higher ranking pharmacological modalities were traced in patient profiles as their combinations, producing protective complexity estimates reflecting degrees of exposure to beneficial polypharmacy. For each age strata, the higher was the protective complexity score, the lower was the prevalence of dementia, with maximized life-long effects for the highest regression score /diversity compositions. The connection was less strong in individuals already diagnosed with cognitive impairment. Confounder analysis confirmed an independent effect of protective complexity in multivariate context. A sub-cohort with lifelong odds of dementia decreased > 5-folds was identified; this sub-cohort should be studied in further details, including controlled clinical trials. In short, our study systematically explored combinatorial preventive treatment regimens for age-associated multi-morbidity, with an emphasis on neurodegeneration, and provided extensive evidence for their feasibility.Funding: AM is the Founder of Neurocombinatorix LLC, and MK is affiliated with the organization. Neurocombinatorix LLC does not conduct commercial activity and did not provide any funds for research. The authors volunteered to the effort without any salaries, no other parties have a role in the study design, data collection and analysis, Recent decreases in the rate of dementia and a shift to later ages of onset are encouraging [4]. However, in a first quartile of life expectancy, dementia still accounts for 1 in every 6 deaths, and is a major source of disability [1]. While multiple clinical trials for single dementia combating agents are ongoing [5], earlier stages of neurodegeneration process largely remain unexplored in humans.On the other hand, recent studies in model animals are encouraging. Particular successful efforts in visible rejuvenation of already differentiated tissues are reviewed in [6]). NAD+ supplementation has been associated with an extension of murine lifespan by 10-15% [7,8] through the mechanism likely related to overall brain function. The maintenance of microvasculature [9,10], the clearance of misfolded proteins [11], the neuroprotection [12,13], and the regulation of cholinesterase [13] were shown to be comparably important for the prevention...

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Association of metformin, sulfonylurea and insulin use with brain structure and function and risk of dementia and Alzheimer’s disease: Pooled analysis from 5 cohorts

Cited by 81 publications

References 62 publications

Beneficial association of angiotensin-converting enzyme inhibitors and statins on the occurrence of possible Alzheimer’s disease after traumatic brain injury

Beneficial association of angiotensin-converting enzyme inhibitors and statins on the occurrence of possible Alzheimer’s disease after traumatic brain injury

Hypoglycemia and the risk of cognitive impairment and dementia in elderly and senile patients with type 2 diabetes

Pharmacological signatures of the reduced incidence and the progression of cognitive decline in ageing populations suggest the protective role of beneficial polypharmacy

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