In Diabetes, Tight Blood Sugar Control Staves Off Dementia

Type 2 diabetes (T2D) raises a person’s risk of developing dementia by about 50 percent. Does tightly controlling blood sugar decrease that risk? Yes, according to researchers led by Eng-Kiong Yeoh and Kailu Wang at the Chinese University of Hong Kong. In the February 12 JAMA Network Open, they reported that a primary-care-based, personalized T2D management program reduced all-cause dementia by almost a third over eight years compared to standard diabetes care. Program participants maintained lower and steadier hemoglobin A1C (HbA1C) levels, which serve as a proxy for average blood sugar over the past three months. HbA1C between 6.5 and 7.5 percent gave the lowest dementia risk. These results highlight the importance of comprehensive, individualized diabetes care to help people steady their blood sugar, the authors concluded.

“This paper is a huge and very exciting step forward suggesting that aggressive diabetic management can reduce the risk of developing incident dementia,” Marwan Sabbagh of the Barrow Neurological Institute in Phoenix told Alzforum. In a broader context, he said this data supports the idea that optimizing one’s health protects the brain. “We talk about it, but here’s objective evidence.”

To see if managing diabetes influenced future dementia risk, co-first authors Wang and Shi Zhao analyzed medical records of 55,618 adults with T2D, average age 62, who came to primary care clinics in Hong Kong. Wang and Zhao split them equally into two groups matched for age, sex, socioeconomic status, baseline blood work values, and medications. One group had received standard diabetes management, i.e., clinic visits every two to four months, regular lab work to monitor blood sugar, and referral to specialists as needed; the other had participated in the Risk Assessment and Management Program-Diabetes Mellitus, aka RAMP-DM.

That meant nurses screened participants for lifestyle behavior, T2D complications, and cardiovascular risks, stratifying them accordingly. The nurses then referred each person to primary care clinicians, specialists, and other healthcare professionals such as dieticians or optometrists, based on their needs. People with more risk factors, or an HbA1C above 7 percent, were monitored more frequently, enabling medications to be adjusted or added accordingly and empowering patients to stay on top of their health through diet and exercise.

The assessment was repeated every one to three years (Fung et al., 2012; Chan et al., 2019; Wan et al., 2018). The program has been enrolling since 2009; for this paper, the scientists analyzed data from 2011 to 2019.

In that time, 1,938 people in the RAMP-DM program and 2,728 following standard care were diagnosed with all-cause dementia (image below). RAMP-DM participants were 28 percent less likely to develop dementia. They had 15 percent lower odds of being diagnosed with Alzheimer’s disease and 39 percent lower odds of vascular dementia. The latter is of particular concern in people with diabetes because the disease damages blood vessels in the body and in the brain.

Sabbagh was surprised by the magnitude of this reduction. “A 30 percent lower dementia risk is huge, especially at a population level,” he said.

Management Matters. People in a personalized diabetes program (RAMP-DM, yellow line) were less likely to develop dementia over eight years than people receiving standard diabetes care (black line). [Courtesy of Wang et al., JAMA Network Open, 2024.]

How did blood sugar play into this? At baseline, the mean HbA1C was 7.3 percent. Across eight years of follow-up, those on standard care hovered around that value, while RAMP-DM participants lowered their HbA1C by 0.1 to 0.2 percent, on average, and stayed there.

RAMP-DM participants were more likely to stay within 6.5 to 7.5 percent HbA1C, a typical target for T2D. Falling outside this range increased dementia risk by up to 54 percent at HbA1C levels above 8.5 and by 39 percent at an HbA1C below 6. Why would the latter, indicating strictly controlled blood sugar, still raise dementia likelihood? The authors think low HbA1C in people with diabetes indicated that they had more bouts of low blood sugar, perhaps due to medication or diet. Hypoglycemia also increases dementia risk (Whitmer et al., 2009; Zheng et al., 2021). 

“This study supports the ever-growing body of evidence that dementia prevention/risk-reduction interventions are most likely to succeed when they are multimodal, multidisciplinary, tailored, sustainable, and sufficiently intensive,” wrote Miia Kivipelto of the Karolinska Institutet in Stockholm, Mariagnese Barbera at the University of Eastern Finland in Kuopio, and Jaakko Tuomilehto of the University of Helsinki (comment below).

Kivipelto runs the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) 2.0 trials. They combine lifestyle changes with medicines (Dec 2022 conference news). In MET-FINGER, participants at risk of T2D take the diabetes drug metformin as part of the multimodal intervention (Barbera et al., 2024).—Chelsea Weidman Burke

Comments

  1. Wang and colleagues' interesting study showed that a multidisciplinary diabetes management program in primary care settings was associated with a reduced risk of dementia incidence among patients with T2D in a cohort study in Hong Kong. Patients with T2D who attended the Risk Assessment and Management Program-Diabetes Mellitus (RAMP-DM), had a 28 percent lower risk of all-cause dementia incidence compared with patients who did not attend the program and received only usual care. A significant risk reduction was seen also for dementia subtypes; Alzheimer’s disease, vascular dementia, and other or unspecified dementia (based on EHR data). A moderate glycaemic control target of HbA1C between 6.5 and 7.5 percent was associated with lower dementia incidence.

    A surprising finding is that the dementia risk started to differ between groups immediately after the study onset. The authors conclude that “patients in the RAMP-DM group were still likely to have greater health consciousness than those in the usual care group, which may have led to differences in dementia incidence” and these could at least partially explain the results. On the other hand, it is also likely that clinical evaluation of patients in the RAMP-DM group, including cognitive assessment, was more comprehensive than in the usual care group leading to a more sensitive dementia diagnosis in the RAMP-DM group. Given all this, it is interesting that the study could still find significant differences between the two groups.

    Although retrospective, this is a large study (55,618 participants) with a long follow-up (eight years), making its finding relevant and promising. It is challenging to study dementia incidence in randomized controlled trial (RCT) settings. This study clearly reinforces the link between T2D and dementia and its subtypes, and indicates that appropriate management has substantial long-term benefits also on the prevention and risk reduction of dementia.

    Importantly, this study supports the ever-increasing body of evidence that dementia prevention/risk reduction interventions are most likely to succeed when they are multimodal, i.e., addressing multiple risk factors and mechanisms at the same time, multidisciplinary, tailored to the patient, sustainable, and sufficiently intensive (Stephen et al., 2021). In this study, RAMP-DM assessment was repeated continuously once every one to three years based on estimated risk level, and the patients were referred to a specialist for related diabetic complications. This risk-stratification process and multidisciplinary coordination enabled more individualized programs and can be one of the key factors behind the positive and strong findings.

    The mean age at the time of dementia diagnosis was around 82 years, thus the study highlights the importance of adequate diabetes management even later in life. More work is needed to determine optimal glycaemic control targets (which may differ across age groups).

    In general, in terms of identifying the most effective dementia risk reduction strategies for different at-risk populations, we are still in relatively uncharted territory and need more evidence from precision prevention RCTs. More tailored approaches combining multidomain lifestyle intervention and pharmacological treatment, for example the MET-FINGER RCT (lifestyle + metformin when appropriate), will provide specific insight on how to better prevent cognitive decline and dementia in specific target populations or individuals depending on their unique risk profile (Barbera et al., 2024). There is also growing interest in studying newer diabetes medications (e.g. GLP-1 agonists) in dementia/AD prevention and treatment, either alone or in combination with multidomain lifestyle interventions (Nowell et al., 2023). 

    References:

    Stephen R, Barbera M, Peters R, Ee N, Zheng L, Lehtisalo J, Kulmala J, Håkansson K, Chowdhary N, Dua T, Solomon A, Anstey KJ, Kivipelto M. Development of the First WHO Guidelines for Risk Reduction of Cognitive Decline and Dementia: Lessons Learned and Future Directions. Front Neurol. 2021;12:763573. Epub 2021 Oct 26 PubMed.

    Barbera M, Lehtisalo J, Perera D, Aspö M, Cross M, De Jager Loots CA, Falaschetti E, Friel N, Luchsinger JA, Gavelin HM, Peltonen M, Price G, Neely AS, Thunborg C, Tuomilehto J, Mangialasche F, Middleton L, Ngandu T, Solomon A, Kivipelto M, MET-FINGER study team. A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: the MET-FINGER randomised controlled trial protocol. Alzheimers Res Ther. 2024 Jan 31;16(1):23. PubMed.

    Nowell J, Blunt E, Gupta D, Edison P. Antidiabetic agents as a novel treatment for Alzheimer's and Parkinson's disease. Ageing Res Rev. 2023 Aug;89:101979. Epub 2023 Jun 14 PubMed.

    View all comments by Mariagnese Barbera View all comments by Jaakko Tuomilehto View all comments by Miia Kivipelto

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References

News Citations

  1. Could Personalizing Multimodal Interventions Give Them Oomph?

Paper Citations

  1. Fung CS, Chin WY, Dai DS, Kwok RL, Tsui EL, Wan YF, Wong W, Wong CK, Fong DY, Lam CL. Evaluation of the quality of care of a multi-disciplinary risk factor assessment and management programme (RAMP) for diabetic patients. BMC Fam Pract. 2012 Dec 5;13:116. PubMed.
  2. Chan JC, Lim LL, Luk AO, Ozaki R, Kong AP, Ma RC, So WY, Lo SV. From Hong Kong Diabetes Register to JADE Program to RAMP-DM for Data-Driven Actions. Diabetes Care. 2019 Nov;42(11):2022-2031. Epub 2019 Sep 17 PubMed.
  3. Wan EY, Fung CS, Jiao FF, Yu EY, Chin WY, Fong DY, Wong CK, Chan AK, Chan KH, Kwok RL, Lam CL. Five-Year Effectiveness of the Multidisciplinary Risk Assessment and Management Programme-Diabetes Mellitus (RAMP-DM) on Diabetes-Related Complications and Health Service Uses-A Population-Based and Propensity-Matched Cohort Study. Diabetes Care. 2018 Jan;41(1):49-59. Epub 2017 Nov 14 PubMed.
  4. Whitmer RA, Karter AJ, Yaffe K, Quesenberry CP, Selby JV. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. JAMA. 2009 Apr 15;301(15):1565-72. PubMed.
  5. Zheng B, Su B, Price G, Tzoulaki I, Ahmadi-Abhari S, Middleton L. Glycemic Control, Diabetic Complications, and Risk of Dementia in Patients With Diabetes: Results From a Large U.K. Cohort Study. Diabetes Care. 2021 Jul;44(7):1556-1563. Epub 2021 May 25 PubMed.
  6. Barbera M, Lehtisalo J, Perera D, Aspö M, Cross M, De Jager Loots CA, Falaschetti E, Friel N, Luchsinger JA, Gavelin HM, Peltonen M, Price G, Neely AS, Thunborg C, Tuomilehto J, Mangialasche F, Middleton L, Ngandu T, Solomon A, Kivipelto M, MET-FINGER study team. A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: the MET-FINGER randomised controlled trial protocol. Alzheimers Res Ther. 2024 Jan 31;16(1):23. PubMed.

Further Reading

Primary Papers

  1. Wang K, Zhao S, Lee EK, Yau SZ, Wu Y, Hung CT, Yeoh EK. Risk of Dementia Among Patients With Diabetes in a Multidisciplinary, Primary Care Management Program. JAMA Netw Open. 2024 Feb 5;7(2):e2355733. PubMed.

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