The impact of frailty on the effectiveness and safety of intensive glucose control and blood pressure-lowering therapy for people with type 2 diabetes: results from the ADVANCE trial
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OBJECTIVE: To develop a frailty index (FI) and explore the relationship of frailty to subsequent adverse outcomes on the effectiveness and safety of more intensive control of both blood glucose and blood pressure (BP), among participants with type 2 diabetes in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. RESEARCH DESIGN AND METHODS: Cox proportional hazard models were used to estimate the effectiveness and safety of intensive glucose control and BP intervention according to frailty (defined as FI >0.21) status. The primary outcomes were macro- and microvascular events. The secondary outcomes were all-cause mortality, cardiovascular mortality, severe hypoglycemia, and discontinuation of BP treatment due to hypotension/dizziness. RESULTS: There were 11,140 participants (mean age, 65.8 years; 42.5% women, 25.7% frail). Frailty was an independent predictor of all primary outcomes and secondary outcomes. The effect of intensive glucose treatment on primary outcomes showed some evidence of attenuation in the frail: hazard ratios for combined major macro- and microvascular events 1.03 (95% CI 0.90–1.19) in the frail versus 0.84 (95% CI 0.74–0.94) in the nonfrail (P = 0.02). A similar trend was observed with BP intervention. Severe hypoglycemia rates (per 1,000 person-years) were higher in the frail: 8.39 (6.15–10.63) vs. 4.80 (3.84–5.76) in nonfrail (P < 0.001). There was no significant difference in discontinuation of BP treatment between frailty groups. CONCLUSIONS: It was possible to retrospectively estimate frailty in a trial population, and this FI identified those at higher risk of poor outcomes. Participants with frailty had some attenuation of benefit from intensive glucose-lowering and BP-lowering treatments.
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Frailty is associated with poorer prognosis, and some attenuation of benefit from intensive glucose-lowering and blood pressure-lowering treatments has been demonstrated in frail individuals.
“Frailty is associated with poorer prognosis, and some attenuation of bene fi t from intensive glucose-lowering and blood pressure-lowering treatments has been demonstrated in frail individuals (263).”
Analyses from ADVANCE suggested that more frail individuals have worse outcomes and benefit less from intensive control of blood glucose levels and blood pressure.
“When older individuals have been studied, analyses from trials such as Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) suggested that more frail individuals have worse outcomes and benefi t less from intensive control of blood glucose levels and blood pressure (263).”
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2024 ESC Guidelines for the management of elevated blood pressure and hypertension
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- Authors
- Nguyen, T. N., Harris, K., Woodward, M., Chalmers, J., Cooper, M., Hamet, P., Harrap, S., Heller, S., MacMahon, S., Mancia, G., Marre, M., Poulter, N., Rogers, A., Williams, B., Zoungas, S., Chow, C. K., & Lindley, R. I.
- Affiliations
- The University of Sydney (AU)
- UNSW Sydney (AU)
- Johns Hopkins University (US)
- Monash University (AU)
- Centre Hospitalier de l’Université de Montréal (CA)
- The Royal Melbourne Hospital (AU)
- University of Sheffield (GB)
- The George Institute for Global Health (GB)
- University of Milan (IT)
- Université Paris Cité (FR)
- Imperial College London (GB)
- National Institute for Health and Care Research (GB)
- Corresponding author
- Nguyen, Tu N.
- Lindley, Richard I.
- ORCID
- Venue
- Diabetes Care
- Publisher
- American Diabetes Association
- Published
- 2021-05-25
- Volume
- 44
- Issue
- 7
- Pages
- 1622-1629
- ISSN
- 0149-5992 (ISSN-L)
- 1935-5548
- PMC
- PMC8323181
- OpenAlex
- W3164577379
- Cited by
- 72
- References
- 39
- Citations by year
- 2026: 12 · 2025: 17 · 2024: 19 · 2023: 12 · 2022: 11 · 2021: 1
- FWCI
- 8.02
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Diabetes Care (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
- BOA (University of Milano-Bicocca) (submittedVersion)
- White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (submittedVersion)
- Minerva Access (University of Melbourne) (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0514-10011)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Geriatrics and Gerontology › Frailty in Older Adults
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- frailty, frailty index, type 2 diabetes, tight glycemic control, blood pressure-lowering therapy, ADVANCE trial, severe hypoglycemia, microvascular complications, cardiovascular mortality, treatment discontinuation, older adults
- MeSH terms
- Frailty, Aged, Blood Glucose, Blood Pressure, Diabetes Mellitus, Type 2, Female, Humans, Male, Retrospective Studies, Risk Factors
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