Follow-up of blood-pressure lowering and glucose control in type 2 diabetes
Open accessAbstract
BACKGROUND: In the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) factorial trial, the combination of perindopril and indapamide reduced mortality among patients with type 2 diabetes, but intensive glucose control, targeting a glycated hemoglobin level of less than 6.5%, did not. We now report results of the 6-year post-trial follow-up. METHODS: We invited surviving participants, who had previously been assigned to perindopril-indapamide or placebo and to intensive or standard glucose control (with the glucose-control comparison extending for an additional 6 months), to participate in a post-trial follow-up evaluation. The primary end points were death from any cause and major macrovascular events. RESULTS: The baseline characteristics were similar among the 11,140 patients who originally underwent randomization and the 8494 patients who participated in the post-trial follow-up for a median of 5.9 years (blood-pressure-lowering comparison) or 5.4 years (glucose-control comparison). Between-group differences in blood pressure and glycated hemoglobin levels during the trial were no longer evident by the first post-trial visit. The reductions in the risk of death from any cause and of death from cardiovascular causes that had been observed in the group receiving active blood-pressure-lowering treatment during the trial were attenuated but significant at the end of the post-trial follow-up; the hazard ratios were 0.91 (95% confidence interval [CI], 0.84 to 0.99; P=0.03) and 0.88 (95% CI, 0.77 to 0.99; P=0.04), respectively. No differences were observed during follow-up in the risk of death from any cause or major macrovascular events between the intensive-glucose-control group and the standard-glucose-control group; the hazard ratios were 1.00 (95% CI, 0.92 to 1.08) and 1.00 (95% CI, 0.92 to 1.08), respectively. CONCLUSIONS: The benefits with respect to mortality that had been observed among patients originally assigned to blood-pressure-lowering therapy were attenuated but still evident at the end of follow-up. There was no evidence that intensive glucose control during the trial led to long-term benefits with respect to mortality or macrovascular events. (Funded by the National Health and Medical Research Council of Australia and others; ADVANCE-ON ClinicalTrials.gov number, NCT00949286.).
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There is a lag time of at least 2 years in type 2 diabetes to over 10 years in type 1 diabetes for the effects of intensive glucose control to manifest as improved eGFR outcomes.
“Moreover, there is a lag time of at least 2 years in type 2 diabetes to over 10 years in type 1 diabetes for the effects of intensive glucose control to manifest as improved eGFR outcomes (57,61,62).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [57]
The discussion accompanying Figure 3 reports a persistent benefit of intensive glucose control for end-stage renal disease in the type 2 diabetes cohort. It does not report improved eGFR or establish a two-year lag. The discussion accompanying Figure 4 mentions more than 10 years of follow-up in other trials, but not a lag of over 10 years before eGFR improves in type 1 diabetes. (LLM, conf=0.81)
Experimental — accuracy not yet measuredLowering blood glucose itself helps prevent CKD and its progression.
“Insulin alone was used to lower blood glucose in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study of type 1 diabetes, while a variety of agents were used in clinical trials of type 2 diabetes, supporting the conclusion that lowering blood glucose itself helps prevent CKD and its progression.”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [57]
The discussion accompanying Figure 3 reports that intensive glucose control reduced new or worsening nephropathy, including albuminuria progression, and that a benefit for end-stage renal disease persisted during follow-up. It does not establish that glucose lowering alone caused the benefit: the authors say blood-pressure differences may have contributed and caution that end-stage renal disease events were few. The paper also does not establish the citing sentence’s comparison of insulin-only treatment in DCCT/EDIC with agents used across type 2 diabetes trials. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIntensive lowering of blood glucose with the goal of achieving near-normoglycemia has been shown in large randomized studies to delay the onset and progression of albuminuria and reduce eGFR in people with type 1 diabetes and type 2 diabetes.
“Intensive lowering of blood glucose with the goal of achieving near-normoglycemia has been shown in large, randomized studies to delay the onset and progression of albuminuria and reduce eGFR in people with type 1 diabetes (52,53) and type 2 diabetes (1,(54)(55)(56)(57)(58)(59).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2025 (2025) · cites this paper as [57]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredThere is a lag time of at least 2 years in type 2 diabetes to over 10 years in type 1 diabetes for the effects of intensive glucose control to manifest as improved eGFR outcomes.
“Moreover, there is a lag time of at least 2 years in type 2 diabetes to over 10 years in type 1 diabetes for the effects of intensive glucose control to manifest as improved eGFR outcomes (59)(60)(61).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [59]
The Figure 3 discussion reports a benefit of intensive glucose control for end-stage renal disease in type 2 diabetes. The Figure 4 discussion suggests that five years of post-trial follow-up may have been too short for some benefits to emerge. Neither passage establishes improved eGFR outcomes or the claimed lag times of at least two years in type 2 diabetes and over ten years in type 1 diabetes; the Study Outcomes section says the biochemical measurements needed to assess nephropathy were unavailable for all follow-up participants. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn the ADVANCE trial, intensive glucose control aimed at reducing A1C ≤6.5% significantly reduced the incidence of major microvascular events, mainly through a 21% relative reduction in nephropathy, but had no beneficial effect on major CV events or all-cause mortality during the trial or subsequent median 5.4-year follow-up.
“There was significant reduction in the incidence of major microvascular events in the intensive control group, mainly through a 21% relative reduction in nephropathy (23); however, no beneficial effect of intensive glucose lowering was found on major CV events or allcause mortality either during the trial or the subsequent median observational follow up of 5.4 years (24).”
From Targets for Glycemic Control (2018) · cites this paper as [24]
Post-trial observational follow-up of the ADVANCE study in ADVANCE-ON demonstrated no significant effect on cardiovascular disease events at 10 years.
“In contrast, post-trial observational follow-up of the ADVANCE study in the Action in Diabetes and Vascular Disease Preterax and Diamicron MR Controlled Evaluation Post Trial Observational Study (ADVANCE-ON) demonstrated no significant effect on CVD events at 10 years (61).”
From 6. Glycemic Goals, Hypoglycemia, and Hyperglycemic Crises: Standards of Care in Diabetes-2026. (2026) · cites this paper as [61]
In the ADVANCE trial, the end-stage renal disease rate was lower in the intensive treatment group over follow-up.
“The endstage renal disease rate was lower in the intensive treatment group over follow-up.”
From 6. Glycemic Targets: <i>Standards of Care in Diabetes—2023</i> (2023) · cites this paper as [63]
Longer-term follow-up of the ADVANCE trial showed no evidence of cardiovascular benefit or harm.
“Longer-term follow-up has shown no evidence of cardiovascular benefit, or harm, in the ADVANCE trial (63).”
From 6. Glycemic Targets: <i>Standards of Care in Diabetes—2023</i> (2023) · cites this paper as [63]
In ACCORD, ADVANCE, and VADT, severe hypoglycemia was significantly more likely in participants randomly assigned to the intensive glycemic control arm.
“In all three trials, severe hypoglycemia was significantly more likely in participants who were randomly assigned to the intensive glycemic control arm.”
From 6. Glycemic Targets: <i>Standards of Care in Diabetes—2023</i> (2023) · cites this paper as [63]
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- Authors
- Zoungas, S., Chalmers, J., Neal, B., Billot, L., Li, Q., Hirakawa, Y., Arima, H., Monaghan, H., Joshi, R., Colagiuri, S., Cooper, M. E., Glasziou, P., Grobbee, D., Hamet, P., Harrap, S., Heller, S., Lisheng, L., Mancia, G., Marre, M., Matthews, D. R., Mogensen, C. E., Perkovic, V., Poulter, N., Rodgers, A., Williams, B., MacMahon, S., Patel, A., & Woodward, M.
- Affiliations
- The University of Sydney (AU)
- The George Institute for Global Health (GB)
- The George Institute for Global Health (AU)
- Baker Heart and Diabetes Institute (AU)
- Bond University (AU)
- University Medical Center Utrecht (NL)
- Centre Hospitalier de l’Université de Montréal (CA)
- The Royal Melbourne Hospital (AU)
- Sheffield Teaching Hospitals NHS Foundation Trust (GB)
- IRCCS Istituto Auxologico Italiano (IT)
- Hôpital Bichat-Claude-Bernard (FR)
- Oxford Centre for Diabetes, Endocrinology and Metabolism (GB)
- Aarhus University Hospital (DK)
- University of Oxford (GB)
- National Institute for Health and Care Research (GB)
- Johns Hopkins University (US)
- ORCID
- Zoungas, Sophia
- Chalmers, John
- Neal, Bruce
- Billot, Laurent
- Li, Qiang
- Hirakawa, Yoichiro
- Arima, Hisatomi
- Monaghan, Helen
- Joshi, Rohina
- Colagiuri, Stephen
- Cooper, Mark E.
- Glasziou, Paul
- Grobbee, Diederick
- Hamet, Pavel
- Harrap, Stephen
- Heller, Simon
- Mancia, Giuseppe
- Marre, Michel
- Matthews, David R.
- Perkovic, Vlado
- Poulter, Neil
- Rodgers, Anthony
- Williams, Bryan
- MacMahon, Stephen
- Patel, Anushka
- Woodward, Mark
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2014-10-09
- Volume
- 371
- Issue
- 15
- Pages
- 1392-1406
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2124909544
- Semantic Scholar
- 377986afccc7604c13c6559134a22432e613cdd7
- Cited by
- 626
- References
- 15
- Citations by year
- 2026: 20 · 2025: 21 · 2024: 32 · 2023: 44 · 2022: 46 · 2021: 47 · 2020: 59 · 2019: 74 · 2018: 64 · 2017: 69 · 2016: 69 · 2015: 73 · 2014: 8
- FWCI
- 58.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
- e-publications@bond (Bond University) (submittedVersion)
- Homo Politicus (Academy of Humanities and Economics in Lodz) (submittedVersion, cc-by-nc-nd)
- Homo Politicus (Academy of Humanities and Economics in Lodz) (submittedVersion)
- BOA (University of Milano-Bicocca) (submittedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Bond University Research Portal (Bond University) (submittedVersion, other-oa)
- ANU Open Research (Australian National University) (submittedVersion)
- Griffith Research Online (submittedVersion)
- Funders
- Eli Lilly and Company
- Pfizer
- AstraZeneca
- Sanofi
- National Institute for Health and Care Research (NF-SI-0611-10248)
- British Heart Foundation (28562, SP/10/6/28562)
- Daiichi-Sankyo
- Novo Nordisk
- Astellas Pharma
- Servier
- Merck Sharp and Dohme
- Medical Research Council (MC_PC_13090)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Blood Pressure and Hypertension Studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- type 2 diabetes, perindopril, indapamide, blood pressure reduction, tight glycemic control, HbA1c, mortality, cardiovascular mortality, ADVANCE trial, post-trial follow-up, renin-angiotensin system inhibitors, ACE inhibitors, thiazide diuretics, long-term follow-up, trial attrition
- MeSH terms
- Antihypertensive Agents, Blood Glucose, Diabetes Mellitus, Type 2, Drug Combinations, Female, Follow-Up Studies, Gliclazide, Glycated Hemoglobin, Humans, Hypertension, Hypoglycemic Agents, Indapamide, Male, Middle Aged, Risk Factors, Perindopril
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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