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Cited by 363Diabetes Management and ResearchDiabetes Treatment and ManagementDiabetes, Cardiovascular Risks, and Lipoproteins

Impact of Visit-to-Visit Glycemic Variability on the Risks of Macrovascular and Microvascular Events and All-Cause Mortality in Type 2 Diabetes: The ADVANCE Trial

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Hirakawa, Yoichiro, Arima, Hisatomi, Zoungas, Sophia, Ninomiya, Toshiharu, Cooper, Mark, Hamet, Pavel, Mancia, Giuseppe, Poulter, Neil +3 more·2014·Diabetes Care
DOI 10.2337/dc14-0199
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Abstract

OBJECTIVE: There is no consensus on the importance of visit-to-visit glycemic variability in diabetes. Therefore, we assessed the effects of visit-to-visit variability (VVV) in HbA1c and fasting glucose on major outcomes in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation) trial. RESEARCH DESIGN AND METHODS: ADVANCE was a factorial randomized controlled trial of intensive glucose control and blood pressure lowering in patients with type 2 diabetes. VVV in the intensive glucose treatment group was defined using the SD of five measurements of HbA1c and glucose taken 3–24 months after randomization. Outcomes were combined macro- and microvascular events and all-cause mortality occurring post 24 months. Sensitivity analyses were performed using other indices of variability and in the standard glucose treatment group. RESULTS: Among 4,399 patients in the intensive group, an increase in VVV of HbA1c was associated with an increased risk of vascular events (P = 0.01) and with mortality (P < 0.001): highest versus lowest tenth hazard ratio (95% CI) 1.64 (1.05–2.55) and 3.31 (1.57–6.98), respectively, after multivariable adjustment. A clear association was also observed between VVV of fasting glucose and increased risk of vascular events (P < 0.001; 2.70 [1.65–4.42]). HbA1c variability was positively associated with the risk of macrovascular events (P = 0.02 for trend), whereas glucose variability was associated with both macro- and microvascular events (P = 0.005 and P < 0.001 for trend, respectively). Sensitivity analyses using other indices, and patients in the standard glucose treatment group, were broadly consistent with these results. CONCLUSIONS: Consistency of glycemic control is important to reduce the risks of vascular events and death in type 2 diabetes.

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  • Fluctuations in blood glucose levels may contribute more to outcomes than constant high blood glucose concentrations.

    “Other studies have demonstrated that fluctuations in blood glucose levels may contribute more to outcomes than constant high blood glucose concentrations.31–35”

    From Increased Time in Range and Fewer Missed Bolus Injections After Introduction of a Smart Connected Insulin Pen (2020) · cites this paper as [33]

  • Glycemic variability is associated with mortality in patients with type 2 diabetes.

    “Recent clinical data indicate that GV is associated with increased risk of hypoglycemia, microvascular and macrovascular complications, and mortality in patients with diabetes, independently of glycated hemoglobin level.”

    From Glycemic variability and cardiovascular disease in patients with type 2 diabetes (2021) · cites this paper as [21]

  • In the ADVANCE trial, HbA1c variability was positively associated with risk of macrovascular events in patients with type 2 diabetes.

    “and that HbA1c variability was positively associated with risk of macrovascular events.21”

    From Glycemic variability and cardiovascular disease in patients with type 2 diabetes (2021) · cites this paper as [21]

  • In ADVANCE, increased HbA1c visit-to-visit variation was associated with increased risk of vascular events (p=0.01, HR 1.64, 1.05-2.55), macrovascular events (p=0.02), and mortality (p<0.001, HR 3.31, 1.57-6.98).

    “Increased HbA1c visit-to-visit variation was associated with increased risk of vascular events (p=0.01, HR 1.64, 1.05–2.55), macrovascular events (p=0.02), and mortality (p<0.001, HR 3.31, 1.57–6.98).”

    From Glycemic variability and cardiovascular disease in patients with type 2 diabetes (2021) · cites this paper as [21]

  • In ADVANCE, fasting glucose visit-to-visit variation was associated with increased risk of cardiovascular events (p<0.001, HR 2.70, 1.65-4.42) and macrovascular (p=0.005) and microvascular (p<0.001) events.

    “FG visit-to-visit variation was associated with increased risk of CV events (p<0.001, HR 2.70, 1.65–4.42) and macrovascular (p=0.005) and microvascular (p<0.001) events.”

    From Glycemic variability and cardiovascular disease in patients with type 2 diabetes (2021) · cites this paper as [21]

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Authors
Hirakawa, Y., Arima, H., Zoungas, S., Ninomiya, T., Cooper, M., Hamet, P., Mancia, G., Poulter, N., Harrap, S., Woodward, M., & Chalmers, J.
Affiliations
  • The University of Sydney (AU)
  • Baker Heart and Diabetes Institute (AU)
  • Centre Hospitalier de l’Université de Montréal (CA)
  • IRCCS Istituto Auxologico Italiano (IT)
  • St Mary's Hospital (GB)
  • The Royal Melbourne Hospital (AU)
Corresponding author
Chalmers, John
ORCID
Venue
Diabetes Care
Publisher
American Diabetes Association
Published
2014-07-12
Volume
37
Issue
8
Pages
2359-2365
ISSN
  • 0149-5992 (ISSN-L)
  • 1935-5548
DOI
10.2337/dc14-0199
OpenAlex
W2122273643
Cited by
363
References
36
Citations by year
2026: 9 · 2025: 20 · 2024: 32 · 2023: 33 · 2022: 44 · 2021: 47 · 2020: 51 · 2019: 35 · 2018: 25 · 2017: 25 · 2016: 18 · 2015: 18 · 2014: 5
FWCI
17.69
Type
journal article
Language
en
Open access
Licence
other-oa
Locations
  • Diabetes Care (publishedVersion)
  • PubMed (publishedVersion)
  • BOA (University of Milano-Bicocca) (submittedVersion)
  • INFM-OAR (INFN Catania) (submittedVersion, other-oa)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
Keywords
type 2 diabetes, HbA1c variability, macrovascular events, all-cause mortality, tight glycemic control, blood pressure reduction, ADVANCE trial
MeSH terms
Aged, Aged, 80 and over, Blood Glucose, Cause of Death, Diabetes Mellitus, Type 2, Diabetic Angiopathies, Drug Combinations, Female, Follow-Up Studies, Gliclazide, Humans, Hypoglycemic Agents, Indapamide, Male, Middle Aged, Office Visits, Risk Factors, Perindopril

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