Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Endocrine
Published in: Endocrine 3/2019

01-06-2019 | Hypoglycemia | Original Article

Prognostic impact of visit-to-visit glycemic variability on the risks of major adverse cardiovascular outcomes and hypoglycemia in patients with different glycemic control and type 2 diabetes

Authors: Bao Sun, Fazhong He, Yongchao Gao, Jiecan Zhou, Lei Sun, Rong Liu, Heng Xu, Xiaoping Chen, Honghao Zhou, Zhaoqian Liu, Wei Zhang

Published in: Endocrine | Issue 3/2019

Login to get access

Abstract

Purpose

The prognostic impact of visit-to-visit glycemic variability on clinical outcomes in patients with different glycemic control and type 2 diabetes remains obscure. We investigated glucose variability and clinical outcomes for patients in the groups of Good glycemic control (GC), Insufficient glycemic control (IC), and Poor glycemic control (PC) in a prospective cohort study.

Methods

By using data from Action in Diabetes and Vascular disease: preterAx and diamicroN-MR Controlled Evaluation (ADVANCE), 930 patients were enrolled from 61 centers in China and grouped into GC, IC, and PC according to their glycated hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG). Visit-to-visit glycemic variability was defined using the coefficient of variation (CV) of five measurements of HbA1c and FPG taken 3–24 months after treatment. Multivariable Cox proportional hazards models were employed to estimate adjusted hazard ratio (aHR).

Results

Among 930 patients in the intensive glucose control, 82, 538, and 310 patients were assigned to GC, IC, and PC, respectively. During the median of 4.8 years of follow-up, 322 patients were observed hypoglycemia and 244 patients experienced major adverse cardiovascular events (MACE). The CV of HbA1c and FPG was significantly lower for GC (6.0 ± 3.8, 11.2 ± 6.2) than IC (8.3 ± 5.6, 17.9 ± 10.6) and PC (9.5 ± 6.3, 19.3 ± 10.8). High glycemic variability was associated with a greater risk of MACE (aHR: 2.21; 95% confidence interval (CI): 1.61–3.03; p < 0.001) and hypoglycemia (aHR: 1.36; 95% CI: 1.04–1.79; p = 0.025) than low glycemic variability in total patients. The consistent trend was also found in subgroups of GC, IC, and PC.

Conclusions

This prospective cohort study showed that glycemic variability was significantly lower for GC than IC and PC. Furthermore, glycemic variability was associated with the risk of MACE and hypoglycemia in total patients and subgroups of different glycemic control.
Appendix
Available only for authorised users
Literature
1.
2.
A.K. Wright, E. Kontopantelis, R. Emsley, I. Buchan, N. Sattar, M.K. Rutter, D.M. Ashcroft, Life expectancy and cause-specific mortality in type 2 diabetes: a population-based cohort study quantifying relationships in ethnic subgroups. Diabetes Care 40(3), 338–345 (2017).CrossRefPubMed
3.
UK Prospective Diabetes Study (UKPDS) Group. UK Prospective Diabetes Study (UKPDS) GroupIntensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet (Lond., Engl.) 352(9131), 837–853 (1998).
4.
D.M. Nathan, S. Genuth, J. Lachin, P. Cleary, O. Crofford, M. Davis, L. Rand, C. Siebert, The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N. Engl. J. Med. 329(14), 977–986 (1993).CrossRefPubMed
5.
B. Hemmingsen, S.S. Lund, C. Gluud, A. Vaag, T. Almdal, C. Hemmingsen, J. Wetterslev, Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. BMJ 343, d6898 (2011).CrossRefPubMedPubMedCentral
6.
H.C. Gerstein, M.E. Miller, R.P. Byington, D.C. Goff Jr., J.T. Bigger, J.B. Buse, W.C. Cushman, S. Genuth, F. Ismail-Beigi, R.H. Grimm Jr., J.L. Probstfield, D.G. Simons-Morton, W.T. Friedewald, Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med. 358(24), 2545–2559 (2008).CrossRefPubMed
7.
D.E. Bonds, M.E. Miller, R.M. Bergenstal, J.B. Buse, R.P. Byington, J.A. Cutler, R.J. Dudl, F. Ismail-Beigi, A.R. Kimel, B. Hoogwerf, K.R. Horowitz, P.J. Savage, E.R. Seaquist, D.L. Simmons, W.I. Sivitz, J.M. Speril-Hillen, M.E. Sweeney, The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ 340, b4909 (2010).CrossRefPubMedPubMedCentral
8.
B. Sun, F. He, L. Sun, J. Zhou, J. Shen, J. Xu, B. Wu, R. Liu, X. Wang, H. Xu, X. Chen, H. Zhou, Z. Liu, W. Zhang, Cause-specific risk of major adverse cardiovascular outcomes and hypoglycemic in patients with type 2 diabetes: a multicenter prospective cohort study. Endocrine (2018). https://​doi.​org/​10.​1007/​s12020-018-1715-0.
9.
M. Kuroda, T. Shinke, H. Otake, D. Sugiyama, T. Takaya, H. Takahashi, D. Terashita, K. Uzu, N. Tahara, D. Kashiwagi, K. Kuroda, Y. Shinkura, Y. Nagasawa, K. Sakaguchi, Y. Hirota, W. Ogawa, K. Hirata, Effects of daily glucose fluctuations on the healing response to everolimus-eluting stent implantation as assessed using continuous glucose monitoring and optical coherence tomography. Cardiovasc. Diabetol. 15, 79 (2016).CrossRefPubMedPubMedCentral
10.
D. Tschope, P. Bramlage, S. Schneider, A.K. Gitt, Incidence, characteristics and impact of hypoglycaemia in patients receiving intensified treatment for inadequately controlled type 2 diabetes mellitus. Diabetes Vasc. Dis. Res. 13(1), 2–12 (2016).CrossRef
11.
Y. Hirakawa, H. Arima, S. Zoungas, T. Ninomiya, M. Cooper, P. Hamet et al., 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. Diabetes Care 37, 2359–2365 (2014).CrossRefPubMed
12.
L. Nalysnyk, M. Hernandez-Medina, G. Krishnarajah, Glycaemic variability and complications in patients with diabetes mellitus: evidence from a systematic review of the literature. Diabetes Obes. Metab. 12(4), 288–298 (2010).CrossRefPubMed
13.
B. Zinman, S.P. Marso, N.R. Poulter, S.S. Emerson, T.R. Pieber, R.E. Pratley, M. Lange, K. Brown-Frandsen, A. Moses, A.M. Ocampo Francisco, J. Barner Lekdorf, K. Kvist, J.B. Buse, Day-to-day fasting glycaemic variability in DEVOTE: associations with severe hypoglycaemia and cardiovascular outcomes (DEVOTE 2). Diabetologia 61(1), 48–57 (2018).CrossRefPubMed
14.
A. Patel, S. MacMahon, J. Chalmers, B. Neal, L. Billot, M. Woodward, M. Marre, M. Cooper, P. Glasziou, D. Grobbee, P. Hamet, S. Harrap, S. Heller, L. Liu, G. Mancia, C.E. Mogensen, C. Pan, N. Poulter, A. Rodgers, B. Williams, S. Bompoint, B.E. de Galan, R. Joshi, F. Travert, Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N. Engl. J. Med. 358(24), 2560–2572 (2008).CrossRefPubMed
15.
Rationale and design of the ADVANCE study: a randomised trial of blood pressure lowering and intensive glucose control in high-risk individuals with type 2 diabetes mellitus, Action in diabetes and vascular disease: PreterAx and DiamicroN modified-release controlled evaluation. J. Hypertens. Suppl. 19(4), S21–S28 (2001)
16.
F. He, M. Liu, Z. Chen, G. Liu, Z. Wang, R. Liu, J. Luo, J. Tang, X. Wang, X. Liu, H. Zhou, X. Chen, Z. Liu, W. Zhang, Assessment of human tribbles homolog 3 genetic variation (rs2295490) effects on type 2 diabetes patients with glucose control and blood pressure lowering treatment. EBioMedicine 13, 181–189 (2016).CrossRefPubMedPubMedCentral
17.
J. Gu, Y.Q. Fan, J.F. Zhang, C.Q. Wang, Association of hemoglobin A1c variability and the incidence of heart failure with preserved ejection fraction in patients with type 2 diabetes mellitus and arterial hypertension. Hell. J. Cardiol. 59(2), 91–97 (2018).CrossRef
18.
J. Gu, Y.Q. Fan, J.F. Zhang, C.Q. Wang, Impact of long-term glycemic variability on development of atrial fibrillation in type 2 diabetic patients. Anatol. J. Cardiol. 18(6), 410–416 (2017).PubMedPubMedCentral
19.
C. Stettler, S. Allemann, P. Juni, C.A. Cull, R.R. Holman, M. Egger, S. Krahenbuhl, P. Diem, Glycemic control and macrovascular disease in types 1 and 2 diabetes mellitus: meta-analysis of randomized trials. Am. Heart J. 152(1), 27–38 (2006).CrossRefPubMed
20.
I.M. Stratton, A.I. Adler, H.A. Neil, D.R. Matthews, S.E. Manley, C.A. Cull, D. Hadden, R.C. Turner, R.R. Holman, Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321(7258), 405–412 (2000).CrossRefPubMedPubMedCentral
21.
M.S. Kirkman, M. McCarren, J. Shah, W. Duckworth, C. Abraira, The association between metabolic control and prevalent macrovascular disease in Type 2 diabetes: the VA Cooperative Study in diabetes. J. Diabetes Complicat. 20(2), 75–80 (2006).CrossRef
22.
23.
24.
S.E. Inzucchi, R.M. Bergenstal, J.B. Buse, M. Diamant, E. Ferrannini, M. Nauck, A.L. Peters, A. Tsapas, R. Wender, D.R. Matthews, Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 38(1), 140–149 (2015).CrossRefPubMed
25.
K.J. Lipska, H. Krumholz, T. Soones, S.J. Lee, Polypharmacy in the aging patient: a review of glycemic control in older adults with type 2 diabetes. J. Am. Med Assoc. 315(10), 1034–1045 (2016).CrossRef
26.
D. Cheng, Y. Fei, Y. Liu, J. Li, Q. Xue, X. Wang, N. Wang, HbA1C variability and the risk of renal status progression in Diabetes Mellitus: a meta-analysis. PLoS ONE 9(12), e115509 (2014).CrossRefPubMedPubMedCentral
27.
C. Gorst, C.S. Kwok, S. Aslam, I. Buchan, E. Kontopantelis, P.K. Myint, G. Heatlie, Y. Loke, M.K. Rutter, M.A. Mamas, Long-term glycemic variability and risk of adverse outcomes: a systematic review and meta-analysis. Diabetes Care 38(12), 2354–2369 (2015).CrossRefPubMed
28.
G. Penno, A. Solini, G. Zoppini, E. Orsi, C. Fondelli, G. Zerbini, S. Morano, F. Cavalot, O. Lamacchia, R. Trevisan, M. Vedovato, G. Pugliese, Hemoglobin A1c variability as an independent correlate of cardiovascular disease in patients with type 2 diabetes: a cross-sectional analysis of the renal insufficiency and cardiovascular events (RIACE) Italian multicenter study. Cardiovasc. Diabetol. 12, 98 (2013).CrossRefPubMedPubMedCentral
29.
E.S. Kilpatrick, A.S. Rigby, S.L. Atkin, The effect of glucose variability on the risk of microvascular complications in type 1 diabetes. Diabetes Care 29(7), 1486–1490 (2006).CrossRefPubMed
30.
R. Borg, J.C. Kuenen, B. Carstensen, H. Zheng, D.M. Nathan, R.J. Heine, J. Nerup, K. Borch-Johnsen, D.R. Witte, HbA(1)(c) and mean blood glucose show stronger associations with cardiovascular disease risk factors than do postprandial glycaemia or glucose variability in persons with diabetes: the A1C-Derived Average Glucose (ADAG) study. Diabetologia 54(1), 69–72 (2011).CrossRefPubMed
31.
C.E. Mendez, K.T. Mok, A. Ata, R.J. Tanenberg, J. Calles-Escandon, G.E. Umpierrez, Increased glycemic variability is independently associated with length of stay and mortality in noncritically ill hospitalized patients. Diabetes Care 36(12), 4091–4097 (2013).CrossRefPubMedPubMedCentral
32.
S. Zoungas, J. Chalmers, B. Neal, L. Billot, Q. Li, Y. Hirakawa, H. Arima, H. Monaghan, R. Joshi, S. Colagiuri, M.E. Cooper, P. Glasziou, D. Grobbee, P. Hamet, S. Harrap, S. Heller, L. Lisheng, G. Mancia, M. Marre, D.R. Matthews, C.E. Mogensen, V. Perkovic, N. Poulter, A. Rodgers, B. Williams, S. MacMahon, A. Patel, M. Woodward, Follow-up of blood-pressure lowering and glucose control in type 2 diabetes. N. Engl. J. Med. 371(15), 1392–1406 (2014).CrossRefPubMed
33.
H.C. Gerstein, M.E. Miller, F. Ismail-Beigi, J. Largay, C. McDonald, H.A. Lochnan, G.L. Booth, Effects of intensive glycaemic control on ischaemic heart disease: analysis of data from the randomised, controlled ACCORD trial. Lancet (Lond., Engl.) 384(9958), 1936–1941 (2014).CrossRef
34.
M. Yamazaki, G. Hasegawa, S. Majima, K. Mitsuhashi, T. Fukuda, H. Iwase, M. Kadono, M. Asano, T. Senmaru, M. Tanaka, M. Fukui, N. Nakamura, Effect of repaglinide versus glimepiride on daily blood glucose variability and changes in blood inflammatory and oxidative stress markers. Diabetol. Metab. Syndr. 6, 54 (2014).CrossRefPubMedPubMedCentral
35.
Chinese Diabetes Society. China guideline for type 2 diabetes (2013). China J. Diabetes Mellitus 22(8), 447–498 (2014).
36.
K. Omori, H. Nomoto, A. Nakamura, Reduction in glucose fluctuations in elderly patients with type 2 diabetes using repaglinide: a randomized controlled trial of repaglinide vs sulfonylurea. J. Diabetes Investig. (2018). https://​doi.​org/​10.​1111/​jdi.​12889.
37.
N.A. Thornberry, B. Gallwitz, Mechanism of action of inhibitors of dipeptidyl-peptidase-4 (DPP-4). Best Pract. Clin. Endocrinol. Metab. 23(4), 479–486 (2009).CrossRef
38.
L. Monnier, E. Mas, C. Ginet, F. Michel, L. Villon, J.P. Cristol, C. Colette, Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. J. Am. Med Assoc. 295(14), 1681–1687 (2006).CrossRef
39.
A. Ceriello, M.A. Ihnat, “Glycaemic variability”: a new therapeutic challenge in diabetes and the critical care setting. Diabet. Med. 27(8), 862–867 (2010).CrossRefPubMed
Metadata
Title
Prognostic impact of visit-to-visit glycemic variability on the risks of major adverse cardiovascular outcomes and hypoglycemia in patients with different glycemic control and type 2 diabetes
Authors
Bao Sun
Fazhong He
Yongchao Gao
Jiecan Zhou
Lei Sun
Rong Liu
Heng Xu
Xiaoping Chen
Honghao Zhou
Zhaoqian Liu
Wei Zhang
Publication date
01-06-2019
Publisher
Springer US
Published in
Endocrine / Issue 3/2019
Print ISSN: 1355-008X
Electronic ISSN: 1559-0100
DOI
https://doi.org/10.1007/s12020-019-01893-1

Other articles of this Issue 3/2019

Endocrine 3/2019 Go to the issue

Original Article

Eleven novel SLC12A1 variants and an exonic mutation cause exon skipping in Bartter syndrome type I

Original Article

Dysbiosis of the gut microbiome is associated with thyroid cancer and thyroid nodules and correlated with clinical index of thyroid function

Meta-Analysis

Hypertriglyceridemic waist phenotype and abnormal glucose metabolism: a system review and meta-analysis

Review

The next step after anti-osteoporotic drug discontinuation: an up-to-date review of sequential treatment

Original Article

Targeted next-generation sequencing in papillary thyroid carcinoma patients looking for germline variants predisposing to the disease

Meta-Analysis

Detection rate of unknown primary tumour by using somatostatin receptor PET/CT in patients with metastatic neuroendocrine tumours: a meta-analysis
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

Read more

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits