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Published in: Osteoporosis International 10/2020

01-10-2020 | Osteoporosis | Original Article

HbA1c variability, in addition to mean HbA1c, predicts incident hip fractures in Chinese people with type 2 diabetes

Authors: D.T.W. Lui, C.H. Lee, Y.H. Chan, W.S. Chow, C.H.Y. Fong, D.C.W. Siu, H.F. Tse, Y.C. Woo, K.S.L. Lam

Published in: Osteoporosis International | Issue 10/2020

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Abstract

Summary

Type 2 diabetes is associated with an increased risk of hip fractures. We hypothesize that long-term glycemic variability predicts incident hip fractures. We demonstrated that HbA1c variability predicted incident hip fractures independent of mean HbA1c, suggesting the potential benefits of minimizing glycemic variability in addition to optimizing mean glycemia for bone health.

Introduction

Type 2 diabetes is associated with an increased risk of hip fractures, and a linear relationship between HbA1c levels and hip fracture incidence has been observed. We hypothesize that HbA1c variability also predicts incident hip fractures in type 2 diabetes.

Methods

Chinese individuals with type 2 diabetes aged ≥ 60 years were identified from electronic health records in Hong Kong between 2008 and 2012 and observed for incident hip fractures. Hip fracture was defined by the International Classification of Diseases (Ninth Revision) code 820. HbA1c variability was determined using standard deviation, adjusted standard deviation, and coefficient of variation of HbA1c measurements in the 5 years preceding the entry date. Multivariable Cox regression analysis was used to evaluate associations between HbA1c variability and incident hip fractures.

Results

A total of 83,282 participants were included. Their mean age was 71.3 ± 7.5 years, duration of diabetes 11.7 ± 7.7 years, baseline HbA1c 56.6 ± 13.5 mmol/mol (7.33 ± 1.23%), and median follow-up 6.8 years. All indices of HbA1c variability were significant independent predictors of incident hip fractures, with an adjusted hazard ratio of up to 1.29 (all p < 0.001), and remained to be independent predictors across groups of different intensity of glycemic control. Mean HbA1c ≥ 64 mmol/mol (8.0%) was associated with a 25% increase in incident hip fractures compared with mean HbA1c < 53 mmol/mol (7.0%).

Conclusion

HbA1c variability is an independent positive predictor of hip fracture in type 2 diabetes, across the spectrum of varying degree of glycemic control, while a high HbA1c is also not advisable from the perspective of bone health.
Literature
1.
go back to reference (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352(9131):837–853 (1998) Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352(9131):837–853
2.
go back to reference Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359(15):1577–1589CrossRef Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW (2008) 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359(15):1577–1589CrossRef
3.
go back to reference (1995) The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes 44(8):968–983 (1995) The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial. Diabetes 44(8):968–983
4.
go back to reference Leslie RD (1999) United Kingdom prospective diabetes study (UKPDS): what now or so what? Diabetes Metab Res Rev 15(1):65–71CrossRef Leslie RD (1999) United Kingdom prospective diabetes study (UKPDS): what now or so what? Diabetes Metab Res Rev 15(1):65–71CrossRef
5.
go back to reference Cavalot F (2013) Do data in the literature indicate that glycaemic variability is a clinical problem? Glycaemic variability and vascular complications of diabetes. Diabetes Obes Metab 15(Suppl 2):3–8CrossRef Cavalot F (2013) Do data in the literature indicate that glycaemic variability is a clinical problem? Glycaemic variability and vascular complications of diabetes. Diabetes Obes Metab 15(Suppl 2):3–8CrossRef
6.
go back to reference Gorst C, Kwok CS, Aslam S, Buchan I, Kontopantelis E, Myint PK et al (2015) Long-term glycemic variability and risk of adverse outcomes : a systematic review and meta-analysis. Diabetes Care 38:2354–2369CrossRef Gorst C, Kwok CS, Aslam S, Buchan I, Kontopantelis E, Myint PK et al (2015) Long-term glycemic variability and risk of adverse outcomes : a systematic review and meta-analysis. Diabetes Care 38:2354–2369CrossRef
7.
go back to reference Janghorbani M, Van Dam RM, Willett WC, Hu FB (2007) Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol 166(5):495–505CrossRef Janghorbani M, Van Dam RM, Willett WC, Hu FB (2007) Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol 166(5):495–505CrossRef
8.
go back to reference Lecka-Czernik B (2017) Diabetes, bone and glucose-lowering agents: basic biology. Diabetologia. 60(7):1163–1169CrossRef Lecka-Czernik B (2017) Diabetes, bone and glucose-lowering agents: basic biology. Diabetologia. 60(7):1163–1169CrossRef
9.
10.
go back to reference Man LP, Angela Ho AWH, Wong SH (2016) Excess mortality for operated geriatric hip fracture in Hong Kong. Hong Kong Med J 22(1):6–10PubMed Man LP, Angela Ho AWH, Wong SH (2016) Excess mortality for operated geriatric hip fracture in Hong Kong. Hong Kong Med J 22(1):6–10PubMed
11.
go back to reference Strom O, Borgstrom F, Kanis JA, Compston J, Cooper C, McCloskey EV et al (2011) Osteoporosis: burden, health care provision and opportunities in the EU: a report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 6:59–155CrossRef Strom O, Borgstrom F, Kanis JA, Compston J, Cooper C, McCloskey EV et al (2011) Osteoporosis: burden, health care provision and opportunities in the EU: a report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos 6:59–155CrossRef
12.
go back to reference Li C-I, Liu C-S, Lin W-Y, Meng N-H, Chen C-C, Yang S-Y et al (2015) Glycated hemoglobin level and risk of hip fracture in older people with type 2 diabetes: a competing risk analysis of Taiwan diabetes cohort study. J Bone Miner Res 30(7):1338–1346CrossRef Li C-I, Liu C-S, Lin W-Y, Meng N-H, Chen C-C, Yang S-Y et al (2015) Glycated hemoglobin level and risk of hip fracture in older people with type 2 diabetes: a competing risk analysis of Taiwan diabetes cohort study. J Bone Miner Res 30(7):1338–1346CrossRef
13.
go back to reference Lafage-Proust M-H, Roche B, Langer M, Cleret D, Vanden Bossche A, Olivier T et al (2015) Assessment of bone vascularization and its role in bone remodeling. Bonekey Rep 4:662CrossRef Lafage-Proust M-H, Roche B, Langer M, Cleret D, Vanden Bossche A, Olivier T et al (2015) Assessment of bone vascularization and its role in bone remodeling. Bonekey Rep 4:662CrossRef
14.
go back to reference Ihnat MA, Thorpe JE, Ceriello A (2007) Hypothesis: the “metabolic memory”, the new challenge of diabetes. Diabet Med 24(6):582–586CrossRef Ihnat MA, Thorpe JE, Ceriello A (2007) Hypothesis: the “metabolic memory”, the new challenge of diabetes. Diabet Med 24(6):582–586CrossRef
15.
go back to reference Ke C, Lau E, Shah BR, Stukel TA, Ma RC, So W-Y et al (2019) Excess burden of mental illness and hospitalization in young-onset type 2 diabetes: a population-based cohort study. Ann Intern Med 170(3):145–154 Ke C, Lau E, Shah BR, Stukel TA, Ma RC, So W-Y et al (2019) Excess burden of mental illness and hospitalization in young-onset type 2 diabetes: a population-based cohort study. Ann Intern Med 170(3):145–154
16.
go back to reference Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130(6):461–470CrossRef Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D (1999) A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130(6):461–470CrossRef
17.
go back to reference Orsi E, Solini A, Bonora E, Fondelli C, Trevisan R, Vedovato M et al (2018) Haemoglobin A1c variability is a strong, independent predictor of all-cause mortality in patients with type 2 diabetes. Diabetes Obes Metab 20(8):1885–1893CrossRef Orsi E, Solini A, Bonora E, Fondelli C, Trevisan R, Vedovato M et al (2018) Haemoglobin A1c variability is a strong, independent predictor of all-cause mortality in patients with type 2 diabetes. Diabetes Obes Metab 20(8):1885–1893CrossRef
18.
go back to reference (2017) Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 40(1):155–157 (2017) Glucose concentrations of less than 3.0 mmol/L (54 mg/dL) should be reported in clinical trials: a joint position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 40(1):155–157
19.
go back to reference Tang CS, Zhang H, Cheung CYY, Xu M, Ho JCY, Zhou W et al (2015) Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese. Nat Commun 6:10206CrossRef Tang CS, Zhang H, Cheung CYY, Xu M, Ho JCY, Zhou W et al (2015) Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese. Nat Commun 6:10206CrossRef
20.
go back to reference Wong Y-K, Cheung CYY, Tang CS, Au K-W, Hai JSH, Lee C-H et al (2018) Age-biomarkers-clinical risk factors for prediction of cardiovascular events in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 38(10):2519–2527CrossRef Wong Y-K, Cheung CYY, Tang CS, Au K-W, Hai JSH, Lee C-H et al (2018) Age-biomarkers-clinical risk factors for prediction of cardiovascular events in patients with coronary artery disease. Arterioscler Thromb Vasc Biol 38(10):2519–2527CrossRef
21.
go back to reference Woo YC, Gao B, Lee CH, Fong CH, Lui DT, Ming J et al (2020) Three-component non-invasive risk score for undiagnosed diabetes in Chinese people: development, validation and longitudinal evaluation. J Diabetes Investig 11(2):341–348 Woo YC, Gao B, Lee CH, Fong CH, Lui DT, Ming J et al (2020) Three-component non-invasive risk score for undiagnosed diabetes in Chinese people: development, validation and longitudinal evaluation. J Diabetes Investig 11(2):341–348
22.
go back to reference Lee CH, Cheung CYY, Woo YC, Lui DTW, Yuen MMA, Fong CHY et al (2019) Prospective associations of circulating adipocyte fatty acid-binding protein levels with risks of renal outcomes and mortality in type 2 diabetes. Diabetologia 62(1):169–177 Lee CH, Cheung CYY, Woo YC, Lui DTW, Yuen MMA, Fong CHY et al (2019) Prospective associations of circulating adipocyte fatty acid-binding protein levels with risks of renal outcomes and mortality in type 2 diabetes. Diabetologia 62(1):169–177
23.
go back to reference Farrell C-JL, Martin S, McWhinney B, Straub I, Williams P, Herrmann M (2012) State-of-the-art vitamin D assays: a comparison of automated immunoassays with liquid chromatography-tandem mass spectrometry methods. Clin Chem 58(3):531–542CrossRef Farrell C-JL, Martin S, McWhinney B, Straub I, Williams P, Herrmann M (2012) State-of-the-art vitamin D assays: a comparison of automated immunoassays with liquid chromatography-tandem mass spectrometry methods. Clin Chem 58(3):531–542CrossRef
24.
go back to reference Therneau TGP (2000) Modeling survival data. In: Statistics for biology and health. Springer-Verlag, New York Therneau TGP (2000) Modeling survival data. In: Statistics for biology and health. Springer-Verlag, New York
25.
go back to reference Kleinbaum D (1995) Survival analysis-a self-learning text. Springer-Verlag, New York Kleinbaum D (1995) Survival analysis-a self-learning text. Springer-Verlag, New York
26.
go back to reference Samelson EJ, Zhang Y, Kiel DP, Hannan MT, Felson DT (2002) Effect of birth cohort on risk of hip fracture: age-specific incidence rates in the Framingham study. Am J Public Health 92(5):858–862CrossRef Samelson EJ, Zhang Y, Kiel DP, Hannan MT, Felson DT (2002) Effect of birth cohort on risk of hip fracture: age-specific incidence rates in the Framingham study. Am J Public Health 92(5):858–862CrossRef
27.
go back to reference von Friesendorff M, Besjakov J, Akesson K (2008) Long-term survival and fracture risk after hip fracture: a 22-year follow-up in women. J Bone Miner Res 23(11):1832–1841CrossRef von Friesendorff M, Besjakov J, Akesson K (2008) Long-term survival and fracture risk after hip fracture: a 22-year follow-up in women. J Bone Miner Res 23(11):1832–1841CrossRef
28.
go back to reference Shen GS, Li Y, Zhao G, Bin ZH, Xie ZG, Xu W et al (2015) Cigarette smoking and risk of hip fracture in women: a meta-analysis of prospective cohort studies. Injury. 46(7):1333–1340CrossRef Shen GS, Li Y, Zhao G, Bin ZH, Xie ZG, Xu W et al (2015) Cigarette smoking and risk of hip fracture in women: a meta-analysis of prospective cohort studies. Injury. 46(7):1333–1340CrossRef
29.
go back to reference Wu Z-J, Zhao P, Liu B, Yuan Z-C (2016) Effect of cigarette smoking on risk of hip fracture in men: a meta-analysis of 14 prospective cohort studies. PLoS One 11(12):e0168990CrossRef Wu Z-J, Zhao P, Liu B, Yuan Z-C (2016) Effect of cigarette smoking on risk of hip fracture in men: a meta-analysis of 14 prospective cohort studies. PLoS One 11(12):e0168990CrossRef
30.
go back to reference Sogaard AJ, Holvik K, Omsland TK, Tell GS, Dahl C, Schei B et al (2016) Age and sex differences in body mass index as a predictor of hip fracture: a NOREPOS study. Am J Epidemiol 184(7):510–519CrossRef Sogaard AJ, Holvik K, Omsland TK, Tell GS, Dahl C, Schei B et al (2016) Age and sex differences in body mass index as a predictor of hip fracture: a NOREPOS study. Am J Epidemiol 184(7):510–519CrossRef
31.
go back to reference Puar TH, Khoo JJ, Cho LW, Xu Y, Chen YT, Chuo AM et al (2012) Association between glycemic control and hip fracture. J Am Geriatr Soc 60(8):1493–1497CrossRef Puar TH, Khoo JJ, Cho LW, Xu Y, Chen YT, Chuo AM et al (2012) Association between glycemic control and hip fracture. J Am Geriatr Soc 60(8):1493–1497CrossRef
32.
go back to reference Schisano B, Tripathi G, McGee K, McTernan PG, Ceriello A (2011) Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells. Diabetologia. 54(5):1219–1226CrossRef Schisano B, Tripathi G, McGee K, McTernan PG, Ceriello A (2011) Glucose oscillations, more than constant high glucose, induce p53 activation and a metabolic memory in human endothelial cells. Diabetologia. 54(5):1219–1226CrossRef
33.
go back to reference Hung YC, Lin CC, Chen HJ, Chang MP, Huang KC, Chen YH et al (2017) Severe hypoglycemia and hip fracture in patients with type 2 diabetes: a nationwide population-based cohort study. Osteoporos Int 28(7):2053–2060CrossRef Hung YC, Lin CC, Chen HJ, Chang MP, Huang KC, Chen YH et al (2017) Severe hypoglycemia and hip fracture in patients with type 2 diabetes: a nationwide population-based cohort study. Osteoporos Int 28(7):2053–2060CrossRef
34.
go back to reference Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA et al (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321(7258):405–412CrossRef Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA et al (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321(7258):405–412CrossRef
35.
go back to reference Penno G, Solini A, Bonora E, Fondelli C, Orsi E, Zerbini G et al (2013) HbA1c variability as an independent correlate of nephropathy, but not retinopathy, in patients with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study. Diabetes Care 36(8):2301–2310CrossRef Penno G, Solini A, Bonora E, Fondelli C, Orsi E, Zerbini G et al (2013) HbA1c variability as an independent correlate of nephropathy, but not retinopathy, in patients with type 2 diabetes: the Renal Insufficiency And Cardiovascular Events (RIACE) Italian multicenter study. Diabetes Care 36(8):2301–2310CrossRef
36.
go back to reference El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG et al (2008) Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med 205(10):2409–2417CrossRef El-Osta A, Brasacchio D, Yao D, Pocai A, Jones PL, Roeder RG et al (2008) Transient high glucose causes persistent epigenetic changes and altered gene expression during subsequent normoglycemia. J Exp Med 205(10):2409–2417CrossRef
37.
go back to reference Ceriello A, Esposito K, Piconi L, Ihnat MA, Thorpe JE, Testa R, Boemi M, Giugliano D (2008) Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes. 57(5):1349–1354CrossRef Ceriello A, Esposito K, Piconi L, Ihnat MA, Thorpe JE, Testa R, Boemi M, Giugliano D (2008) Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes. 57(5):1349–1354CrossRef
38.
go back to reference Chiang JI-H, Li T-C, Li C-I, Liu C-S, Meng N-H, Lin W-Y et al (2016) Visit-to-visit variation of fasting plasma glucose is a predictor of hip fracture in older persons with type 2 diabetes: the Taiwan Diabetes Study. Osteoporos Int 27(12):3587–3597CrossRef Chiang JI-H, Li T-C, Li C-I, Liu C-S, Meng N-H, Lin W-Y et al (2016) Visit-to-visit variation of fasting plasma glucose is a predictor of hip fracture in older persons with type 2 diabetes: the Taiwan Diabetes Study. Osteoporos Int 27(12):3587–3597CrossRef
39.
go back to reference Holvik K, Ahmed LA, Forsmo S, Gjesdal CG, Grimnes G, Samuelsen SO et al (2013) Low serum levels of 25-hydroxyvitamin D predict hip fracture in the elderly: a NOREPOS study. J Clin Endocrinol Metab 98(8):3341–3350CrossRef Holvik K, Ahmed LA, Forsmo S, Gjesdal CG, Grimnes G, Samuelsen SO et al (2013) Low serum levels of 25-hydroxyvitamin D predict hip fracture in the elderly: a NOREPOS study. J Clin Endocrinol Metab 98(8):3341–3350CrossRef
40.
go back to reference Majumdar SR, Josse RG, Lin M, Eurich DT (2016) Does sitagliptin affect the rate of osteoporotic fractures in type 2 diabetes? Population-based cohort study. J Clin Endocrinol Metab 101(5):1963–1969CrossRef Majumdar SR, Josse RG, Lin M, Eurich DT (2016) Does sitagliptin affect the rate of osteoporotic fractures in type 2 diabetes? Population-based cohort study. J Clin Endocrinol Metab 101(5):1963–1969CrossRef
41.
go back to reference Johnston SS, Conner C, Aagren M, Ruiz K, Bouchard J (2012) Association between hypoglycaemic events and fall-related fractures in Medicare-covered patients with type 2 diabetes. Diabetes Obes Metab 14(7):634–643CrossRef Johnston SS, Conner C, Aagren M, Ruiz K, Bouchard J (2012) Association between hypoglycaemic events and fall-related fractures in Medicare-covered patients with type 2 diabetes. Diabetes Obes Metab 14(7):634–643CrossRef
42.
go back to reference An T, Hao J, Sun S, Li R, Yang M, Cheng G et al (2017) Efficacy of statins for osteoporosis: a systematic review and meta-analysis. Osteoporos Int 28(1):47–57CrossRef An T, Hao J, Sun S, Li R, Yang M, Cheng G et al (2017) Efficacy of statins for osteoporosis: a systematic review and meta-analysis. Osteoporos Int 28(1):47–57CrossRef
Metadata
Title
HbA1c variability, in addition to mean HbA1c, predicts incident hip fractures in Chinese people with type 2 diabetes
Authors
D.T.W. Lui
C.H. Lee
Y.H. Chan
W.S. Chow
C.H.Y. Fong
D.C.W. Siu
H.F. Tse
Y.C. Woo
K.S.L. Lam
Publication date
01-10-2020
Publisher
Springer London
Published in
Osteoporosis International / Issue 10/2020
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI
https://doi.org/10.1007/s00198-020-05395-z

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