Age at diagnosis, glycemic trajectories, and responses to oral glucose-lowering drugs in type 2 diabetes in Hong Kong: A population-based observational study

Autoři: Calvin Ke aff001;  Thérèse A. Stukel aff003;  Baiju R. Shah aff002;  Eric Lau aff001;  Ronald C. Ma aff001;  Wing-Yee So aff001;  Alice P. Kong aff001;  Elaine Chow aff001;  Juliana C. N. Chan aff001;  Andrea Luk aff001
Působiště autorů: Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China aff001;  Department of Medicine, University of Toronto, Canada aff002;  Institute of Health Policy, Management and Evaluation, University of Toronto, Canada aff003;  ICES, Toronto, Canada aff004;  Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Canada aff005;  Asia Diabetes Foundation, Metropole Square, Shatin, Hong Kong SAR, China aff006;  Hong Kong Institute of Diabetes and Obesity and Li Ka Shing Institute of Health Science, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, China aff007
Vyšlo v časopise: Age at diagnosis, glycemic trajectories, and responses to oral glucose-lowering drugs in type 2 diabetes in Hong Kong: A population-based observational study. PLoS Med 17(9): e32767. doi:10.1371/journal.pmed.1003316
Kategorie: Research Article



Lifetime glycemic exposure and its relationship with age at diagnosis in type 2 diabetes (T2D) are unknown. Pharmacologic glycemic management strategies for young-onset T2D (age at diagnosis <40 years) are poorly defined. We studied how age at diagnosis affects glycemic exposure, glycemic deterioration, and responses to oral glucose-lowering drugs (OGLDs).

Methods and findings

In a population-based cohort (n = 328,199; 47.2% women; mean age 34.6 and 59.3 years, respectively, for young-onset and usual-onset [age at diagnosis ≥40 years] T2D; 2002–2016), we used linear mixed-effects models to estimate the association between age at diagnosis and A1C slope (glycemic deterioration) and tested for an interaction between age at diagnosis and responses to various combinations of OGLDs during the first decade after diagnosis. In a register-based cohort (n = 21,016; 47.1% women; mean age 43.8 and 58.9 years, respectively, for young- and usual-onset T2D; 2000–2015), we estimated the glycemic exposure from diagnosis until age 75 years.

People with young-onset T2D had a higher mean A1C (8.0% [standard deviation 0.15%]) versus usual-onset T2D (7.6% [0.03%]) throughout the life span (p < 0.001). The cumulative glycemic exposure was >3 times higher for young-onset versus usual-onset T2D (41.0 [95% confidence interval 39.1–42.8] versus 12.1 [11.8–12.3] A1C-years [1 A1C-year = 1 year with 8% average A1C]). Younger age at diagnosis was associated with faster glycemic deterioration (A1C slope over time +0.08% [0.078–0.084%] per year for age at diagnosis 20 years versus +0.02% [0.016–0.018%] per year for age at diagnosis 50 years; p-value for interaction <0.001). Age at diagnosis ≥60 years was associated with glycemic improvement (−0.004% [−0.005 to −0.004%] and −0.02% [−0.027 to −0.0244%] per year for ages 60 and 70 years at diagnosis, respectively; p-value for interaction <0.001). Responses to OGLDs differed by age at diagnosis (p-value for interaction <0.001). Those with young-onset T2D had smaller A1C decrements for metformin-based combinations versus usual-onset T2D (metformin alone: young-onset −0.15% [−0.105 to −0.080%], usual-onset −0.17% [−0.179 to −0.169%]; metformin, sulfonylurea, and dipeptidyl peptidase-4 inhibitor: young-onset −0.44% [−0.476 to −0.405%], usual-onset −0.48% [−0.498 to −0.459%]; metformin and α-glucosidase inhibitor: young-onset −0.40% [−0.660 to −0.144%], usual-onset −0.25% [−0.420 to −0.077%]) but greater responses to other combinations containing sulfonylureas (sulfonylurea alone: young-onset −0.08% [−0.099 to −0.065%], usual-onset +0.06% [+0.059 to +0.072%]; sulfonylurea and α-glucosidase inhibitor: young-onset −0.10% [−0.266 to 0.064%], usual-onset: 0.25% [+0.196% to +0.312%]). Limitations include possible residual confounding and unknown generalizability outside Hong Kong.


In this study, we observed excess glycemic exposure and rapid glycemic deterioration in young-onset T2D, indicating that improved treatment strategies are needed in this setting. The differential responses to OGLDs between young- and usual-onset T2D suggest that better disease classification could guide personalized therapy.

Klíčová slova:

Diabetes diagnosis and management – diabetes mellitus – Gestational diabetes – Hong Kong – Insulin – Observational studies – Type 2 diabetes


1. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW. 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. New England Journal of Medicine. 2008;359(15):1577–89. doi: 10.1056/NEJMoa0806470 18784090

2. Roussel R, Steg PG, Mohammedi K, Marre M, Potier L. Prevention of cardiovascular disease through reduction of glycaemic exposure in type 2 diabetes: A perspective on glucose-lowering interventions. Diabetes Obes Metab. 2018 Feb 1;20(2):238–44. doi: 10.1111/dom.13033 28597588

3. Brown JB, Nichols GA, Perry A. The Burden of Treatment Failure in Type 2 Diabetes. Diabetes Care. 2004 Jul 1;27(7):1535–40. doi: 10.2337/diacare.27.7.1535 15220224

4. Nichols GA, Rosales AG, Perrin NA, Fortmann SP. The Association Between Different A1C-Based Measures of Glycemia and Risk of Cardiovascular Disease Hospitalization. Diabetes Care. 2014 Jan;37(1):167–72. doi: 10.2337/dc13-1300 23990520

5. van Wijngaarden RPT, Overbeek JA, Heintjes EM, Schubert A, Diels J, Straatman H, et al. Relation Between Different Measures of Glycemic Exposure and Microvascular and Macrovascular Complications in Patients with Type 2 Diabetes Mellitus: An Observational Cohort Study. Diabetes Ther. 2017 Oct 1;8(5):1097–109. doi: 10.1007/s13300-017-0301-4 28921256

6. Chan JCN, Lau ESH, Luk AOY, Cheung KKT, Kong APS, Yu LWL, et al. Premature Mortality and Comorbidities in Young-onset Diabetes: A 7-Year Prospective Analysis. The American Journal of Medicine. 2014 Jul 1;127(7):616–24. doi: 10.1016/j.amjmed.2014.03.018 24680795

7. Ke C, Lau E, Shah BR, Stukel TA, Ma RC, So W-Y, et al. Excess Burden of Mental Illness and Hospitalization in Young-Onset Type 2 Diabetes: A Population-Based Cohort Study. Annals of Internal Medicine. 2019 Feb 5;170(3):145–54. doi: 10.7326/M18-1900 30641547

8. Pavkov ME, Bennett PH, Knowler WC, Krakoff J, Sievers ML, Nelson RG. Effect of Youth-Onset Type 2 Diabetes Mellitus on Incidence of End-Stage Renal Disease and Mortality in Young and Middle-Aged Pima Indians. JAMA. 2006 Jul 26;296(4):421–6. doi: 10.1001/jama.296.4.421 16868300

9. Steinarsson AO, Rawshani A, Gudbjörnsdottir S, Franzén S, Svensson A-M, Sattar N. Short-term progression of cardiometabolic risk factors in relation to age at type 2 diabetes diagnosis: a longitudinal observational study of 100,606 individuals from the Swedish National Diabetes Register. Diabetologia. 2018 Mar 1;61(3):599–606. doi: 10.1007/s00125-017-4532-8 29318343

10. Yeung RO, Zhang Y, Luk A, Yang W, Sobrepena L, Yoon K-H, et al. Metabolic profiles and treatment gaps in young-onset type 2 diabetes in Asia (the JADE programme): a cross-sectional study of a prospective cohort. The Lancet Diabetes & Endocrinology. 2014 Jan 12;2(12):935–43.

11. van Raalte DH, Diamant M. Glucolipotoxicity and beta cells in type 2 diabetes mellitus: Target for durable therapy? Diabetes Research and Clinical Practice. 2011 Aug 1;93:S37–46. doi: 10.1016/S0168-8227(11)70012-2 21864750

12. Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, et al. Glycemic Durability of Rosiglitazone, Metformin, or Glyburide Monotherapy. New England Journal of Medicine. 2006 Dec 7;355(23):2427–43. doi: 10.1056/NEJMoa066224 17145742

13. Donnelly LA, Zhou K, Doney ASF, Jennison C, Franks PW, Pearson ER. Rates of glycaemic deterioration in a real-world population with type 2 diabetes. Diabetologia. 2018 Mar;61(3):607–15. doi: 10.1007/s00125-017-4519-5 29260253

14. Wallace TM, Matthews DR. Coefficient of failure: a methodology for examining longitudinal β-cell function in Type 2 diabetes. Diabetic Medicine. 2002 Jun;19(6):465–9. doi: 10.1046/j.1464-5491.2002.00718.x 12060057

15. Ke C, Shah BR, Luk AO, Di Ruggiero E, Chan JCN. Cardiovascular Outcomes Trials in Type 2 Diabetes: Time to Include Young Adults. Diabetes, Obesity and Metabolism. 2020 Jan 20;22(1):3–5. doi: 10.1111/dom.13874 31486276

16. TODAY Study Group, Zeitler P, Hirst K, Pyle L, Linder B, Copeland K, et al. A clinical trial to maintain glycemic control in youth with type 2 diabetes. N Engl J Med. 2012 Jun 14;366(24):2247–56. doi: 10.1056/NEJMoa1109333 22540912

17. Consortium RISE. Effects of Treatment of Impaired Glucose Tolerance or Recently Diagnosed Type 2 Diabetes With Metformin Alone or in Combination With Insulin Glargine on β-Cell Function: Comparison of Responses In Youth And Adults. Diabetes. 2019 Aug;68(8):1670–80. doi: 10.2337/db19-0299 31178433

18. 2016 Population By-census Office. 2016 Population By-Census—Main Results [Internet]. Hong Kong: Census and Statistics Department, Hong Kong Special Administrative Region Government. 2017 Nov [cited 2019 Jan 7].

19. Quan J, Li TK, Pang H, Choi CH, Siu SC, Tang SY, et al. Diabetes incidence and prevalence in Hong Kong, China during 2006–2014. Diabet Med. 2017 Jul 1;34(7):902–8. doi: 10.1111/dme.13284 27859570

20. Lau IT. A Clinical Practice Guideline to Guide a System Approach to Diabetes Care in Hong Kong. Diabetes Metab J. 2017 Apr;41(2):81–8. doi: 10.4093/dmj.2017.41.2.81 28447435

21. Leung GM, Wong IO.L., Chan W-S, Choi S, Lo S-V. The ecology of health care in Hong Kong. Social Science & Medicine. 2005 Aug;61(3):577–90.

22. Legislative Council Panel on Health Services. Enhancements of Medical Fee Waiver Mechanism of Hospital Authority [Internet]. Hong Kong: Legislative Council Panel on Health Services; 2017 Jul [cited 2020 Jun 8] p. 8. (LC Paper). Report No.: CB(2)1843/16-17(02).

23. Chan JCN, So W, Ma RCW, Tong PCY, Wong R, Yang X. The Complexity of Vascular and Non-Vascular Complications of Diabetes: The Hong Kong Diabetes Registry. Curr Cardiovasc Risk Rep. 2011 Jun;5(3):230–9. doi: 10.1007/s12170-011-0172-6 21654912

24. Hospital Authority. Hospital Authority Drug Formulary [Internet]. 15.5. Hong Kong: Hospital Authority; 2020 [cited 2020 Jun 9].

25. Ke C, Stukel TA, Luk A, Shah BR, Jha P, Lau E, et al. Development and validation of algorithms to classify type 1 and 2 diabetes according to age at diagnosis using electronic health records. BMC Med Res Methodol. 2020 Feb 24;20(35):1–15.

26. Levy J, Atkinson AB, Bell PM, McCance DR, Hadden DR. Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in Type 2 diabetes mellitus: the 10-year follow-up of the Belfast Diet Study. Diabetic Medicine. 1998 Apr 1;15(4):290–6. 9585393

27. Sherifali D, Nerenberg K, Pullenayegum E, Cheng JE, Gerstein HC. The Effect of Oral Antidiabetic Agents on A1C Levels: A systematic review and meta-analysis. Diabetes Care. 2010 Aug 1;33(8):1859–64. doi: 10.2337/dc09-1727 20484130

28. Mearns ES, Sobieraj DM, White CM, Saulsberry WJ, Kohn CG, Doleh Y, et al. Comparative Efficacy and Safety of Antidiabetic Drug Regimens Added to Metformin Monotherapy in Patients with Type 2 Diabetes: A Network Meta-Analysis. PLoS ONE. 2015 Apr 28;10(4):e0125879. doi: 10.1371/journal.pone.0125879 25919293

29. Maruthur NM, Tseng E, Hutfless S, Wilson LM, Suarez-Cuervo C, Berger Z, et al. Diabetes Medications as Monotherapy or Metformin-Based Combination Therapy for Type 2 Diabetes: A Systematic Review and Meta-analysis. Annals of Internal Medicine. 2016 Jun 7;164(11):740. doi: 10.7326/M15-2650 27088241

30. Alberti KGMM Eckel RH, Grundy SM Zimmet PZ, Cleeman JI Donato KA, et al. Harmonizing the Metabolic Syndrome: A Joint Interim Statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009 Oct 20;120(16):1640–5. doi: 10.1161/CIRCULATIONAHA.109.192644 19805654

31. Harrell FE. SAS macros and data step programs useful in survival analysis and logistic regression [Internet]. Duke University Medical Center: Takima West Corporation; 1991 [cited 2018 Dec 28].

32. Turner RC, McCarthy ST, Holman RR, Harris E. Beta-cell function improved by supplementing basal insulin secretion in mild diabetes. Br Med J. 1976 May 22;1(6020):1252–4. doi: 10.1136/bmj.1.6020.1252 1268654

33. Matthews DR, Paldánius PM, Proot P, Chiang Y, Stumvoll M, Del Prato S. Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5-year, multicentre, randomised, double-blind trial. The Lancet. 2019 Oct 26;394(10208):1519–29.

34. TODAY Study Group. Effects of metformin, metformin plus rosiglitazone, and metformin plus lifestyle on insulin sensitivity and β-cell function in TODAY. Diabetes Care. 2013 Jun;36(6):1749–57. doi: 10.2337/dc12-2393 23704674

35. Lascar N, Brown J, Pattison H, Barnett AH, Bailey CJ, Bellary S. Type 2 diabetes in adolescents and young adults. The Lancet Diabetes & Endocrinology. 2018 Jan;6(1):69–80.

36. Ma RCW, Chan JCN. Type 2 diabetes in East Asians: similarities and differences with populations in Europe and the United States. Ann NY Acad Sci. 2013 Apr 1;1281(1):64–91.

37. Lipska KJ, Ross JS, Miao Y, Shah ND, Lee SJ, Steinman MA. Potential Overtreatment of Diabetes Mellitus in Older Adults With Tight Glycemic Control. JAMA Intern Med. 2015 Mar 1;175(3):356–62. doi: 10.1001/jamainternmed.2014.7345 25581565

38. Ahlqvist E, Storm P, Käräjämäki A, Martinell M, Dorkhan M, Carlsson A, et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. The Lancet Diabetes & Endocrinology. 2018;6(5):361–369. doi: 10.1016/S2213-8587(18)30051-2

39. Wu H, Lau ESH, Yang A, Ma RCW, Kong APS, Chow E, et al. Trends in diabetes-related complications in Hong Kong, 2001–2016: a retrospective cohort study. Cardiovascular Diabetology. 2020 May 12;19(1):60. doi: 10.1186/s12933-020-01039-y 32398003

40. Gao Z, Yan W, Fang Z, Zhang Z, Yuan L, Wang X, et al. Annual decline in β-cell function in patients with type 2 diabetes in China. Diabetes Metab Res Rev. 2020 Jun 8;e3364. doi: 10.1002/dmrr.3364 32515043

41. U. K. Prospective Diabetes Study Group. U.K. Prospective Diabetes Study 16: Overview of 6 Years’ Therapy of Type II Diabetes: A Progressive Disease. Diabetes. 1995 Nov 1;44(11):1249–58. 7589820

42. Althoff T, Sosič R, Hicks JL, King AC, Delp SL, Leskovec J. Large-scale physical activity data reveal worldwide activity inequality. Nature. 2017 Jul 10;547(7663):336–9. doi: 10.1038/nature23018 28693034

43. Lu Y, Chen L, Yang Y, Gou Z. The Association of Built Environment and Physical Activity in Older Adults: Using a Citywide Public Housing Scheme to Reduce Residential Self-Selection Bias. Int J Environ Res Public Health. 2018 Sep 10;15(9):1973. doi: 10.3390/ijerph15091973 30201927

44. Edelman SV, Polonsky WH. Type 2 Diabetes in the Real World: The Elusive Nature of Glycemic Control. Diabetes Care. 2017 Nov 1;40(11):1425–32. doi: 10.2337/dc16-1974 28801473

45. Carls GS, Tuttle E, Tan R-D, Huynh J, Yee J, Edelman SV, et al. Understanding the Gap Between Efficacy in Randomized Controlled Trials and Effectiveness in Real-World Use of GLP-1 RA and DPP-4 Therapies in Patients With Type 2 Diabetes. Diabetes Care. 2017 Nov 1;40(11):1469–78. doi: 10.2337/dc16-2725 28801475

46. Kim YG, Hahn S, Oh TJ, Kwak SH, Park KS, Cho YM. Differences in the glucose-lowering efficacy of dipeptidyl peptidase-4 inhibitors between Asians and non-Asians: a systematic review and meta-analysis. Diabetologia. 2013 Apr 1;56(4):696–708. doi: 10.1007/s00125-012-2827-3 23344728

47. Davis TME, Mulder H, Lokhnygina Y, Aschner P, Chuang L-M, Grado CAR, et al. Effect of race on the glycaemic response to sitagliptin: Insights from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS). Diabetes, Obesity and Metabolism. 2018;20(6):1427–34. doi: 10.1111/dom.13242 29405540

48. Ohn JH, Kwak SH, Cho YM, Lim S, Jang HC, Park KS, et al. 10-year trajectory of β-cell function and insulin sensitivity in the development of type 2 diabetes: a community-based prospective cohort study. The Lancet Diabetes & Endocrinology. 2016 Jan 1;4(1):27–34.

49. Ng MCY, Lee S-C, Ko GTC, Li JKY, So W-Y, Hashim Y, et al. Familial Early-Onset Type 2 Diabetes in Chinese Patients: Obesity and genetics have more significant roles than autoimmunity. Diabetes Care. 2001 Apr 1;24(4):663–71. doi: 10.2337/diacare.24.4.663 11315828

50. Hattersley AT, Patel KA. Precision diabetes: learning from monogenic diabetes. Diabetologia. 2017 May 1;60(5):769–77. doi: 10.1007/s00125-017-4226-2 28314945

51. Holman RR, Coleman RL, Chan JCN, Chiasson J-L, Feng H, Ge J, et al. Effects of acarbose on cardiovascular and diabetes outcomes in patients with coronary heart disease and impaired glucose tolerance (ACE): a randomised, double-blind, placebo-controlled trial. The Lancet Diabetes & Endocrinology. 2017 Nov;5(11):877–86.

52. Chiasson J-L, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. The Lancet. 2002 Jun 15;359(9323):2072–7.

53. Lam KS, Tiu SC, Tsang MW, Ip TP, Tam SC. Acarbose in NIDDM patients with poor control on conventional oral agents. A 24-week placebo-controlled study. Diabetes Care. 1998 Jul;21(7):1154–8. doi: 10.2337/diacare.21.7.1154 9653611

54. Chan JC, Chan KW, Ho LL, Fuh MM, Horn LC, Sheaves R, et al. An Asian multicenter clinical trial to assess the efficacy and tolerability of acarbose compared with placebo in type 2 diabetic patients previously treated with diet. Asian Acarbose Study Group. Diabetes Care. 1998 Jul;21(7):1058–61. doi: 10.2337/diacare.21.7.1058 9653595

55. Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669–701. doi: 10.2337/dci18-0033 30291106

56. American Diabetes Association. 6. Glycemic Targets: Standards of Medical Care in Diabetes—2019. Diabetes Care. 2019 Jan 1;42(Supplement 1):S61–70.

57. Imran SA, Agarwal G, Bajaj HS, Ross S. Targets for Glycemic Control. Canadian Journal of Diabetes. 2018 Apr 1;42:S42–6. doi: 10.1016/j.jcjd.2017.10.030 29650110

58. National Institute for Health and Care Excellence. Type 2 diabetes in adults: management [Internet]. National Institute for Health and Care Excellence; 2015 Dec [cited 2019 Feb 26] p. 1–44.

59. Lim LL, Lau ESH, Kong APS, Davies MJ, Levitt NS, Eliasson B, et al. Aspects of Multicomponent Integrated Care Promote Sustained Improvement in Surrogate Clinical Outcomes: A Systematic Review and Meta-analysis. Diabetes Care. 2018 Jun 1;41(6):1312–20. doi: 10.2337/dc17-2010 29784698

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