Calvin Ke, Thérèse A. Stukel, Baiju R. Shah, Eric Lau, Ronald C. Ma, Wing-Yee So, Alice P. Kong,
Elaine Chow, Juliana C. N. Chan , Andrea Luk
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).
Life-threatening complications of type 2 diabetes (T2D) are caused by long-term exposure to hyperglycemia . Glycemic exposure is defined as the area under the glycated hemoglobin A1c (A1C) curve in excess of 7% over time [2–5]. A meta-analysis of randomized control trials showed that every 10 A1C-years of glycemic exposure (that is, 10 years of A1C at 8%) predicts a 25% increase in the relative risk of major adverse cardiovascular events (MACE) . Young-onset T2D (defined here as age at diagnosis <40 years) is an aggressive phenotype associated with higher lifetime risks of MACE and other complications compared to usual-onset T2D (age at diagnosis ≥40 years) [6–9]. Although early age at diagnosis and poor glycemic control are important risk factors for complications , lifetime glycemic exposure and its relationship with age at T2D diagnosis are unknown.
Hong Kong has a population of 7.3 million people, 92% of whom are of Chinese ethnicity . The estimated diabetes prevalence was 10.3% in 2014 . The Hong Kong Hospital Authority (HA) provides universal public healthcare modeled after the British National Health Service. Because of the high out-of-pocket cost of private healthcare, 95% of people with diabetes in Hong Kong receive care in HA clinics . Consultation, prescription, and medication dispensing services are all provided on site under an all-inclusive nominal user fee , which is waived for low-income and other vulnerable groups . All hospitals and clinics managed by the HA share the same electronic health record (EHR) with data including laboratory tests, discharge summaries, and dispensed prescriptions. Dispensed prescription records are comprehensive because drugs are prescribed and dispensed on site at the time of consultation. These data are linked by the unique Hong Kong Identity Card number.
In this large population- and register-based study, we found that people with young-onset T2D had poorly controlled hyperglycemia throughout their life span, resulting in more than triple the cumulative glycemic exposure versus usual-onset T2D. This disparity was driven by rapid glycemic deterioration, which was particularly steep among people diagnosed with T2D before age 30 years. Conversely, we revealed that T2D diagnosis after age 60 years was associated with glycemic improvement—a novel finding that has not been previously reported to our knowledge. In this real-world study, people with young-onset T2D had slightly smaller A1C decrements compared with usual-onset T2D for most combinations of OGLDs including metformin, whereas young-onset T2D was unexpectedly associated with greater responsiveness to sulfonylureas and α-glucosidase inhibitors than usual-onset T2D. Although most OGLD combinations appear to lower A1C by similar decrements across age at diagnosis, the rapidity of glycemic deterioration in young-onset T2D suggests that early combination therapy  and aggressive treatment escalation are needed to reduce the massive excess in glycemic exposure that we observed.
We thank Dr. Allan Detsky for his useful comments on an earlier version of this manuscript and the Hong Kong Hospital Authority for providing the data for this study. Part of this work was presented at the American Diabetes Association’s 79th Scientific Sessions in San Francisco, California, June 7–11, 2019.
Citation: Ke C, Stukel TA, Shah BR, Lau E, Ma RC, So W-Y, et al. (2020) 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): e1003316. https://doi.org/10.1371/journal.pmed.1003316
Academic Editor: Sanjay Basu, Harvard Medical School, UNITED STATES
Received: April 20, 2020; Accepted: August 14, 2020; Published: September 18, 2020
Copyright: © 2020 Ke et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: Due to local laws and regulations regarding the use and distribution of personal data, the data used in the present study cannot be deposited in a public repository. Data access can be applied for through the Data Sharing Portal of the Hong Kong Hospital Authority (https://www3.ha.org.hk/data/DCL/Index/).
Funding: CK is supported by the Canadian Institutes of Health Research (https://cihr-irsc.gc.ca/) Canada Graduate Scholarship and Michael Smith Foreign Study Supplements, the University of Toronto Clinician Investigator Program (https://cip.utoronto.ca/), the Canadian Society of Endocrinology and Metabolism (https://www.endo-metab.ca/) Dr. Fernand Labrie Research Fellowship Grant, and the Royal College of Physicians and Surgeons of Canada (http://www.royalcollege.ca/) Detweiler Traveling Fellowship. (Grant numbers not applicable.) The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: RCWM acknowledges receiving research support (outside of this work) from AstraZeneca, Bayer, and Pfizer for conducting clinical trials and honoraria or consultancy fees from AstraZeneca and Boehringer Ingelheim, all of which has been donated to the Chinese University of Hong Kong to support diabetes research. RCWM is a member of the Editorial Board of PLOS Medicine. AOYL acknowledges receiving research support (outside of this work) from Boehringer Ingelheim, MSD, Sanofi, and Amgen and travel grants from travel grant from AstraZeneca, Boehringer Ingelheim, MSD, Novartis, Novo Nordisk, and Sanofi. JCNC and RCWM are cofounders of GemVCare, a diabetes genetic testing laboratory, which was established through support from the Technology Start-up Support Scheme for Universities (TSSSU) from the Hong Kong Government Innovation and Technology Commission (ITC). JCNC is the Chief Executive Officer, on a pro bono basis, of the Asia Diabetes Foundation (ADF), which is a nonprofit research organization which designed and implemented the Joint Asia Diabetes Evaluation (JADE) Technology as an extension to the HKDR, under the governance of the CUHK Foundation. The HKDR was established as a research-driven quality improvement program initiated by the Chinese University of Hong Kong (CUHK)-Prince of Wales Hospital Diabetes Care and Research Team, supported by the Hong Kong Foundation for Research and Development in Diabetes established at CUHK. In 2007, this was merged with the web-based JADE Technology, complete with care protocols, risk stratification, personalized reporting, and decision support. The JADE Technology was designed and implemented by the ADF to enable other clinics and hospitals to establish diabetes registers and contribute anonymized data for research purposes. The ADF was set up as a charitable research organization governed by the CUHK Foundation.
Abbreviations: A1C, hemoglobin A1c; MACE, major adverse cardiovascular events; OGLD, oral glucose-lowering drug; T2D, type 2 diabetes