Pathophysiology/Complications B R I E F
R E P O R T
Complications of Type 2 Diabetes Among Aboriginal Canadians Prevalence and associated risk factors ANTHONY J.G. HANLEY, PHD1,2 STEWART B. HARRIS, MD3 MARY MAMAKEESICK, RPN4 KEN GOODWIN4 EDITH FIDDLER4 ROBERT A. HEGELE, MD5 J. DAVID SPENCE, MD5
ANDREW A. HOUSE, MD6 ED BROWN, MD7 BLAIR SCHOALES, MD8 JOHN R. MCLAUGHLIN, PHD9 RONALD KLEIN, MD10 BERNARD ZINMAN, MD1,2,9
D
risk factors that are associated with these conditions.
espite a dramatically increasing burden of type 2 diabetes in Aboriginal Canadian communities (1–5), relatively little information is available regarding the prevalence of, and risk factors for, the complications of type 2 diabetes in this population (6). Although previous studies have documented micro- and macrovascular disease in Aboriginal Canadians with diabetes, the majority of these reports have relied heavily on hospital records, chart reviews, and disease registries (6). These approaches may underestimate the magnitude of the complications burden because only those with the severest disease are included, and standardized methods are infrequently used to document complications. The objective of the present research project was to systematically determine, using validated methods, the prevalence of micro- and macrovascular complications among Aboriginal Canadians who have type 2 diabetes and to identify
RESEARCH DESIGN AND METHODS — The Sandy Lake Diabetes Complications Study has been presented in detail previously (6). Briefly, all community members known to have type 2 diabetes were invited to participate; 189 of 250 (76%) eligible subjects were enrolled, although the sample size varies given time-limited access to certain equipment. Participants were older than nonparticipants and more likely to be male but did not differ in diabetes treatment. Signed informed consent was obtained from all participants, and the study was approved by the Sandy Lake First Nation Band Council and the Mount Sinai Hospital Ethics Review Committee. We used validated measures to assess retinopathy, neuropathy, nephropathy, and cardiovascular disease risk
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From the 1Leadership Sinai Centre for Diabetes, Mt. Sinai Hospital, Toronto, Ontario, Canada; the 2Division of Endocrinology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; the 3Centre for Studies in Family Medicine, University of Western Ontario, London, Ontario, Canada; the 4Sandy Lake Health and Diabetes Project, Sandy Lake, Ontario, Canada; the 5Robarts Research Institute, London, Ontario, Canada; the 6Department of Medicine, University of Western Ontario, London, Ontario, Canada; the 7 Northern Ontario Remote Telecommunication Health (NORTH) Network, Toronto, Ontario, Canada; the 8 Department of Surgery, Thunder Bay Regional Health Sciences Centre, Thunder Bay, Ontario, Canada; the 9 Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada; and the 10Department of Ophthalmology and Visual Sciences, University of Wisconsin Medical School, Madison, Wisconsin. Address correspondence and reprint requests to Anthony Hanley, PhD, Leadership Sinai Centre for Diabetes, Lebovic Building, Room 5-210, Mt. Sinai Hospital, 600 University Ave., Toronto, Ontario, M5G 1X5, Canada. E-mail:
[email protected]. Received for publication 8 March 2005 and accepted in revised form 29 April 2005. Abbreviations: IMT, intimal-media thickness; NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion factors for many substances. © 2005 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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factors, as described previously (6). Digital fundus photography was performed using a nonmydriatic retinal camera, with no pharmacological pupillary dilation. Three 45o images were taken in each eye, as described (7). After initial clinical assessment and referral by an ophthalmologist (B.S.), photographs were transferred to the Ocular Epidemiology Grading Center at the University of Wisconsin (Madison, WI), where they were graded for retinopathy (mild nonproliferative diabetic retinopathy [NPDR]), moderate/severe NPDR, or proliferative diabetic retinopathy [PDR]) and macular edema (8,9). Diabetic sensory neuropathy was determined using a modification of the Michigan Neuropathy Screening Instrument (10). (In the current study monofilament testing was added and the questionnaire portion was not used.) Scores range from 0 to 9, and individuals with scores ⬎2 were considered to have neuropathy. Diabetic nephropathy was determined by measuring the albumin-tocreatinine ratio in a single, random, daytime urine sample (11) using the Bayer DCA 2000 Point-of-Care Analyzer, which has been validated (r ⫽ 0.95) against laboratory techniques (12). Intimal-media thickness (IMT) was determined using a high-resolution duplex ultrasound scanner (ATL 5000 HDI; Advanced Technology Laboratories, Seattle, WA), as described (13– 15). The ankle-brachial blood pressure index was determined using a blood pressure cuff and Doppler stethoscope. Angina and intermittent claudication were assessed using the Rose questionnaire (16,17). Risk factors were assessed using laboratory and physical measurements and standardized, interviewer-administered questionnaires (6). Measures included HbA1c (A1C) using the DCA 2000 Analyzer (validity 0.90 – 0.98 vs. laboratory measures) (18), high-sensitivity C-reactive protein and lipid concentrations (19), height, weight, waist circumference, duDIABETES CARE, VOLUME 28, NUMBER 8, AUGUST 2005
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Table 1—Subject characteristics and prevalence of diabetes complications and associated risk factors, Sandy Lake Diabetes Complications Study, 2001 Definition Age (average years ⫾ SD) Sex (% female) Duration of diabetes 关median years (interquartile range)兴 Complications Microalbuminuria* Macroalbuminuria* Neuropathy† Retinopathy‡
Macular edema§ Increased carotid IMT Peripheral arterial disease储 Angina Claudication Risk factors Poor glycemic control¶ Hypertension (%)¶# Elevated LDL¶ Elevated total-to-HDL cholesterol ratio¶ Elevated triglyceride¶ Elevated C-reactive protein** Duration of diabetes Smoking
n 46.5 ⫾ 13.3 65.0 9.0 (3–11)
Albumin-to-creatinine ratio 2.0–20 mg/mmol (men), 2.8–28 mg/mmol (women) Albumin-to-creatinine ratio ⬎20 mg/mmol (men), ⬎28 mg/mmol (women) ⬎2 points on MNSI Mild NPDR Moderate/severe NPDR PDR Non-CSME or CSME IMT ⬎1 mm Ankle-brachial index ⬍0.95 Positive on Rose questionnaire Positive on Rose questionnaire
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44.0% (36.4–51.9)
166
16.9% (11.7–23.6)
147
133 132 140 141 183 183
46.3% (38.1–55.6) 8.3% (4.6–15.2) 13.5% (8.8–21.6) 1.5% (0.3–6.1) 3.1% (1.0–8.2) 9.3% (5.2–15.7) 14.9% (9.7–22.1) 10.9% (6.9–16.5) 6.0% (3.2–10.8)
A1C ⬎7% SBP/DBP ⬎130/80 mmHg LDL ⱖ2.5 mmol/l Total-to-HDL cholesterol ratio ⱖ4 Triglyceride ⱖ1.5 mmol/l C-reactive protein ⱖ3 mg/l ⬎10 years Currently smoking cigarettes
171 180 144 147 147 147 189 183
63.2% (55.4–70.3) 61.7% (54.1–68.7) 61.1% (52.6–69.0) 45.6% (37.4–54.0) 61.2% (52.8–69.0) 51.7% (43.3–60.0) 47.1% (39.9–54.5) 51.4% (43.9–58.8)
Data are prevalence (95% CI) unless otherwise indicated. *Micro- and macroalbuminuria cut points taken from Canadian Diabetes Association clinical practice guidelines (11); to convert cut points presented in mg/mmol to mg/g, multiply by 8.83. †Diabetic sensory neuropathy assessed using MNSI (range 0 –9; subjects with scores ⬎2 considered to have neuropathy) (10). ‡Retinopathy definitions based on the Early Treatment Diabetic Retinopathy Study adaptation of the modified Airlie House classification (8). §Macular edema graded as described in detail previously (9). 储Peripheral artery disease was defined as an ankle-brachial index of ⬍0.95; subjects with ankle-brachial index ⬎1.40 were considered to have noncompressible vessels. ¶Risk factor cut points taken from Canadian Diabetes Association clinical practice guidelines (11). #Hypertension: systolic blood pressure (SBP) ⱖ130 mmHg and/or diastolic blood pressure (DBP) ⱖ80 mmHg or on hypertension treatment. **C-reactive protein risk cutoff proposed by Centers for Disease Control and Prevention/American Heart Association (29). CSME, clinically significant macular edema.
ration of diabetes, method of diabetes and hypertension treatment, and cigarette smoking (2,6). Multivariate linear regression analysis was used to identify variables that were associated with the natural logs of albumin-to-creatinine ratio, neuropathy score, and IMT, and logistic regression was used to assess risk factors for retinopathy. RESULTS — Kidney disease was common, with prevalence rates of 44% for microalbuminuria and 16.9% for macroalbuminuria (Table 1). In addition, early neuropathy was prevalent (46.3%), and although 23.3% of the population had some level of retinopathy, PDR was uncommon. The prevalence rates of poor glycemic control, hypertension, current smoking, and elevated LDL cholesterol, DIABETES CARE, VOLUME 28, NUMBER 8, AUGUST 2005
triglyceride, and C-reactive protein each exceeded 50% (Table 1). Linear regression revealed that longer duration of diabetes and elevated A1C were independently associated with higher albumin-to-creatinine ratio (both P ⬍ 0.05). Age and longer diabetes duration were determinants of the log of the neuropathy score (both P ⬍ 0.05), while systolic blood pressure, age, and packyears of smoking were significant determinants of the log of IMT (all P ⬍ 0.05). Duration of diabetes (odds ratio 2.3 [95% CI 1.2– 4.6] per 5-year increase), systolic blood pressure (1.6 [1.1–2.3] per 10mmHg increase), and A1C (1.8 [1.0 –3.4] per 2% increase) were significantly associated with risk of retinopathy using logistic regression.
CONCLUSIONS — The high prevalence rates of both micro- and macroalbuminurua in this study are notable and consistent with previous data suggesting that Aboriginal Canadians may be especially susceptible to the renal complications of diabetes (6,20 –26). The mechanism underlying this elevated renal risk is unknown, although suboptimal glucose and blood pressure control likely play a role. In addition, a variant of the gene encoding angiotensinogen, AGT 235, has been associated with a qualitative measure of microalbuminuria in this population (26). Previous chart review studies in Aboriginal Canadians have documented neuropathy prevalence ranging from 0 to 12% (20 –22,27); these rates are notably lower than the estimate from the 2055
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present study (46.3%). This divergence is likely due to differences in procedures used to measure neuropathy. Cases of diabetic neuropathy recorded in medical charts likely represent only the severest portion of the disease spectrum, whereas the Michigan Neuropathy Screening Instrument will have also detected subjects in the earlier stages of sensory neuropathy (10). Limited data are available on the prevalence of diabetic retinopathy among Aboriginal Canadians. Maberley et al. (28) reported prevalence rates of macular edema, NPDR, and PDR that were remarkably similar to those from the present study (24% NPDR, 5% macular edema, and 2% PDR). The relatively low prevalence rates of PDR and macular edema in this population, especially in light of the high rate of nephropathy, possibly reflect the low median duration of diabetes or the presence of protective genetic factors. The strengths of this study include the high participation rate, the community-based setting, and the use of a wide range of validated, systematically applied exposure and outcome measures. Limitations include the small sample size and the cross-sectional design. Notwithstanding, this study represents the first comprehensive, systematic, and standardized documentation of diabetes complications and associated risk factors among Aboriginal Canadians. In conclusion, in a community-based study of Aboriginal Canadians, we found high prevalence rates of both diabetes complications and associated risk factors and, furthermore, that well-established associations between risk factors and complications were apparent. These results highlight the urgent need to implement culturally appropriate strategies for the prevention of diabetes complications in this population. Acknowledgments — T h i s r e s e a r c h h a s been supported through an operating grant from the Canadian Institutes of Health Research (CIHR) (MOP 4407). A.J.G.H. is supported through a Canadian Diabetes Association Research Scholarship and by a University of Toronto Banting and Best Diabetes Centre New Investigator Award. S.B.H. is a Career Scientist of the Ontario Ministry of Health. J.D.S. was supported by a grant from the Canadian Stroke Network. J.R.M. is an investigator of the CIHR. B.Z.
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holds the Sam and Judy Pencer Family Chair in Diabetes Research at Mount Sinai Hospital and the University of Toronto. We are indebted to the leadership and community members of Sandy Lake First Nation for their enthusiastic partnership and participation in this project. We thank Maria DiCicco, RVT, and Janine Boere, RVT, for performing the carotid artery scans. Finally, we would like to thank the NORTH Network team for their essential contributions to the retinal screening aspects of this project. References 1. Young TK, Reading J, Elias B, O’Neil JD: Type 2 diabetes in Canada’s First nations: status of an epidemic in progress. CMAJ 163:561–566, 2000 2. Harris SB, Gittelsohn J, Hanley AJG, Barnie A, Wolever TMS, Gao XJ, Logan A, Zinman B: The prevalence of NIDDM and associated risk factors in Native Canadians. Diabetes Care 20:185–187, 1997 3. Delisle H, E´koe´ JM: Prevalence of noninsulin dependent diabetes mellitus and impaired glucose tolerance in two Algonquin communities in Quebec. CMAJ 148: 41– 47, 1993 4. Dean HJ, Mundy RL, Moffatt M: Non-insulin dependent diabetes mellitus in Indian children in Manitoba. CMAJ 147:52– 57, 1992 5. Harris SB, Perkins B, Whalen-Brough E: Non-insulin dependent diabetes mellitus among First Nations children: new entity among First Nations people of northwestern Ontario. Can Fam Physician 42:869 – 876, 1996 6. Hanley AJG, Harris SB, Mamakeesick M, Goodwin K, Fiddler E, Hegele RA, McLaughlin JR, Zinman B: Complications of type 2 diabetes among Native Canadians: increasing our understanding of prevalence and risk factors. Can J Diabetes 27:455– 463, 2003 7. Bursell SE, Cavallerano JD, Cavallerano AA, Clermont AC, Birkmire-Peters D, Aiello LP, Aiello LM, the Joslin Vision Network Research Team: Stereo nonmydriatic digital-video color retinal imaging compared with Early Treatment Diabetic Retinopathy Study seven standard field 35-mm stereo color photos for determining level of diabetic retinopathy. Ophthalmology 108:572– 585, 2001 8. Early Treatment Diabetic Retinopathy Study Research Group: Early photocoagulation for diabetic retinopathy: ETDRS report number 9. Ophthalmology 98 (Suppl. 5):766 –785, 1991 9. Varma R, Torres M, Pena F, Klein R, Azen SP, the Los Angeles Latino Eye Study Group: Prevalence of diabetic retinopathy in adult Latinos: the Los Angeles Latino eye study. Ophthalmology 111:1298–1306, 2004
10. Feldman EL, Stevens MJ, Thomas PK, Brown MB, Canal N, Greene DA: A practical two stem clinical and electrophysiological assessment for the diagnosis and staging of diabetic neuropathy. Diabetes Care 17:1281–1289, 1994 11. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee: Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 27 (Suppl. 2):S1– S152, 2003 12. Parsons MP, Newman DJ, Newall RG, Price CP: Validation of a point-of-care assay for the urinary albumin:creatinine ratio. Clin Chem 45:414 – 417, 1999 13. Al-Shali KZ, House AA, Hanley AJ, Khan HM, Harris SB, Zinman B, Mamakeesick M, Fenster A, Spence JD, Hegele RA: Genetic variation in PPARG encoding peroxisome proliferator-activated receptor gamma associated with carotid atherosclerosis. Stroke 2036 –2040, 2004 14. Selzer RH, Hodis HN, Kwong-Fu H, Mack WJ, Lee PL, Liu CR, Liu CH: Evaluation of computerized edge tracking for quantifying intima-media thickness of the common carotid artery from B-mode ultrasound images. Atherosclerosis 111:1–11, 1994 15. Kanters SD, Algra A, van Leeuwen MS, Banga JD: Reproducibility of in vivo carotid intima-media thickness measurements: a review. Stroke 28:665– 671, 1997 16. Rose GA: Cardiovascular Survey Methods. Geneva, World Health Org., 1968 (Monograph Ser., no. 56) 17. Sorlie PD, Cooper L, Schreiner PJ, Rosamond W, Szklo M: Repeatability and validity of the Rose questionnaire for angina pectoris in the Atherosclerosis Risk in Communities Study. J Clin Epidemiol 49: 719 –725, 1996 18. John WG, Edwards R, Price CP: Laboratory evaluation of the DCA 2000 clinic HbA1c immunoassay analyser. Ann Clin Biochem 31:367–370, 1994 19. Connelly PW, Hanley AJG, Harris SB, Hegele RA, Zinman B: The relationship of waist circumference and glycemic status to C-reactive protein in the Sandy Lake Oji-Cree. Int J Obes 27:347–354, 2003 20. Young TK, McIntyre LL, Dooley J, Rodriguez J: Epidemiologic features of diabetes mellitus among Indians in northwestern Ontario and northeastern Manitoba. CMAJ 132:793–797, 1985 21. Macaulay AC, Montour LT, Adelson N: Prevalence of diabetic and atherosclerotic complications among Mohawk Indians of Kahnawake, PQ. CMAJ 139:221–224, 1988 22. Montour LT, Macaulay AC, Adelson N: Diabetes mellitus in Mohawks of Kahnawake, PQ: a clinical and epidemiologic description. CMAJ 141:549 –552, 1989 23. Young TK, Kaufert JM, McKenzie JK,
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Hawkins A, O’Neil J: Excessive burden of end stage renal disease among Canadian Indians: a national survey. Am J Public Health 79:756 –758, 1989 24. Wilson R, Krefting LH, Sutcliffe P, VanBussel L: Incidence and prevalence of end-stage renal disease among Ontario’s James Bay Cree. Can J Public Health 83: 143–146, 1992 25. Dyck RF, Tan L: Rates and outcomes of diabetic end stage renal disease among registered Native people in Saskatchewan. CMAJ 150:203–208, 1994 26. Hegele RA, Harris SB, Hanley AJ, Zinman
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B: Association between AGT T235 variant and microalbuminuria in Canadian OjiCree with type 2 diabetes mellitus. Clin Biochem 32:201–205, 1999 27. Brassard P, Robinson E: Factors associated with glycaemia and microvascular complications among James Bay Cree Indian diabetics of Quebec. Arct Med Res 54:116 – 124, 1995 28. Maberley D, Cruess AF, Barile G, Slakter J: Digital photographic screening for diabetic retinopathy in the James Bay Cree. Ophthalmic Epidemiol 9:169 –178, 2002
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