1. Risk of Type 2 Diabetes and It’s Complications Along The Continuum of Fasting Plasma Glucose Gregory A. Nichols, PhD Collaborative Diabetes Education Conference for Health Professionals January 30, 2010

2. Disclosures  Employed by Kaiser Permanente Center for Health Research, Portland, Oregon  Government Research Funding: –National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK) –Agency for Healthcare Research and Quality (AHRQ)  Industry Funding: –GlaxoSmithKline –Novo Nordisk –Novartis Pharmaceuticals –Tethys Bioscience –Takeda Pharmaceuticals North America

3. Overview  Part I - Diabetes and “Pre-diabetes”  Part II - Fasting Glucose as a Diabetes Risk Factor  Part III – Nondiabetic Fasting Glucose as a Risk Factor for Complications of Diabetes

4. Part I Diabetes and “Pre-diabetes”  A brief history of the definition of a diabetes diagnosis  Defining other forms of dysglycemia

5. Diagnosing Diabetes  Oral Glucose Tolerance Test (OGTT)  2-hour post-load > 200mg/dl  Fasting Plasma Glucose (FPG)  Prior to 1997, > 140 mg/dl  Now, > 126 mg/dl  HbA1c > 6.5% (as of 2010)  These tests measure different things and often identify different people

6. Other Forms of Dysglycemia (“Pre-Diabetes”)  Impaired Glucose Tolerance (IGT)  OGTT 2-hour post-load 140 - 199 mg/dl  Impaired Fasting Glucose (IFG)  From 1997-2003, 110 - 125 mg/dl  Since 2003, 100 - 125 mg/dl  HbA1c 5.7 – 6.4%

7. Summary of Part I  Diabetes is a “category” on the continuum of glucose and is based on the point at which risk of diabetic retinopathy becomes elevated  IFG and IGT are categories on the continuum of glucose that were designed to represent increased risk of developing diabetes

8. Part II - Fasting Glucose as a Diabetes Risk Factor  Impaired Fasting Glucose (IFG) and Risk of Diabetes  Normal Plasma Glucose and Risk of Diabetes  Glucose, other Risk Factors, and Risk of Diabetes

9. Risk of Progression From IFG to Diabetes Population Years of F/U Isolated IFG IFG & IGT Hoorn Study (1998)Dutch5.8-6.533.0%64.5% Paris Prospective Study (2001)French2.52.7%14.9% Vaccaro et al. (1999)Italian11.59.1%44.4% Shaw et al. (1999)Mauritius5.021.6%-- Gabir et al. (2000) Pima Indians5.0--41.2% Gimeno et al. (1998) Brazilian- Japanese7.0--72.7% Baltimore Longitudinal Study on Aging (2003)U.S.10.0--25.0%

11. Sample Selection  28,335 KPNW non-diabetic members with at least two FPG tests 100-125 mg/dl between 1994 and 2003  5,452 with a prior test < 100 mg/dl  4,526 had first abnormal value 100-109  926 had first abnormal value 110-125  Follow-up through 12/31/05

12. Study Sample Added IFG (100-109 mg/dl) Original IFG (110-125 mg/dl)p value Number (%) of Subjects4,526 (83.0%)926 (17.0%)-- Age at IFG Incidence59.7 (11.1)57.9 (11.6)<0.0001 Percent Female48.1%53.9%0.001 Systolic Blood Pressure134 (13)136 (13)0.017 Diastolic Blood Pressure79 (7)80 (7)0.033 Body Mass Index31.0 (6.3)33.2 (7.2)<0.0001 HDL Cholesterol51 (15)48 (14)<0.0001 Triglycerides190 (215)212 (138)0.004 LDL Cholesterol126 (30)121 (31)<0.0001 Nichols et al., Diabetes Care 2007;30:228-233

13. Nichols et al., Diabetes Care 2007;30:228-233.

14. Proportion of Subjects Progressing to Diabetes, Months Until Progression, and Rate of Progression, by IFG Stage Did Not Progress to Original IFG Progressed to Original IFG Total Initial IFG Stage was Added IFG Initial IFG Stage was Original IFG Total Total, All Subjects n (%) (%)3,753(82.9%)773(17.1%)4,526773(45.5%)926(54.5%)1,6995,452 Progressed to Diabetes 201(5.4%)164(21.2%)365(8.1%)164(21.2%)249(26.8%)413(24.3%)614(11.3%) Mean (SD) Months from 1 st FPG Measure to Progression to Diabetes 31.1(23.2)54.1(27.6)41.4(25.8)29.5(25.9)28.7(26.5)29.0(26.2)36.3(27.9) Diabetes Incidence per Year 0.913.241.345.165.875.561.95 Added IFG (100-109 mg/dL)Original IFG (110-125 mg/dL) Nichols et al., Diabetes Care 2007;30:228-233.

15. Predictors of Progression to Diabetes Risk Ratio95% CIp valueRisk Ratio95% CIp value Progressed to Original IFG3.112.43 – 3.98<0.0001-- Initially Added IFG-- 1.120.88 - 1.420.352 Initial FPG (per mg/dl)1.081.04 - 1.130.00031.071.04 - 1.10<0.0001 Age (per 10 Years)0.920.86 - 0.990.0200.920.87 – 0.980.015 Female Sex1.471.11 - 1.930.0071.331.02 - 1.720.032 Current Smoker1.511.15 - 1.990.0031.170.89 - 1.530.255 BMI (per kg/m 2 )1.041.02 - 1.06<0.00011.031.02 - 1.05<0.0001 Systolic BP (per 5mmHg)1.101.04 - 1.16<0.00011.081.03 - 1.140.001 HDL-C (per 5mg/dl)0.880.83 - 0.93<0.00010.880.84 - 0.93<0.0001 LDL-C (per 5mg/dl)0.970.95 - 0.990.0030.990.97 - 1.010.411 Triglycerides (per 50mg/dl)1.011.00 - 1.020.0261.031.01 - 1.040.0003 Progression from IFG 100-109Progression from IFG 110-125 Adapted from Nichols et al., Diabetes Care 2007;30:228-233

16. Summary  Patients with IFG progress to diabetes at a rate of 1.3-5.6% per year  Those who progress do so in 29-59 months, and more rapid progression prior to diabetes is a warning sign  High BMI and low HDL-C are the strongest non- glucose predictors of progression  Each mg/dl of fasting glucose increases risk of progression to diabetes by 7-8%

17. Next Question Does the apparently linear relationship between fasting glucose and progression to diabetes extend below 100 mg/dl?

19. Sample Selection  46,578 KPNW members with FPG < 100 mg/dl between 1997 and 2000  No diabetes or previous FPG > 100 mg/dl  Categories of baseline FPG:  < 85 mg/dl  85-89 mg/dl  90-94 mg/dl  95-99 mg/dl  Followed through 4/30/07 for development of diabetes (mean of 81 months)

20. Study Sample < 85 mg/dL 85-89 mg/dL 90-94 mg/dL 95-99 mg/dL n (%) 8,705 (18.7%) 10,983 (23.6%) 13,704 (29.4%) 13,186 (28.3%) Age*55.4 (11.0)56.6 (10.7)57.8 (11.0)59.1 (11.1) % Male*28.7%35.5%42.9%49.4% BMI*28.0 (5.8)28.6 (5.8)29.2 (5.9)29.9 (6.0) Systolic BP*128 (19)130 (18)131 (19)134 (19) Diastolic BP *79 (10) 80 (10)81 (10) HDL-Cholesterol*57 (17)56 (17)54 (16)52 (16) LDL-Cholesterol*123 (34)126 (34)129 (35)130 (34) Triglycerides*142 (122)147 (115)156 (106)164 (114) Adapted from Nichols et al., Am J Med 2008;121:519-524

21. Cumulative Diabetes Incidence by Category of Normal Fasting Glucose Nichols et al., Am J Med 2008;121:519-524

22. Hazard Ratios of Diabetes Incidence Adjusted for Risk Factors Nichols et al., Am J Med 2008;121:519-524.

23. Cox Regression of Diabetes Incidence (Continuous FPG) Hazard Ratio95% CIp value Fasting Plasma Glucose (per mg/dL)1.061.05 - 1.07<0.0001 Age (per year)1.011.00 - 1.02<0.001 Male Sex1.010.90 - 1.130.837 BMI (per kg/m 2 )1.081.07 - 1.09<0.0001 Systolic BP (per 5 mmHg)1.021.01 - 1.030.008 HDL-Cholesterol (per 5 mg/dL)0.900.88 - 0.92<0.0001 LDL-Cholesterol (per 10 mg/dL)0.970.96 - 0.990.0001 Triglycerides (per 50 mg/dL)1.091.07 - 1.10<0.0001 Current Smoker1.371.22 - 1.54<0.0001 Diagnosed Cardiovascular Disease1.651.40 - 1.93<0.0001 Diagnosed Hypertension1.511.35 - 1.68<0.0001 Nichols et al., Am J Med 2008;121:519-524

24. Characteristics of Patients Who Developed Diabetes < 85 mg/dL85-89 mg/dL90-94 mg/dL95-99 mg/dL Age56.6 (9.7)57.4 (9.5)58.7 (10.4)59.1 (10.5) % Male42.9%45.5%46.5%49.8% BMI32.7 (6.7)33.5 (7.2)33.4 (7.3)33.0 (6.8) Systolic BP134 (18)137 (18)136 (20)136 (19)% Diastolic BP82 (10)82 (11) 82 (10) HDL-Cholesterol49 (15)46 (15)47 (14) LDL-Cholesterol123 (37)124 (36)127 (37)125 (34) Triglycerides239 (364)213 (257)212 (149)209 (131) Current Smoker27.4%25.8%25.0%22.0% Cardiovascular Disease9.7%8.3%11.9%11.7% Hypertension41.1%49.6%43.7%43.6% Months to Diabetes59.0 (28.3)54.6 (28.3)54.4 (28.3)53.8 (29.9) Mean FPG at Diagnosis150 (63)145 (52)141 (53)142 (51) Adapted from Nichols et al., Am J Med 2008;121:519-524

25. Characteristics of Patients who Did and Did Not Develop Diabetes Developed DiabetesNo Diabetesp value Age58.5 (10.3)57.4 (10.9)<0.0001 % Male47.6%40.1%<0.0001 BMI33.2 (7.0)28.8 (5.8)<0.0001 Systolic BP136 (19)131 (19)<0.0001 Diastolic BP82 (10)80 (10)<0.0001 HDL-Cholesterol47 (14)54 (16)<0.0001 LDL-Cholesterol125 (36)128 (34)0.005 Triglycerides213 (191)151 (109)<0.0001 Current Smoker23.9%20.2%<0.001 Cardiovascular Disease11.1%6.0%<0.0001 Hypertension44.2%25.8%<0.0001 Nichols et al., Am J Med 2008;121:519-524

26. Summary  Elevated risk of diabetes is associated with higher values of “normal” fasting glucose, perhaps to as low as 87 mg/dl  The 6% increase in risk per mg/dl was similar to the 7% found among patients with IFG  The same risk factors consistently predict diabetes regardless of FPG

27. Diabetes Risk and The Metabolic Syndrome  Fasting Glucose > 100 mg/dl  BP > 130/85 mmHg  Triglycerides > 150 mg/dl  HDL-C < 40/50 mg/dl  Waist circumference > 102/88 cm

30. Summary of Part II  Risk of diabetes associated with fasting glucose is continuous  Other metabolic risk factors that are commonly associated with elevated glucose play important but largely supplementary roles

31. Part III – Nondiabetic Fasting Glucose as a Risk Factor for Complications of Diabetes  Cardiovascular Disease  Microvascular Diseases:  Nephropathy  Retinopathy  Neuropathy  Heart Failure  Medical Costs

32. Glucose and CVD Events  Fasting glucose is (probably) associated with CVD  Coutinho et al. (1999): 20 studies, RR 1.33 (1.06- 1.67) for 75 vs. 110 mg/dl  Levitan et al. (2004): 34 studies, RR 1.27 (1.13- 1.43) comparing top and bottom categories, possible threshold effect at 100 mg/dl  Danaei et al. (2006): 1 in 5 deaths from ischemic heart disease are attributable to higher-than- optimum blood glucose excluding deaths attributable to diabetes

33. Glucose and Microvascular Disease  No data on neuropathy  Diabetes diagnosis based on increased prevalence of retinopathy, which is present for up to 7 years prior to diagnosis  Cox et al. (2005) - No relationship between IFG/IGT and CKD, but strong association with diabetes

34. IFG and Heart Failure  FPG test in 1997 or 1998 < 126mg/dl  Age 50 or older and no evidence of diabetes or CHF  10,113 subjects with IFG (100-125mg/dl)  10,113 subjects with glucose < 100mg/dl matched on sex and 5-year age group  Followed for ~6.5 years

35. IFG and Heart Failure Nichols et al., Journal of Diabetes and Its Complications 2009;23:224-228

36. IFG and Heart Failure (2) Nichols et al., Journal of Diabetes and Its Complications 2009;23:224-228

37. Comorbidities and Risk of Diabetes IFG (n=15,732) NPG (n=40,962) Relative Risk of Diabetes* Cardiovascular Disease 18.5%11.6%1.69(1.58-1.82) Chronic Kidney Disease 8.7%6.7%1.45(1.32-1.60) Heart Failure 3.4%1.8%2.13(1.88-2.41) History of Depression 20.5%20.6%1.41(1.32-1.50) *Controlling for fasting plasma glucose

38. Medical Care Costs  Diabetes is enormously expensive  If a diabetes diagnosis is an arbitrary point on a continuum of glucose, then wouldn’t costs also be elevated at sub- diabetic levels of hyperglycemia (relative to those with normal glycemia)?

39. Incremental Cost of Diabetes Before and After Diagnosis Nichols et al. Diabetes Care 2000;23:1654-1658

40. Costs of Impaired Fasting Glucose Nichols and Brown, Diabetes Care 2005;28:2223-2229

41. Costs of Impaired Fasting Glucose (2) Nichols and Brown, Diabetes Care 2005;28:2223-2229

42. Incremental Costs of Normal Fasting Glucose Nichols and Brown, ADA 65 th Scientific Sessions;2005:Abstract #117-OR

43. Summary  The risk of developing diabetes is strongly associated with level of fasting glucose  That risk is continuous, or at least extends well below the point at which glucose is considered abnormal

44. Summary (2)  Other metabolic risk factors that are commonly associated with elevated glucose play important but largely supplementary roles  Non-diabetic levels of glucose increase the risk of “diabetic” complications as well as costs of medical care

45. Conclusion  The relationships between glucose, other metabolic disturbances, diabetes, and it’s complications are complex and confounded  Categorizing glucose helps us understand these interrelationships, but limits our ability to predict risk