Epidemiology of Diabetes Dr Joseph Longenecker

Epidemiology of Diabetes Joseph C. Longenecker, MD, MPH, PhD Kuwait University Faculty of Medicine Learner Objectives • To classify and describe the epidemiology of Type 1 and Type 2 diabetes mellitus • To describe the increasing global and local impact of diabetes and the etiologies thereof • To identify the risk factors for Type 1 and for Type 2 diabetes • To understand the concepts of “double burden of disease,” “the thrifty genes hypothesis,” and “the metabolic syndrome” • To enumerate and describe the risk factors for the microvascular and macrovascular complications of diabetes • To identify evidence-based strategies for the primary prevention of diabetes and secondary prevention of its complications, and to name several important clinical trials guiding such strategies Diabetes: Classification • Type 1 Diabetes (old name: IDDM)  ~10% – Beta-cell destruction  absolute insulin deficiency – Most often immune-mediated (Ab against islet cells) • Type 2 Diabetes (old name: NIDDM)  85-90% – Combination of insulin resistance (at the cellular level) and relative insulin deficiency • Other  <2% – – – – – – Gestational Diabetes Genetic defects (Mature-Onset Diabetes of Young: MODY) Pancreatitis (when >80% of exocrine cells destroyed) Endocrinopathies (Cushing, acromegaly, glucagonoma) Drug-induced (pentamidine, steroids) Infections (coxsackie) Incidence of Type 1 and Type 2 Diabetes, by Age Cases of Type 1 Per 1000 per year Cases of Type 2 Per 1000 per year Type 1 DM Type 2 DM 0 10 20 30 40 50 60 70 80 Years of Age Adapted from http://www.gpnotebook.co.uk/cache/973471819.htm Burden of Disease: Diabetes • WHO Global estimates: – 180 million people with diabetes worldwide – Globally, DM accounts for ~1.5% (~800,000) of all deaths, apart from its contribution to CVD – Rapid increase in global diabetes prevalence • • • • • 1980: 30 million 1995: 135 million 2004: 180 million 2010: 221 million 2025: 333 million Global Prevalence of DM, 2000 and 2010, and % Increase, by Region Zimmet, et al, Nature. 414. Dec. 2001 Comparison of the Growth of Diabetes and the World Population (Compared to 1980 population) 12 10 8 6 4 2 1 0 1980 1990 2000 2010 2020 2030 2004: • Diabetics: 180 million • World population: 6.3 billion Developed from WHO data Year The Global Epidemic of Diabetes • The world is in the midst of a global epidemic of DM • The epidemic primarily includes Type 2 DM, but Type 1 DM is also on the rise • Reasons for the epidemic – – – – Ageing of the population Sedentary lifestyle Overweight and obesity Unhealthy diet • While 75% of diabetes currently exists in developed countries, the rate of increase is much higher in developing countries Wide Geographic Variation: Prevalence of DM among Adults in Different Countries Rewers, et al. http://www.uchsc.edu/misc/diabetes/oxch9.html. Type 1 Diabetes (Previously known as “IDDM” or “Juvenile Diabetes) Incidence of Type 1 Diabetes Among Children ≤14 40 36.8 36.5 Incidence of Type 1 DM . (per 100,000-year) . 35 30 25 20 15 10 5 0 ar k Ve ne zu el a Sa rd in ia Fi nl an d La zi o en m C uw K C an da hi na U SA ai t 24.7 16.4 17.3 15.5 6.8 0.1 0.1 D Highest incidence of Type 1 DM: Scandanavian countries Karvonnen et al., Diabetes Care, 23:1516, 2000 But Kuwait among the highest Incidence of Type 1 Diabetes among Arab children ≤14 years old Incidence of DM (# new cases/100,000) . 25.0 20.0 15.0 10.0 5.0 0.0 Oman Jordan Libya Algeria Sudan Saudi Arabia Kuwait Adapted from Shaltout, et al. Diabet. Med. 2002;19:522-525. The Diabetes Epidemic in Kuwait Incidence of Type 1 DM in Children≤14: 1981, 1992, & 1997 >6-fold increase since 1981! 1981 1992 1997 20 15 10 5 0 Boys Girls Total 4.0 14.1 17.4 15.7 24 27.3 25.6 Incidence (# new cases/100,000) . 30 25 Adapted from Shaltout, et al. Diabet. Med. 2002;19:522-525. Genetic Susceptibility to Type 1 DM: Many candidate genes, but MHC has strongest association IDDM IDDM1 Marker MHC Chromosome LOD 6p21.3 11p15.5 6q21 16q 16p* 2q31 1q 2* 5* 65.8, 39.4* 4.28 2.36, 3.12* 4.23 2.34* 2.8 2.62 2.27 2.1* 2.1* IDDM2 Insulin IDDM15 D6S283 D16S3098 Iddm10 Iddm7 10p13-q11 1q42 LOD score: log(p with marker/p without marker) Rewers/Eisenbarth, et al. http://www.uchsc.edu/misc/diabetes/oxch9.html. HLA Types Associated with Type 1 DM HLA type DR3 DR4 DR3/DR4 DR2 Risk of T1DM     Rewers/Eisenbarth, et al. http://www.uchsc.edu/misc/diabetes/oxch9.html. HLA Class II Antigens: Associated with Type 1 DM • The majority of Type 1 DM patients carry DR3 or DR4 or DQ Class II antigens, particularly the HLADQ molecule • 30% of Type 1 DM patients carry both DR3 and DR4 antigens • The incidence of Type 1 DM in DR3+/DR4+ carriers is 1/15, compared to 1/300 overall Familial Risk in Type 1 DM Relationship Monozygotic twin Dizygotic twin/sibling Child of parent with DM Concordance (%) 20-70% 2-8% 2-5% Besser. Comprehensive Clinical Endocrinology. 2002. Auto-Antibodies Associated with Type 1 DM Antibody Islet cell Ab Glutamate Decarboxylase Ab Insulin Ab Prevalence in T1 DM (%) 60-70% 80% 50% Seasonal Variation in Incidence of Type 1 DM • Incidence rate of IDDM spikes in Winter months and is lower in Spring and Summer Study of 1830 new Type 1 diabetes infections in Finland and Sardinia • Winter Spring Summer Fall Winter Karvonen. Diabetes Care. 1998;21(7):1101-1109. Seasonal Variation of Type 1 Diabetes Incidence in Kuwait • • Similar seasonal pattern of incidence in Kuwait 1992-1997 Shaltout, et al. Diabet. Med. 2002;19:522-525. What Does All This Mean? • Evidence favoring genetic causes – Strong association with HLA Class II antigens • Evidence favoring environmental causes – Relatively low concordance among identical twins – Association with auto-antibodies – Seasonal variation Hypothetical Mechanism of the Progression to Type 1 Diabetes Initiators -Virus? -Diet? -Environment Genetic susceptibility Promoters -Virus? -Diet ? -Other genes? Clinical diabetes Autoimmunity No autoimmunity Remission Rewers/Eisenbarth, et al. http://www.uchsc.edu/misc/diabetes/oxch9.html. Type 2 Diabetes (Previously known as “NIDDM” or “AODM”) The Diabetes Epidemic in Kuwait: The Prevalence of Type 2 DM in Kuwait Prevalence of Type 2 DM (%) . Kuwait is among nations with the highest prevalence of Type 2 DM in the world 20 14.8 15 10 5.7 5 0 Overall Men Women Age 20- Age 4039 59 14.7 14.8 18.3 Adapted from Abdella, et al. Diabet. Res. Clin. Pract. 1998;42(3):187-196. Risk Factors for Type 2 Diabetes • Genetic factors (thrifty gene) • Demographic factors – Age – Black/Hispanic ethnicity • Lifestyle factors – Diet – Obesity/Sedentary lifestyle – Westernization/urbanization • Metabolic/other – Insulin resistance/impaired glucose tolerance – Pregnancy Zimmet, et al, Nature. 414. Dec. 2001 Insidious Onset of Type 2 DM Results in Undiagnosed Cases • Onset of Type 2 DM is insidious • It is estimated that only 50% of Type 2 diabetics at any given time have actually been diagnosed • Type 2 DM has traditionally been a disease of adults, but now, the incidence in adolescents is increasing at an alarming rate Age and Prevalence of Diabetes Risk of Type 2 DM, by “Western” Diet and BMI Categories Low fat van Dam, Annals of Internal Medicine. 2002;136:201-209. High fat Prevalence of Type 2 DM Among Chinese in Different Countries in 1999 • Wide range in DM prevalence among Chinese • Prevalence in Singapore doubled from 1984 to 1994! • Suggests that lifestyle plays an important role Zimmet, et al, Nature. 414. Dec. 2001 The Metabolic Syndrome Shaw, et al, MJA. 2003. 179:379 The “Thrifty Genes” Hypothesis • Survival advantage in hunter/gatherer societies: – Rapid weight gain and fat storage during times of plenty – Alternating periods of famine and plenty – “Thrifty” genes may promote rapid fat storage • In modern society, more susceptible to obesity/DM – Continuous food supply – Physical inactivity • The Pima Indians – Traditionally, lean and healthy – Exposed to the high fat diet/sedentary lifestyle – Most are obese, and almost 50% are diabetic! Twin Study of Type 2 DM • NHLBI Twin Study: 250 monozygotic twin pairs born between 1917 and 1927. • If a twin was diabetic, the co-twin had a 58% chance of being diabetic • If the co-twin was not diabetic, he/she had a 68% chance of having hyperglycemia. • Since concordance is not 100%, environmental factors play a role. Newman B, et al, Diabetologia. 1987;30(10):763-768. Complications of Diabetes Complications of DM • Symptoms can be troublesome, but the vascular complications of DM are deadly • Microvascular Complications – Retinopathy  blindness – Nephropathy  ESRD – Peripheral neuropathy • Macrovascular Complications – Coronary heart disease – Stroke – Peripheral artery disease  amputations • Death – 2x higher in those with DM Hyperglycemia and Risk of Micro- and Macrovascular Disease: UKPDS Adjusted incidence per 1000 p-years • UKPDS 35: Prospective study of diabetes complications • 4585 type 2 diabetics • Duration of diabetes 7-12 years • Incidence of macrovascular and microvascular disease 80 60 40 20 0 5 Stratton, et al. BMJ. 321. pp405-412. 6 7 8 9 10 11 Mean HgbA1C Concentration (%) Hyperglycemia and Risk of Death Among Type 2 Diabetics: UKPDS-35 Stratton, et al. BMJ. 321. pp405-412. Diabetes and CVD Death: Interaction with Other CVD Risk Factors CVD Death in Diabetes • Cardiovascular diseases and stroke account for 75% of all deaths among people with diabetes in developed countries. • Diabetes increases the risk of CVD death by 3 to 5 times Primary Prevention of Diabetes Effect of Lifestyle Change on Progression to Type 2 DM • The Finnish Diabetes Prevention Study • 522 overweight Finns • Randomized to intensive lifestyle advice vs. normal care • Followed for up to 6 years for the onset of Type 2 DM Tuomilehto, et al, NEJM. 2001;344:1343-50 Preventing the Complications of Diabetes (Secondary Prevention) Does Treating Hyperglycemia Improve Outcomes? Intensive Insulin for Type 1 DM: DCCT Trial – Prevention of Retinopathy • 1441 Type 1 Diabetics • Randomized to intensive insulin Rx vs. usual insulin dosing • Followed for up to 9 years for the onset of microvascular complications • Not sufficiently large to study macrovascular complications NEJM. 1993 Incidence of sustained retinopathy Intensive Insulin for Type 1 DM: DCCT – Prevention of Microalbuminuria Incidence of microalbuminuria NEJM. 1993 Intensive Insulin for Type 1 DM: DCCT – Prevention of Neuropathy Incidence of Peripheral Neuropathy Solid bars: intensive group Hatched bars: usual Rx group NEJM. 1993 Intensive Glucose Control in Type 2 DM: UKPDS-33 Prev of Microvascular Events • 3867 newly Dx’d Type 2 Diabetics • Randomized to intensive Rx (insulin or oral Rx) vs. usual diet Rx • Followed for up to 15 years for the onset of complications Usual Intensive Lancet. 1998; 352:837-53. 25% Risk Reduction For Microvascular Events Intensive Glucose Control in Type 2 DM: UKPDS-33 Prev of Macrovascular Events Endpoint All-cause mortality MI Stroke PVD/amputation RR 0.94 0.84 1.11 0.65 p-value 0.44 0.052 0.52 0.15 No clear reduction in CVD events in UKPDS-33 Future large studies are needed Lancet. 1998; 352:837-53. Does Treating Hypertension Improve Outcomes? “Tight” Vs. “Less Tight” BP Control Among 1148 Type 2 Diabetics with HTN 1.6 1.4 RR of Outcome . 1.2 1 0.8 0.6 0.4 0.2 0 All Diabetes Total death mortality MI Stroke PVD Microvascular Adapted from UKPDS-38; BMJ. 317:703-713; Participants given ACE-I or B-blocker ACE-Inhibitor Therapy and Prevention in Diabetes: The MICRO-HOPE Trial Myocardial Infarction Stroke Cardiovascular Death P=0.01 P=0.007 P<0.001 22% Reduction 33% Reduction 37% Reduction • 3577 Type 2 Diabetics, age 55+ • All participants either had a Hx of CVD or at least one other risk factor for CVD (and not taking any ACE inhibitors) • Randomized to ramipril or placebo • Followed for up to 6 years for the onset of complications Lancet. 2000;355:253-59. Does Treating Hyperlipidemia Improve Outcomes? Simvastatin for CVD Prevention in DM: MRC/BHF Heart Protection Study • 5963 UK diabetic adults with cholesterol > 135 mg/dl (3.5 mmol/L) • Randomized to receive simvastatin vs. placebo • Followed for major vascular endpoints (MI, CABG, PTCA, stroke, PVD) 24% Reduction Preventive Approach in Diabetes • Weight loss and exercise are key “therapy”  they improve all metabolic derangements • Aggressive antihypertensive therapy is needed in those with concomitant HTN. • Treatment with ACE Inhibitors in patients with microalbuminuria or with other CVD risk factors reduces renal and CVD risk Source: Fuster, et al. Hurst’s The Heart. 2001 Preventive Approach in Diabetes • Aggressive lipid management (to an LDL-C <100 mg/dl) in diabetics reduces CHD significantly. • Treating hyperglycemia in diabetics reduces microvascular diseases, but does not appear to have a marked effect on macrovascular diseases. • Treating HTN and hyperlipidemia have a greater effect on reducing macrovascular disease than does treating the hyperglycemia Thank you for your attention Can Medical Therapy in DM Reduce Cardiovascular Risk? • UGDP (University Group Diabetes Program), 1970 – Large RCT of sulfonylurea in Type 2 DM  Rx was a/w increased CHD! Created a firestorm of controversy • DCCT (Diabetes Control/Complications Trial), 1993 – Intensive insulin Rx vs. usual insulin Rx in Type 1 DM • UKPDS-33 (UK Prospective Diabetes Study), 1998 – Intensive Rx vs. diet control in Type 2 DM • UKPDS-38: tight vs. less tight BP control (Type 2 DM), 1998 • MICRO-HOPE (Microalbuminuria/Heath Outcomes Prevention Evaluation Study): ramipril vs. placebo (Type 2 DM), 2000 • Heart Protection Study: simvistatin vs placebo (Type 2 DM), 2003 Source: Fuster, et al. Hurst’s The Heart. 2001 Characteristics of Adolescents at Diagnosis with Type 2 Diabetes • Most are minority children (AA, AI, H) • More girls than boys (F:M ratio = 1.7-3.0) • Mean age: 13 years • > 80% have a history of diabetes in a first degree relative • Obese (Average BMI > 30) Rewers/Eisenbarth, et al. http://www.uchsc.edu/misc/diabetes/oxch9.html. Inherited Susceptibility Loci for T1 DM LOCUS IDDM1 IDDM2 IDDM3 IDDM4 IDDM5 IDDM6 IDDM7 IDDM8 IDDM9 IDDM10 IDDM11 IDDM12 IDDM13 OTHERS CHROMOSOME 6p21 11p15 15q26 11q13 6q24-27 18q12-q21 2q31 6q25-27 3q21-25 10p11-q11 14q24.3-q31 2q33 2q34 CANDIDATE GENES/MICROSATELLITES HLA-DQ\DR INS VNTR D15s107 MDU1, ZFM1, RT6, FADD/MORT1 ESR, MnSOD D18s487, D18s64, JK (Kidd locus) D2s152, IL-1, NEUROD, GALNT3 D6s264, D6s446, D6s281 D3s1303 D10s193, D10s208, D10s588 D14s67 CTLA-4, CD28 D2s137, D2s164, IGFBP2, IGFBP5 Rewers/Eisenbarth, et al. http://www.uchsc.edu/misc/diabetes/oxch9.html. Control of Hyperglycemia among US Type 2 Diabetics, 2000: NHANES III Percent of Type 2 Diabetics (%) . 45 40 35 30 25 20 15 10 5 0 37 26 37 <7.0 7.0-8.0 HgbA1C Level (%) >8.0 Saydah, et al. JAMA. 2004 . New Epidemic of Type 2 Diabetes in Adolescents Cases of Type 1 Per 100 per year Cases of Type 2 Per 100 per year Type 1 DM Type 2 DM 0 10 20 30 40 50 60 70 80 Years of Age Adapted from http://www.gpnotebook.co.uk/cache/973471819.htm