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Management of Common Comorbidities in Diabetes

Management of Common Comorbidities in Diabetes. Management of Common Comorbidities in Diabetes. Obesity. Prevalence of Obesity in Type 2 Diabetes. NHANES 1999-2004 (N=984). Normal (BMI <25). 12%. Overweight (BMI 25-29). 27%. T2DM Patients (%). Obese (BMI ≥30). 61%.

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Management of Common Comorbidities in Diabetes

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  1. Management of Common Comorbidities in Diabetes

  2. Management of Common Comorbidities in Diabetes Obesity

  3. Prevalence of Obesity inType 2 Diabetes NHANES 1999-2004 (N=984) Normal (BMI <25) 12% Overweight(BMI 25-29) 27% T2DM Patients (%) Obese(BMI ≥30) 61% BMI, body mass index, in kg/m2. Suh DC, et al. J Diabetes Complications. 2010;24:382-391.

  4. Consequences of Obesity in Diabetes • Increases risk of cardiovascular comorbidities • Hypertension • Dyslipidemia • Atherosclerosis • May limit ability to engage in physical activity • Increases insulin resistance • Worsens glucose tolerance • Necessitates higher exogenous insulin doses • Changes neuroendocrine signaling and metabolism • Reduces quality of life Goal: 5% to 10% weight loss Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

  5. Energy Homeostasis Body Weight Increase Decrease Energy intake Ingestion of: Proteins Fats Carbohydrates Energy expenditure Physical activity Diet-induced thermogenesis Basal metabolic rate

  6. Vagal afferents Hypothalamus GI tract Adipose tissue Ghrelin Hindbrain CCK Leptin PYY3-36 Insulin GLP-1 Amylin Resistin Visfatin OXM Adiponectin GIP Pancreatic islets PP Multihormonal Control of Body Weight: Fat-, Gut-, and Islet-Derived Signals Badman MK, et al. Science. 2005;307(5717):1909-1914.

  7. Small Amounts of Weight Gain or Loss Have Important Effects on CHD Risk Framingham Offspring Study 16-year Follow-up* ** ** Change in Risk Factor Sum (%) ** ** *Patients with Low HDL-C, high cholesterol, high BMI, high systolic BP, high triglyceride, high glucose. **P <0.002 vs baseline. Wilson PW, et al. Arch Intern Med. 1999;159:1104-1109.

  8. Abdominal Obesity and Increased Risk of Cardiovascular Events The HOPE Study Waist Circumference (cm) Men Women Tertile 1 <95 <87 Tertile 2 95-103 87-98 Tertile 3 >103 >98 *Adjusted for BMI, age, smoking, sex, CVD disease, DM, HDL-cholesterol, total-C; CVD: cardiovascular disease; MI: myocardial infarction; BMI: body mass index; DM: diabetes mellitus; HDL: high-density lipoprotein cholesterol. Dagenais GR, et al. Am Heart J.  2005;149:54-60.

  9. Medical Complications of Obesity Pulmonary disease Abnormal function Obstructive sleep apnea Hypoventilation syndrome Idiopathic intracranial hypertension Stroke Cataracts Nonalcoholic fatty liver disease Steatohepatitis Cirrhosis Coronary heart disease Diabetes Dyslipidemia Hypertension Gall bladder disease Severe pancreatitis Gynecologic abnormalities Abnormal menses Infertility Polycystic ovary syndrome (PCOS) Cancer Breast, uterus, cervix, colon, esophagus, kidney, pancreas, prostate Phlebitis Venous stasis Osteoarthritis Skin Gout

  10. Health Effects of Weight Change in T2DM • Weight loss • Every kg of weight loss is associated with 3-4 months of improved survival1 • In a prospective analysis of 5000 people with type 2 diabetes, 35% reported intentional weight loss; this subgroup experienced a 25% reduction in mortality over 12 years2 • Weight gain • A 5-kg weight gain increases CHD risk by 30%3 1. Lean ME, et al. Diabet Med. 1990;7:228-233. 2. Williamson DF, et al. Diabetes Care. 2000;23:1499-1503. 3. Anderson JW, et al. J Am Coll Nutr. 2003;22:331-339.

  11. AACE Healthful Eating Recommendations Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

  12. AACE Physical Activity Recommendations • Evaluate for contraindications and/or limitations to increased physical activity before patient begins or intensifies exercise program • Develop exercise recommendations according to individual goals and limitations • ≥150 minutes per week of moderate-intensity exercise • Flexibility and strength training • Aerobic exercise (eg, brisk walking) • Start slowly and build up gradually Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53.

  13. Weight Gain/Loss Potential with Antidiabetic Agents Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. Rodbard HW, et al. Endocr Pract. 2009;15:540-559. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Stenlof K, et al. Diabetes Obes Metab 2013;15:372-382.

  14. Management of Common Comorbidities in Diabetes Dyslipidemia

  15. Prevalence of Hyperlipidemia in T2DM Retrospective Medical Database Study, T2DM (N=125,464) NHANEST2DM Patients With Hyperlipidemia* 1%, No need for treatment 63% Receiving statin 35% Eligible for lipid-lowering therapy but untreated *LDL-C ≥100 mg/dL, TC≥200 mg/dL, or TG≥150 mg/dL (treatment not assessed). Fu AZ, et al. Curr Med Res Opin. 2011;27:1035-1040. Suh DC, et al. J Diabetes Complications. 2010;24:382-391.

  16. Atherogenic Dyslipidemia • Common in T2DM and the insulin resistance syndrome • Features • Elevated triglycerides • Decreased HDL-C • Small, dense LDL particles • Postprandial increase in triglyceride-rich lipoproteins HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein. Jellinger PS, et al. Endocr Pract. 2012;18(suppl 1):1-78.

  17. Dyslipidemia Treatment Options HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein. Jellinger PS, et al. Endocr Pract. 2012;18(suppl 1):1-78.

  18. Benefits of Aggressive LDL-C Lowering in Diabetes Primary event rate (%) Aggressive lipid-loweringbetter Aggressive lipid-lowering worse Difference in LDL-C(mg/dL) Treatment Control P TNT Diabetes, CHD ASCOT-LLA Diabetes, HTN CARDS Diabetes, no CVD HPS All diabetes Diabetes, no CVD 13.8 9.2 5.8 9.4 9.3 17.9 11.9 9.0 12.6 13.5 0.026 0.036 0.001 <0.0001 0.0003 22* 35† 46† 39† 39† 0.75 0.77 0.63 0.73 0.67 0.5 0.7 0.9 1 1.7 *Atorvastatin 10 vs 80 mg/day †Statin vs placebo Relative risk Shepherd J, et al. Diabetes Care. 2006;29:1220-1226. Sever PS, et al. Diabetes Care. 2005;28:1151-1157.Colhoun HM, et al. Lancet. 2004;364:685-696. HPS Collaborative Group. Lancet. 2003;361:2005-2016.

  19. Randomized Trials of Statins: A Meta-Analysis of CV Events Patients with Diabetes (N=18,686; 14 RCTs) Risk Reduction in Major Vascular Events per mmol/L Decrease in LDL-C Cholesterol Treatment Trialists’ Collaborators. Lancet. 2008;371:117-125.

  20. Treat Patients With the Greatest Absolute Risk the Most Aggressively Robinson JG, et al. Am J Cardiol. 2006;98:1405-1408.

  21. Residual Cardiovascular Risk in Major Statin Trials CHD events still occur in patients treated with statins Secondary Primary LIPID CARE HPS CARDS TotalPopulation(%) N = 9014 4159 20,536 2841  LDL-C -25% -28% -29% -40% Patients with Diabetes(%) N = 782 586 5963 2841 LIPID Study Group. N Engl J Med. 1998;339:1349-1357. Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.HPS Collaborative Group. Lancet. 2002;360:7-22. Colhoun HM, et al. Lancet. 2004:364:685-696.

  22. Lipid Effects of Adding a Fenofibrate to a Statin in Patients With T2DM Action to Control Cardiovascular Risk in Diabetes (N=5518) ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.

  23. Effects of Adding a Fenofibrate to a Statin on CV Events in Patients With T2DM Action to Control Cardiovascular Risk in Diabetes (N=5518) ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.

  24. Adding a Fenofibrate to a Statin in Patients With T2DM: Subgroup Analyses Action to Control Cardiovascular Risk in Diabetes (N=5518) ACCORD Study Group. N Engl J Med. 2010;362:1563-1574.

  25. Effect of Fenofibrate on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes Diabetes Atherosclerosis Intervention Study * Change in Stenosis (%) (n=207) (n=211) *P=0.02 vs placebo Diabetes Atherosclerosis Intervention Study. Lancet. 2001;357:905-910.

  26. Coronary Drug Project:15-Year Follow-up 11% Reduction P =0.0004 Event Rate (%) 12% Reduction P <0.05 Canner PL, et al. J Am Coll Cardiol. 1986;8:1245-1255. Canner PL, et al. J Am Coll Cardiol. 2005;95:254-257.

  27. Dyslipidemia Summary • Patients with diabetes and insulin resistance syndrome have atherogenic dyslipidemia and an increased risk for CVD • Although statin therapy is effective in lowering LDL-C, residual CVD risk remains after statin therapy • To reduce residual CVD risk, lipid abnormalities beyond LDL-C (non–HDL-C, triglycerides,HDL-C) should be intensively treated CVD, cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. Jellinger PS, et al. Endocr Pract. 2012;18(suppl 1):1-78.

  28. Management of Common Comorbidities in Diabetes Hypertension

  29. Meta-Regression Analysis of Major CV Events and BP Reduction 2.0 1.0 Relative Risk 0.5 Reduction in risk per 5 mm Hg reduction in SBP Age <65: 11.9% (5.3% to 18.0%) Age >65: 9.1% (3.6% to 14.3%) P for heterogeneity of slopes = 0.38 0.25 -15 -12 - 9 -6 -3 0 3 6 Difference in reduction in systolic BP (mm Hg) BPLTTC. BMJ. 2008;336:1121-1123.

  30. BP Reduction and Effect on CV Mortality at 4 Years Hypertension Optimal Treatment Trial The lower the target BP in patients with diabetes,the lower the rates of CV events and CV deaths Major CV Events CV Deaths DBP ≤ 90 DBP ≤85 DBP ≤ 80 P=0.005 P=0.016 51% Events per 1000 Patient-years Events per 1000 Patient-years P=0.50 67% P=0.49 n=1501 n=18,790 n=1501 n=18,790 DBP, diastolic blood pressure, in mmHg. Hansson L, et al. Lancet. 1998;351:1755-1762.

  31. Blood Pressure and Diabetic Complications United Kingdom Prospective Diabetes Study 10 10 P<0.0001 P<0.0001 Myocardial InfarctionHazard Ratio Microvascular ComplicationsHazard Ratio 12% Decreaseper 10 mmHg reduction in SBP 13% Decreaseper 10 mmHg reduction in SBP 1 1 0.5 0.5 Updated Mean A1C Updated Mean A1C 140 140 110 110 120 120 130 130 150 150 160 160 170 170 Adler Al, et al. BMJ. 2000;321:412-419.

  32. BP Reductions and Risk of Micro- and Macrovascular Complications in T2DM United Kingdom Prospective Diabetes Study Benefits of 144/82 vs. 154/87 mm Hg (N=1148) Any diabetes-related endpoint Vision deterior-ation Diabetes-related death Renal failure Heart failure Myocardial infarction Stroke Retinopathy P=0.13 Risk Reduction (%) P=0.005 P=0.019 P=0.004 P=0.29 P=0.013 P=0.004 P=0.004 UKPDS Group. BMJ. 1998;317:703-713.

  33. Effect of Intensive Blood-Pressure Control on CV Outcomes and Death in T2DM Action to Control Cardiovascular Risk in Diabetes (N=4733) ACCORD Study Group. N Engl J Med. 2010;362:1575-1585.

  34. Long-Term Follow-up After Tight Control of Blood Pressure in T2DM UKPDS Post-monitoring Study • BP became similar within 2 years of trial termination (mainly due to increased BP in tight control group) • Relative risk reductions achieved with tight BP control during the trial were not sustained for: • Any diabetes-related end point • Diabetes-related death • Microvascular disease • Stroke • Peripheral vascular disease risk reduction became significant during the follow-up (P = 0.02) Good BP control must be continued if benefits are to be maintained Any Diabetes-related Endpoint Holman RR, et al. N Engl J Med. 2008;359;1565-1576.

  35. Intensive Blood Pressure Control in T2DM Action to Control Cardiovascular Risk in Diabetes (N=4733) ACCORD Study Group. N Engl J Med. 2010;362:1575-1585.

  36. Multiple Antihypertensive Agents Are Usually Required to Achieve BP Control ABCD, Appropriate Blood pressure Control in Diabetes trial; DBP, diastolic blood pressure, in mm Hg; HOT, Hypertension Optimal Treatment trial; IDNT, Irbesartan in Diabetic Nephropathy trial; IRMA-2, Irbesartan Microalbuminuria Type 2 Diabetes in Hypertensive Patients trial; RENAAL, Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan study; UKPDS, United Kingdom Prospective Diabetes Study. Bakris G, et al. Am J Kidney Dis. 2000;36:646-661.

  37. Compelling Indications for Individual Drug Classes Aldo ANT = aldosterone antagonist. Chobanian AV, et al. Hypertension. 2003;42:1206-1252.

  38. Bradykinin AT1 NO, PGI2 AT2 The Renin Angiotensin System: ACE Inhibition ACEI Angiotensin I ACE-independent formation of ANG II ACE Angiotensin II B2 Vasoconstriction Proliferation Aldosterone Sympathetic NS NaCl retention Inflammation Apoptosis Antiproliferation Differentiation Regeneration Anti-inflammation Apoptosis? Vasodilation, etc NO Vasodilation Tissue protection Unger T, et al. Am J Cardiol. 2007;100:25J-31J.

  39. AT1 NO, PGI2 AT2 The Renin Angiotensin System: AT1 Blockade Angiotensin I ARB ACE Angiotensin II B2 Vasoconstriction Proliferation Aldosterone Sympathetic NS NaCl retention Inflammation Apoptosis Antiproliferation Differentiation Regeneration Anti-inflammation Apoptosis? Vasodilation, etc NO Vasodilation Tissue protection Unger T, et al. Am J Cardiol. 2007;100:25J-31J.

  40. MI Risk With ACEIs and ARBs 0.51.0 2.0 favors 2nd listed favors 1st listed Odds Ratio Volpe M, et al. J Hypertension. 2009;27:941-946.

  41. Hypertension Summary • In T2DM, blood pressure lowering has the greatest and most immediate effect on morbidity and morality • The recommended BP target for patients with diabetes is 130/80 mm Hg • Multiple agents are usually required to achieve target BP • BP treatment must be continued for benefits to be maintained • An ACE inhibitor or ARB should be included in the BP-control regimens of patients with diabetes because of beneficial effects on the renin-angiotensin system Torre JJ, et al. Endocr Pract. 2006;12:193-222.

  42. Management of Common Comorbidities in Diabetes Chronic Kidney Disease

  43. Reducing A1C Reduces Nephropathy Riskin T2DM *Intensive vs standard glucose control. UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:837-853.ADVANCE Collaborative Group. N Engl J Med. 2008;358:2560-2572.Ismail-Beigi F, et al. Lancet. 2010;376:419-430.

  44. Prevalence of CKD in Diagnosed Diabetes Diabetic Kidney Disease Is the Leading Cause of Kidney Failure in the United States *Pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. ESRD, end-stage renal disease; GFR, glomerular filtration rate (mL/min/1.73 m2); NKF, National Kidney Foundation. CDC. National diabetes fact sheet, 2011. http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf. Plantinga LC, et al. Clin J Am Soc Nephrol. 2010;5:673-682.

  45. Cardiovascular Outcomes Worsen With CKD Progression Valsartan in Acute Myocardial Infarction Trial (N=14,527*) eGFR (mL/min/1.73 m2) 75 † 60-74 45-59 <45 † † † † † *23% of patients had diabetes.†P<0.001 vs GFR ≥75 by Cox model. CHF, congestive heart failure; CV, cardiovascular. Anavekar NS, et al. N Engl J Med. 2004;351:1285-1295.

  46. x 2.8 x 2.0 x 2.1 x 1.7 x 2.5 x 2.3 CV Risk Increases With Comorbid Diabetes and CKD CHF, congestive heart failure; AMI, acute myocardial infarction; CVA/TIA, cerebrovascular accident/transient ischemic attack; PVD, peripheral vascular disease; ASVD, atherosclerotic vascular disease. *ASVD was defined as the first occurrence of AMI, CVA/TIA, or PVD. Foley RN, et al. J Am Soc Nephrol. 2005;16:489-495.

  47. Appropriate Staging and Management of CKD CKD, chronic kidney disease. *Includesactions from preceding stages. †Pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. National Kidney Foundation. Am J Kidney Dis. 2002;49(suppl 1):S1-S266.

  48. KDIGO CKD Classification by Relative Risk Levey AS, et al. Kidney Int. 2011;80:17-28.

  49. DKD Risk Factor Management Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.

  50. Dietary Guidelines for DKD Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179.

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