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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). 13%. Overweight (BMI 25-29). 24%. T2DM Patients (%). Obese (BMI ≥30). 63%.

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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) 13% Overweight(BMI 25-29) 24% T2DM Patients (%) Obese(BMI ≥30) 63% BMI, body mass index, in kg/m2. Ali MK, et al. New Engl J Med. 2013;368:1613-1624.

  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. Intensive Intervention Reduces Significantly More Weight than Standard Approaches in T2DM Look AHEAD Trial (N=5145) Diabetes support and education Intensive lifestyle intervention 0 -1.1% -2 P<0.0001 -4 -4.7% Reduction in initial weight (%) -6 Retention at 4 years: ILI = 94.1% DSE = 93.1% -8 -10 0 1 3 2 4 Years Differences between groups were statistically significant (P˂0.0001) at all 4 years. ILI, intensive lifestyle intervention; DSE, diabetes support and education. Look AHEAD Research Group. Arch Intern Med. 2010;170:1566-1575.

  12. Long-term Limitations of Weight Loss Benefits in T2DM Look AHEAD Trial (N=5145) Estimated mean A1C (%) Estimated mean weight (kg) Main effect:-0.22 (95% CI -0.28 to -0.16)P<0.001 Main effect: -4 (95% CI -5 to -3)P<0.001 *P<0.05 for between-group comparison. Main effect is the average of post-baseline differences. CI, confidence interval; T2DM, type 2 diabetes mellitus. Look AHEAD Research Group. N Engl J Med. 2013;369:145-154.

  13. Long-term Effects of Lifestyle Change on Cardiovascular Risk in T2DM Look AHEAD Trial Patients experiencing death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina (%) HR 0.95 (95% CI, 0.80 to 1.09) P=0.51 • Lack of difference between treatment groups may be due to: • Educational sessions in control group, contributing to weight loss • Increased use of statins in control group • Intensification of CV risk control in routine clinical care T2DM, type 2 diabetes mellitus. Look AHEAD Research Group. N Engl J Med. 2013;369:145-154.

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

  15. 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.

  16. Weight Gain/Loss Potential with Antidiabetic Agents Inzucchi SE, et al. Diabetes Care. 2012;35:1364-1379. Garber AJ, et al. Endocr Pract. 2013;19:327-336. Handelsman Y, et al. Endocr Pract. 2011;17(suppl 2):1-53. Stenlof K, et al. Diabetes Obes Metab 2013;15:372-382.

  17. Effects of Phentermine/Topiramate ERin Advanced T2DM Poorly Controlled Type 2 Diabetes Weight Glucose Control BaselineMean A1C (%) 8.6 8.8 Phen/TPN 15/92 mg (n=75) Placebo (n=55) LS MeanA1C (%) P=0.038 Mean Weight (%) Change in diabetes medications (score) Placebo (n=55) Phen/TPN 15/92 mg (n=75) P<0.0001 *P=0.038 vs placebo. †Net score reflecting change in medication number and change in dose level of diabetes medications.Garvey WT, et al. Diabetes. 2009;58(suppl 2): Abstr. 361-OR.

  18. Effect of Lorcaserinin Type 2 Diabetes BLOOM-DM Study Weight Glucose Control BaselineMean A1C (%) 8.0 8.1 8.1 Lorcaserin 10 mg BID (n=251) Lorcaserin 10 mg QD (n=95) Placebo (n=248) LS MeanA1C (%) LS MeanA1C (%) * * † † Patients Increasing Use of Antidiabetic Agents (%) * * Lorcaserin 10 mg BID (n=251) Lorcaserin 10 mg QD (n=95)‡ Placebo (n=248) *P<0.001 vs placebo. †P=0.087 vs placebo. ‡Mean A1C from 93 patients in lorcaserin 10 mg QD group. BLOOM-DM, Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus. O’Neil PM, et al. Obesity. 2012;20:1426-1436.

  19. Management of Common Comorbidities in Diabetes Dyslipidemia

  20. 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.

  21. 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.

  22. Effect of Weight Loss in T2DM on Lipids Look AHEAD Trial (N=5145) LDL-C HDL-C 115 49 * 110 48 * * * Main effect: 1.6 (95% CI 0.3, 2.9)P<0.05 * 105 47 Estimated mean (mg/dL) Estimated mean (mg/dL) * 100 46 * 95 45 * Main effect: 1.2 (95% CI 0.6, 1.9)P<0.05 90 44 43 85 6 8 9 10 6 7 8 9 10 7 0 1 2 3 4 5 0 1 2 3 4 5 Years Years Triglycerides 160 Main effect (%): 99 (95% CI 96, 101)P=0.261 * 150 * ILI DSE Estimated mean (mg/dL) 140 130 120 Years 6 7 8 9 10 0 1 2 3 4 5 *P<0.05 for between-group comparisons. Main effect is the average of post-baseline differences. CI, confidence interval; DSE, diabetes support and education; ILI, intensive lifestyle intervention; T2DM, type 2 diabetes mellitus. Look AHEAD Research Group. N Engl J Med. 2013;369:145-154.

  23. LDL-C and LDL Particle Number in T2DM Patients With LDL-C <100 mg/dL (N=2355) 5th 20th 50th 80th percentile LDL-C 37% (n=870) 63% (n=1485) Subjects (%) 70 100 130 160 mg/dL LDL-P 7% (n=162) 31% (n=741) 38% (n=891) 16% (n=383) 8% (n=178) 62% at high risk (LDL-P exceeds 1000) despite optimum LDL-C (<100 mg/dL) 62% Subjects (%) 24% 700 1000 1300 1600 nmol/L LDL-C, low-density lipoprotein cholesterol; LDL-P, low-density lipoprotein particles. Cromwell WC, Otvos JD Am J Cardiol. 2006;98:1599-1602.

  24. LDL Particle Number Distribution in T2DM 5th 20th 50th 80th percentile 43% (n=631) 21% (n=307) 1% (n=19) 24% (n=364) LDL-C71-99 mg/dL (n=1484) 11% (n=163) 63% 32% Subjects (%) 70 100 130 160 mg/dL LDL-C≤70 mg/dL (n=871) 16% (n=147) 43% (n=377) 30% (n=260) 9% (n=76) 2% (n=15) 41% Subjects (%) 11% 700 1000 1300 1600 nmol/L LDL-C, low-density lipoprotein cholesterol. Cromwell WC, Otvos JD Am J Cardiol. 2006;98:1599-1602.

  25. 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. FIELD Study Investigators. Lancet. 2005;366:1849-1861.

  26. 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.

  27. 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.

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

  29. 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.

  30. 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.

  31. 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.

  32. 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.

  33. 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.

  34. 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.

  35. 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.

  36. Management of Common Comorbidities in Diabetes Hypertension

  37. 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.

  38. 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.

  39. 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.

  40. 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.

  41. 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.

  42. 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.

  43. 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.

  44. Effect of Weight Loss on Blood Pressure in T2DM Look AHEAD Trial (N=5145) 71 130 Systolic Blood Pressure Diastolic Blood Pressure 70 128 Main effect: -0.1 (95% CI -0.5, 0.3)P=0.72 69 126 68 * * * * * * 67 * * 124 * Estimated mean(mm Hg) Estimated mean(mm Hg) 66 122 65 * 120 64 Main effect: -1.9 (95% CI -2.6, -1.1)P<0.05 6 7 8 9 10 6 7 8 9 10 0 1 2 3 5 0 1 2 3 5 4 4 ILI DSE Years Years *P<0.05 for between-group comparisons. Main effect is the average of post-baseline differences. CI, confidence interval; DSE, diabetes support and education; ILI, intensive lifestyle intervention;T2DM, type 2 diabetes mellitus. Look AHEAD Research Group. N Engl J Med. 2013;369:145-154.

  45. 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.

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

  47. 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.

  48. 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.

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