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Management of Common Comorbidities in Diabetes 1 Management of Common Comorbidities in Diabetes OBESITY 2 3 4 More Than Two Thirds of US Adults Are Overweight or Obese NHANES Data US Adults Age ≥20 Years (Crude Estimate) 87.5 Population (%) 70. 30.5 52.5 35. 33.9 35.9 35.1 37.7 22.5 14.1 14.5 30.5 32.0 31.5 32.0 34.0 34.4 33.3 33.9 33.9 1962 1974 1980 1994 2000 2008 2010 2012 2014* 12.8 2.9-fold increase in obesity since 1962 BMI ≥30 BMI 25-29 17.5 0. *2014 rate of overweight not reported in Flegal et al 2016; 2012 rate carried over based on historic stability of overweight prevalence. BMI, body mass index (in kg/m 2); NHANES, National Health and Nutrition Examination Survey (x-axis lists last year of each survey). Flegal KM, et al. Int J Obes Relat Metab Disord. 1998;22:39-47; Flegal KM, et al. JAMA. 2002;288:1723-1727; Flegal KM, et al. JAMA. 2010;303:235-241; Flegal KM, et al. JAMA. 2012;307:491-497. Ogden CL, et al. JAMA. 2014;311:806-814. Flegal KM, et al. JAMA. 2016;315:2284-2291. 5 T2D Prevalence Parallels Prevalence of Obesity 70 Obese Diagnosed Diabetes NHANES Data, U.S. Adults ≥20 Years1-5 CDC Data, U.S. Population6,7 Population (%) 60 12 10 50 8 40 6 30 4 20 10 2 0 0 White men White women Black men Black women Mexican American men Mexican American women Asian men Asian women 1980 1994 2000 2008 2010 2012 BMI, body mass index (in kg/m 2); CDC, Centers for Disease Control and Prevention; NHANES, National Health and Nutrition Examination Survey (x-axis lists last year of each survey). *NHANES 1994 data. 1. Flegal KM, et al. Int J Obes Relat Metab Disord. 1998;22:39-47. 2. Flegal KM, et al. JAMA. 2002 ;288:1723-1727. 3. Flegal KM, et al. JAMA. 2010;303:235-241. 4. Flegal KM, et al. JAMA. 2012;307:491-497. 5. Ogden CL, et al. JAMA. 2014;311:806-814. 6. Harris MI, et al. Diabetes Care. 1998;21:518-524. 7. CDC. Diabetes data & trends. Available at: https://www.cdc.gov/diabetes/statistics/prev/national/figraceethsex.htm and http://www.cdc.gov/diabetes/statistics/prev/national/fighispanicthsex.htm. 6 Increase in Diabetes Parallels the Increase in Obesity in the United States Obesity* Diabetes 12 111% increase 45 37.7 10 Population (%) Population (%) 36 27 18 17.9 9 43% increase 9.3 8 6.5 6 4 2 0 0 1998 2014 1998 2014 *BMI ≥30 kg/m2. CDC. National diabetes statistics report, 2014. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2014. Mokdad AH, et al. JAMA. 1999;282:1519-1522; Mokdad AH, et al. Diabetes Care. 2000;23:1278-1283; Flegal KM, et al. JAMA. 2016;315:2284-2291. 7 Prevalence of Overweight and Obesity in Diabetes Normal BMI <25 kg/m2 12.9% Overweight Obese BMI 25-<30 kg/m2 BMI ≥30 kg/m2 25.9% 61.2% BMI, body mass index. Selvin S, et al. Ann Intern Med. 2014;160:517-525. CDC. National diabetes statistics report, 2014. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2014. 8 Incidence Diabetes by Waist Circumference and Race/Ethnicity The Multi-Ethnic Study of Atherosclerosis (2000–2007) 8.00 Chinese Hispanic Incidence of Diabetes Per 100 Person-Years 7.00 Black 6.00 5.00 4.00 White 3.00 2.00 1.00 0.00 70 80 90 100 110 120 130 Waist Circumference (cm) Solid lines pertain to values between the race-specific 5th and 95th percentiles of waist circumference. Dotted lines are extrapolated values outside the aforementioned race-specific ranges. Adjusted for age, sex, education, and income. Lutsey PL, et al. Am J Epidemiol. 2010;172:197-204. 9 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 YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 10 Energy Homeostasis Body Weight Increase Decrease Energy intake Energy expenditure Ingestion of: Physical activity Proteins Fats Diet-induced thermogenesis Carbohydrates Basal metabolic rate Mechanick JI, et al. Endocr Pract. 2012;18:642-648. 11 Peripheral and Central Regulation of Energy Intake Bray GA, et al. Lancet. 2016;387:1947-1956. 12 Obesity Impairs Appetite and Energy Balance Regulation Key Hormone Changes Associated with Weight Gain and Regain Hormone Source Normal function Alteration Cholecystokinin (CCK) Duodenum Suppress appetite Levels decrease during dieting and weight loss Glucose-dependent insulinotropic polypeptide (GIP) Duodenum, jejunum Energy storage Levels increase during dieting and weight loss Ghrelin Gastric fundus Stimulate appetite, particularly for high-fat, highsugar foods Levels increase during dieting and weight loss Glucagon-like peptide 1 (GLP-1) Ileum Suppress appetite and increase satiety Decreased functionality Insulin Pancreas Regulate energy balance Signal satiety to brain Insulin resistance in obese persons Reduced insulin levels after dieting Leptin Adipocytes Regulate energy balance Suppress appetite Levels decrease during weight loss Peptide YY (PYY) Distal small intestine Suppress appetite Levels decreased in obese persons Sumithran P, Proietto J. Clin Sci (Lond). 2013;124:231-241. 13 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 (%) Loss ≥2.25 kg Gain ≥2.25 kg 60 ** 37 40 ** 20 20 0 -20 -40 -40 -60 -48 ** Men ** Women *Patients with low HDL-C, high cholesterol, high BMI, high systolic BP, high triglyceride, high glucose. **P<0.002 vs baseline. BMI, body mass index; BP, blood pressure; HDL-C, high density lipoprotein cholesterol. Wilson PW, et al. Arch Intern Med. 1999;159:1104-1109. 14 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 1.4 1.35 Relative risk* 1.29 1.17 1.2 1 1.27 1 1.16 1 1.14 1 0.8 CVD death MI All-cause deaths *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. 15 Medical Complications of Obesity Obesity Biomechanical Dismotility/disability GERD Lung function defects Osteoarthritis Sleep apnea Urinary incontinence Cardiometabolic Dyslipidemia Hypertension Prediabetic states NAFLD PCOS Diabetes Cardiovascular Disease Other Androgen deficiency Cancer Gallbladder disease Psychological disorders GERD, gastroesophageal reflux disease; NAFLD, nonalcoholic fatty liver disease; PCOS, polycystic ovary syndrome. Pi-Sunyer X. Postgrad Med. 2009;121:21-33. 16 Weight Loss With Intensive Lifestyle Intervention in T2D Look AHEAD Trial (N=5145) Reduction in initial weight (%) 0 -1.1% -2 P<0.0001 Diabetes support and education Intensive lifestyle intervention -4 -4.7% -6 Retention at 4 years: ILI = 94.1% DSE = 93.1% -8 -10 0 1 2 3 4 Years Differences between groups were statistically significant (P˂0.0001) at all 4 years. DSE, diabetes support and education; ILI, intensive lifestyle intervention; T2D, type 2 diabetes. Look AHEAD Research Group. Arch Intern Med. 2010;170:1566-1575. 17 Effect of Weight Loss in T2D on CV Risk Factors and Diabetes Measures Look AHEAD Trial (N=5145) 1 Year 4 Years DSE ILI DSE ILI Weight loss (%) -0.7 -8.6 -0.88 -6.15* A1C (%) -0.14 -0.64* -0.09 -0.36* FPG (mg/dL) -7.2 -21.5* — — % on diabetes medications 2.2 -7.8* — — Systolic BP (mm Hg) -2.8 -6.8* -2.97 -5.33* Diastolic BP (mm Hg) -1.8 -3.0* -2.48 -2.92† LDL-C (mg/dL) -5.7 -5.2 -12.84 -11.27 HDL-C (mg/dL) 1.4 3.4* 1.97 3.67* -14.6 -30.3* -19.75 -25.56* TG (mg/dL) *P≤0.001, †P=0.01 vs customary support. BP, blood pressure; CV, cardiovascular; DSE, diabetes support and education; ILI, intensive lifestyle intervention; T2D, type 2 diabetes. Look AHEAD Research Group. Diabetes Care. 2007;30:1374-1383. Look AHEAD Research Group. Arch Intern Med. 2010;170:1566-1575. 18 Long-term Limitations of Weight Loss Benefits in T2D Main effect: -4 (95% CI -5 to -3) P<0.001 Estimated mean A1C (%) Estimated mean weight (kg) Look AHEAD Trial (N=5145) Main effect: -0.22 (95% CI -0.28 to -0.16) P<0.001 *P<0.05 for between-group comparison. Main effect is the average of post-baseline differences. CI, confidence interval; T2D, type 2 diabetes. Look AHEAD Research Group. N Engl J Med. 2013;369:145-154. 19 Long-Term Effects of Lifestyle Change on Cardiovascular Risk in T2D 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 T2D, type 2 diabetes mellitus. Look AHEAD Research Group. N Engl J Med. 2013;369:145-154. 20 AACE Recommendations: Therapeutic Lifestyle Changes Parameter Treatment Goal Weight loss (for overweight and obese patients) Reduce by 5% to 10% Physical activity 150 min/week of moderate-intensity exercise (eg, brisk walking) plus flexibility and strength training • • Diet • • • • Eat regular meals and snacks; avoid fasting to lose weight Consume plant-based diet (high in fiber, low calories/glycemic index, and high in phytochemicals/antioxidants) Understand Nutrition Facts Label information Incorporate beliefs and culture into discussions Use mild cooking techniques instead of high-heat cooking Keep physician-patient discussions informal Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 21 AACE Recommendations: Healthful Eating Carbohydrate Specify healthful carbohydrates (fresh fruits and vegetables, legumes, whole grains); target 7-10 servings per day Preferentially consume lower-glycemic index foods (glycemic index score <55 out of 100: multigrain bread, pumpernickel bread, whole oats, legumes, apple, lentils, chickpeas, mango, yams, brown rice) Fat Specify healthful fats (low mercury/contaminant-containing nuts, avocado, certain plant oils, fish) Limit saturated fats (butter, fatty red meats, tropical plant oils, fast foods) and trans fat; choose fat-free or low-fat dairy products Protein Consume protein in foods with low saturated fats (fish, egg whites, beans); there is no need to avoid animal protein Avoid or limit processed meats Micronutrients Routine supplementation is not necessary; a healthful eating meal plan can generally provide sufficient micronutrients Chromium; vanadium; magnesium; vitamins A, C, and E; and CoQ10 are not recommended for glycemic control Vitamin supplements should be recommended to patients at risk of insufficiency or deficiency Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 22 AACE Physical Activity Recommendations • Evaluate for contraindications • ≥150 minutes per week of and/or limitations to increased moderate-intensity exercise physical activity before patient – Flexibility and strength training begins or intensifies exercise – Aerobic exercise (eg, brisk program walking) • Develop exercise • Start slowly and build up recommendations according to gradually individual goals and limitations Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 23 Antidiabetic Agents and Weight Class Amylin analog Biguanide GLP1 receptor agonists SGLT-2 inhibitors -Glucosidase inhibitors Bile acid sequestrant DPP4 inhibitors Dopamine-2 agonist Glinides Sulfonylureas Insulin Thiazolidinediones • Agent(s) Pramlintide Metformin Albiglutide, dulaglutide, exenatide, exenatide XR, liraglutide Canagliflozin, dapagliflozin, empagliflozin Acarbose, miglitol Colesevelam Alogliptin, linagliptin, saxagliptin, sitagliptin Bromocriptine Nateglinide, repaglinide Glimepiride, glipizide, glyburide Aspart, detemir, glargine, glulisine, lispro, NPH, regular, inhaled Pioglitazone, rosiglitazone Weight Effect ↓ ↓ ↓ ↓ ↔ ↔ ↔ ↔ ↑ ↑ ↑↑ ↑↑ Risk of additional weight gain must be balanced against the benefits of the agent – Sulfonylureas may negate weight loss benefits of GLP1 receptor agonists or metformin – Insulin should not be withheld because of the risk of weight gain Garber AJ, et al. Endocr Pract. 2017;23:207-238. ADA. Diabetes Care. 2017;40:S64-S74. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 24 Effect of Phentermine/Topiramate ER on A1C and Number of Diabetes Medications SEQUEL Type 2 Diabetes Subgroup LS Mean A1C (%) Baseline Mean A1C (%) 0 -0.1 Placebo (n=55) 6.9 Phen/TPM Phen/TPM 7.5/46 mg 15/92 mg (n=26) (n=64) 7.3 6.9 -0.04 -0.2 -0.23 -0.3 -0.4 -0.42 -0.5 Change in Diabetes Medications (Overall safety population†) Patients With Net Change* in Concomitant Antihyperglycemics (%) Change in A1C *Percent increase minus percent decrease. †The safety population was defined as all subjects who received at least 1 dose of study drug. ‡ P=0.013 for between-group differences. 8 7.1 7 6 5 4 ‡ 3 1.9 2 ‡ 1 0 0 Placebo (n=227) Phen/TPM Phen/TPM 7.5/46 mg 15/92 mg (n=153) (n=295) Phen/TPM, phentermine/topiramate. Garvey WT, et al. Am J Clin Nutr. 2012;95:297-308. 25 Effects of Phentermine/Topiramate ER on Glucose Control in Advanced T2D Poorly Controlled Type 2 Diabetes Change in Diabetes Medications† Change in A1C 8.6 8.8 40 30 30 20 -0.5 Score LS Mean A1C (%) Baseline Mean A1C (%) 0 Placebo (n=55) Phen/TPN 15/92 mg (n=75) -1 10 0 -1.13 -10 -1.5 -1.61 -2 -20 * *P=0.038 vs placebo. †Net score reflecting change in medication number and change in dose level of diabetes medications. -16 Placebo (n=55) Phen/TPN 15/92 mg (n=75) T2D, type 2 diabetes. Garvey WT, et al. Diabetes. 2009;58(suppl 2): Abstr. 361-OR. 26 Effect of Lorcaserin on Glycemia in Type 2 Diabetes BLOOM-DM Study LS Mean A1C (%) Baseline Mean A1C (%) 0 Placebo (n=248) 8.0 Change in Diabetes Medications Lorcaserin Lorcaserin 10 mg BID 10 mg QD (n=251) (n=93) 8.1 8.1 -0.2 -0.4 -0.4 -0.6 -0.8 -1 -1.2 -0.9 * -1 * Patients Increasing Use of Antidiabetic Agents (%) Change in A1C 100 88.3 80 † 82.9 † 76.6 60 40 20 0 Placebo Lorcaserin Lorcaserin (n=248) 10 mg BID 10 mg QD (n=251) (n=95) *P<0.001 vs placebo. †P=0.087 vs placebo. BLOOM-DM, Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus. O’Neil PM, et al. Obesity. 2012;20:1426-1436. 27 Effects of High- and Low-Dose Liraglutide in Type 2 Diabetes SCALE Diabetes Study Change in A1C -0.5 Liraglutide Liraglutide 1.8 mg 3 mg (n=211) (n=423) 7.9 -0.38 -1 -1.13 -1.5 * -1.32 * 0 LS Mean Weight (%) LS Mean A1C (%) Baseline Mean A1C (%) 0 Placebo (n=212) Change in Weight Placebo (n=212) Liraglutide Liraglutide 1.8 mg 3 mg (n=211) (n=423) -1 -2 -3 -2 -4 -5 -4.6 -6 * -7 -5.9 * *P<0.0001 vs placebo. Davies M, et al. Diabetes. 2014;63(suppl 1):A26, Abstr. 97-OR. 28 Management of Common Comorbidities in Diabetes DYSLIPIDEMIA 29 Prevalence of Hyperlipidemia in Type 2 Diabetes Normal 35% 35% Eligible for lipid-lowering therapy but untreated LDL-C ≥100 mg/dL or using cholesterollowering medication 65% LDL-C, low density lipoprotein cholesterol. CDC. National diabetes statistics report, 2014. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2014. 30 Common Secondary Causes of Dyslipidemia Affected lipids Conditions • • • ↑ Total cholesterol • and LDL-C • ↑ Triglycerides and VLDL-C • Hypothyroidism Nephrosis Dysgammaglobulinemia (systemic lupus erythematosus, multiple myeloma) Progestin or anabolic steroid treatment Cholostatic diseases of the liver due to abnormal lipoproteins, as in primary biliary cirrhosis Protease inhibitors for treatment of HIV infection • • • • • • • • • Chronic renal failure T2D Obesity Excessive alcohol intake Hypothyroidism Antihypertensive medications (thiazide diuretics and b-adrenergic blocking age Corticosteroid therapy (or severe stress that increases endogenous corticosteroids) Orally administered estrogens, oral contraceptives, pregnancy Protease inhibitors for treatment of HIV infection HIV, human immunodeficiency virus; LDL-C, low-density lipoprotein cholesterol; T2D, type 2 diabetes; VLDL-C, very low-density lipoprotein cholesterol. Jellinger P, et al. Endocr Practice. 2017;23(4):479-497; NHLBI. NIH Publication No. 02-5215. 2002; Rodbard HW, et al. Endocr Pract. 13(Suppl 1):1-68; Vodnala D, et al. Am J Cardiol. 2012;110(6):823-825. 31 Atherogenic Dyslipidemia • Common in type 2 diabetes 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. 2017;23(suppl 2):1-87. 32 Effect of Weight Loss on Lipids in T2D Look AHEAD Trial (N=5145) LDL-C HDL-C 49 110 105 Main effect: 1.6 (95% CI 0.3, 2.9) P<0.05 100 * 95 * Estimated mean (mg/dL) Estimated mean (mg/dL) 115 * 90 48 * * 47 * * * 46 45 Main effect: 1.2 (95% CI 0.6, 1.9) P<0.05 44 43 85 0 1 2 3 4 5 6 7 8 9 10 Estimated mean (mg/dL) Years 0 1 2 3 150 * 140 * 5 6 7 8 9 10 Years Triglycerides 160 4 Main effect (%): 99 (95% CI 96, 101) P=0.261 ILI DSE 130 120 0 1 *P<0.05 for between-group comparisons. 2 3 4 5 6 7 8 9 10 Years Main effect is the average of post-baseline differences. CI, confidence interval; DSE, diabetes support and education; ILI, intensive lifestyle intervention; T2D, type 2 diabetes. Look AHEAD Research Group. N Engl J Med. 2013;369:145-154. 33 LDL-C and LDL Particle Number in T2D Patients With LDL-C <100 mg/dL (N=2355) th th th th 5 LDL-C Subjects (%) 30 50 80 percentile 130 160 mg/dL 37% 63% (n=870) (n=1485) 20 10 0 LDL-P 20 Subjects (%) 20 70 7% (n=162) 100 31% (n=741) 38% (n=891) 16% (n=383) 62% 15 10 8% (n=178) 62% at high risk (LDL-P exceeds 1000) despite optimum LDL-C (<100 mg/dL) 24% 5 0 700 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. 34 LDL Particle Number Distribution in T2D 5th LDL-C 71-99 mg/dL Subjects (%) (n=1484) 20 1% (n=19) 21% (n=307) 63% 80th percentile 11% (n=163) 32% 10 5 20 Subjects (%) (n=871) 43% (n=631) 50th 15 0 LDL-C ≤70 mg/dL 24% (n=364) 20th 70 16% (n=147) 100 43% (n=377) 15 130 160 30% (n=260) 9% (n=76) mg/dL 2% (n=15) 41% 10 11% 5 0 700 1000 1300 1600 nmol/L LDL-C, low-density lipoprotein cholesterol. Cromwell WC, Otvos JD Am J Cardiol. 2006;98:1599-1602. 35 36 CVD Risk Factors: AACE Targets Risk Factor Recommended Goal Individualize, but generally: Blood pressure, mm Hg Lipids Systolic <130 Diastolic <80 High CV risk Very high CV risk Extreme CV risk LDL-C, mg/dL <100 <70 <55 Non-HDL-C, mg/dL <130 <100 <80 Triglycerides, mg/dL ApoB, mg/dL Garber AL, et al. Endocr Pract. 2017;23:207-238. <150 <90 <80 <70 37 Lipid Management in Diabetes LDL-C at goal but nonHDL-C not at goal (TG ≥200 mg/dL and/or low HDL-C) TG ≥500 mg/dL • May use fibrate, niacin, or high-dose omega-3 fatty acid to achieve non-HDLC goal • Use high-dose omega-3 fatty acid, fibrate, or niacin to reduce TG and risk of pancreatitis Elevated LDL-C, non-HDLC, TG, TC/HDL-C ratio, ApoB, LDL particles • Statin = treatment of choice • Add bile acid sequestrant, niacin, and/or cholesterol absorption inhibitor if target not met on maximum-tolerated dose of statin • Use bile acid sequestrant, niacin, or cholesterol absorption inhibitor instead of statin if contraindicated or not tolerated ApoB, apolipoprotein B; ASCVD, atherosclerotic cardiovascular disease; CV, cardiovascular; HDL-C, high density lipoprotein cholesterol; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; TC = total cholesterol. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 38 Dyslipidemia Treatment Options Class MOA Efficacy LDL-C HDL-C Triglycerides HMG CoA reductase inhibitors (statins) Competitively inhibit rate-limiting step of cholesterol synthesis, slowing production in liver Cholesterol absorption inhibitors Inhibit intestinal absorption of cholesterol PCSK9 inhibitors Inhibit PCSK9 binding to LDL receptors, increasing availability of receptors for LDL clearance Fibric acid derivatives Stimulate lipoprotein lipase activity Main Limitations • 21-55% 2-10% 6-30% • • • Risk of myopathy, increased liver transaminases Contraindicated in liver disease Liver enzyme monitoring required Risk of new-onset diabetes 10-18% (monotherapy) 34-61% (add-on to statins) — — • Risk of myopathy 48-71% (add-on to statins) — — • Injection • GI symptoms, possible cholelithiasis Gemfibrozil may LDL-C Myopathy risk increased when used with statins VLDL Fenofibrate may LDL-C 20-25% 6-18% 20-35% • • HDL-C, high-density lipoprotein cholesterol; HMG-CoA, hydroxymethylglutaryl-coenzyme A; LDL-C, low-density lipoprotein cholesterol; PCSK9, proprotein convertase subtilisin/kexin type 9; VLDL-C, very low density lipoprotein cholesterol. Jellinger PS, et al. Endocr Pract. 2017;23(suppl 2):1-87. Continued on next slide 39 Dyslipidemia Treatment Options Class MOA Efficacy LDL-C HDL-C Triglycerides Niacin/nicotinic acid Reduce hepatic synthesis of LDL-C and VLDL-C Bile acid sequestrants Bind bile acids in the intestine • Skin flushing, pruritus, GI symptoms, potential increases in blood glucose and uric acid • • GI symptoms May triglycerides • • Liver enzyme monitoring required Steatosis of liver and small intestine 21% • • Liver enzyme monitoring required Steatosis of liver and small intestine VLDL-C 20-42% • • • Increase LDL-C levels Monitor coagulation status Increased frequency of symptomatic AF 10-25% 10-35% 20-30% 15-25% — — Up to 40% — 45% MTP inhibitor Inhibit synthesis of chylomicrons and VLDL Anti-sense ApoB oligonucleotide Degrade mRNA for apoB-100, which is needed for synthesis of LDL Omega-3 fatty acids Reduce hepatic synthesis of VLDL-triglycerides and/or enhancing triglyceride clearance Main Limitations 27-45% ApoB, apolipoprotein B; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MTP, microsomal transfer triglyceride; VLDL-C, very low density lipoprotein cholesterol. Jellinger PS, et al. Endocr Pract. 2017;23(suppl 2):1-87. Continued from previous slide 40 Statin Starting Dosages and Dosage Ranges Agent Usual recommended starting daily dosage Dosage range Administration Lovastatin 20 mg 10-80 mg Oral Pravastatin 40 mg 10-80 mg Oral Simvastatin 20-40 mg 5-80 mg* Oral 40 mg 20-80 mg Oral 10-20 mg 10-80 mg Oral 10 mg 5-40 mg Oral 2 mg 2-4 mg Oral Fluvastatin Atorvastatin Rosuvastatin Pitavastatin *Simvastatin 80 mg not approved for therapy unless individual has been on treatment for more than 1 year without myopathy. Crestor (rosuvastatin calcium); [PI]; 2016; Jellinger P, et al. Endocr Practice. 2017;23:479-497; Lescol (fluvastatin sodium) [PI]; 2012 Lipitor (atorvastatin calcium) [PI]; 2015; Livalo (pitavastatin) [PI]; 2013; ; Mevacor (lovastatin) [PI]; 2014; Pravachol (pravastatin sodium) [PI]; 2016; Zocor (simvastatin) [PI]; 2015. 41 Statins: Primary Metabolic Effects and Main Considerations Metabolic Effects • • Primarily ↓ LDL-C 21%-55% by competitively inhibiting rate-limiting step of cholesterol synthesis in the liver, leading to upregulation of hepatic LDL receptors Effects on TG and HDL-C are less pronounced (↓ TG 6%-30% and ↑ HDL-C 2%-10%) Main Considerations • • • • • • • • Liver function test prior to therapy and as clinically indicated thereafter Myalgias and muscle weakness in some individuals Potential for drug-drug interaction between some statins and CYP450 3A4 inhibitors, cyclosporine, warfarin, and protease inhibitors Myopathy/rhabdomyolysis in rare cases; increased risk with coadministration of some drugs (see product labeling) Simvastatin dosages should not exceed 40 mg in most individuals; dosages of 80 mg are no longer recommended except in those who have tolerated 80 mg for 12 months or more without muscle toxicity Do not exceed 20 mg simvastatin daily with amlodipine or ranolazine Plasma elevations of rosuvastatin may be higher among Asian persons than other ethnic groups New-onset diabetes is increased in individuals treated with statins; however, it is dose-related, occurs primarily in individuals with MetS, appears to be less common with pravastatin and possibly pitavastatin, and occurs overall to a lesser extent than the associated decrease in ASCVD ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; MetS, metabolic syndrome; TG, triglycerides. Bissonnette S, et al. Can J Cardiol. 2006;22:1035-1044; Denke M, et al. Diab Vasc Dis Res. 2006;3:93-102; Jellinger P, et al. Endocr Practice. 2017;23:479-497; Preiss D, et al. JAMA. 2011;305: 2556-2564. 42 Comparison of Statin Effects on Lipids After 6 Weeks of Treatment Men and Women With LDL-C ≥160 and ≤250 mg/dL (N=2,431) Dosage range, mg daily TC (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) TG (mg/dL) Lovastatin 20-80 ↓ 21 to ↓ 36 ↓ 29 to ↓ 48 ↑ 4.6 to ↑ 8.0 ↓ 12 to ↓ 13 Pravastatin 10-40 ↓15 to ↓ 22 ↓ 20 to ↓30 ↑ 3.2 to ↑ 5.6 ↑ 8 to ↓ 13 Simvastatin 10-80* ↓ 20 to ↓ 33 ↓ 28 to ↓ 46 ↑ 5.2 to ↑ 6.8 ↓ 12 to ↓ 18 Fluvastatin 20-40 ↓ 13 to ↓ 19 ↓ 17 to ↓ 23 ↑ 0.9 to ↓ 3.0 ↓ 5 to ↓ 13 Atorvastatin 10-80 ↓ 27 to ↓ 39 ↓ 37 to ↓ 51 ↑ 2.1 to ↑ 5.7 ↓ 20 to ↓ 28 Rosuvastatin 10-40 ↓ 33 to ↓ 40 ↓ 45 to ↓ 55 ↑ 7.7 to ↑ 9.6 ↓ 20 to ↓ 26 Statin *Not to be used at dosages of 80 mg unless individual has been on treatment for more than 12 months. HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides. AAP NCEP Pediatrics. 1992;89:525-584; Daniels SR, et al. EPIGCVHRRCAFR, 2012; Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23:479-497; Jones P, et al. Am J Cardiol. 1998;81:582-587; Jones PH, et al. Am J Cardiol. 2003; 92:152-160; ; LIPID Study Group. N Engl J Med. 1998;339:1349-1357; Pfeffer MA, et al. J Am Coll Cardiol. 1999;33:125-130; Plehn JF, et al. Circulation. 1999;99:216-223. 43 PCSK9 Inhibitor Starting Dosages and Dosage Ranges Agent Usual recommended starting daily dosage Dosage range Administration Alirocumab 75 mg every 2 weeks 75-150 mg every 2 weeks SC Evolocumab 140 mg every 2 weeks or 420 mg once monthly Not applicable SC Metabolic Effects • ↓LDL-C 48%-71%, ↓ non-HDL-C 49%-58%, ↓TC 36%-42%, ↓Apo B 42%-55% by inhibiting PCSK9 binding with LDLRs, increasing the number of LDLRs available to clear LDL, and lowering LDL-C levels Main Considerations • • • • Require subcutaneous self-injection; refrigeration generally needed Overall levels of adverse reactions and discontinuation very low Adverse reactions with significantly different rates between drug and placebo were: local injection site reactions and influenza The most common adverse reactions with similar rates for drug vs. placebo were: • Alirocumab: nasopharyngitis, influenza, urinary tract infections, diarrhea, bronchitis, and myalgia • Evolocumab: nasopharyngitis, back pain, and upper respiratory tract infection Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; SC, subcutaneous injection; TC, total cholesterol. Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23:479-497; Praluent (alirocumab) [PI] 2015; Repatha (evolocumab) [PI]; 2016. 44 Fibrate Starting Dosages and Dosage Ranges Usual recommended starting daily dose Dosage range Administration Fenofibrate 48-145 mg 48-145 mg Oral Gemfibrozil 1200 mg 1200 mg Oral 45-135 mg 45-135 mg Oral Agent Fenofibric acid Metabolic Effects • Primarily ↓ TG 20%-35%, ↑ HDL-C 6%-18% by stimulating lipoprotein lipase activity • Fenofibrate may ↓ TC and LDL-C 20%-25% • Lower VLDL-C and LDL-C; reciprocal rise in LDL-C transforms the profile into a less atherogenic form by shifting fewer LDL particles to larger size • Fenofibrate ↓ fibrinogen level HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein, LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides; VLDL-C, very low-density lipoprotein cholesterol. Aguilar-Salinas CA, et al. Metabolism. 2001;50:729-733; Athyros VG, et al. Coron Artery Dis. 1995;6:25-1256; Avellone G, et al. Blood Coagul Fibrinolysis. 1995;6:543-548; Bröijersen A, et al. Arterioscler Thromb Vasc Biol. 1996;16:511-516; Bröijersén A, et al. Thromb Haemost. 1996;76:171-176; Davidson MH, et al. Am J Cardiol. 2007;99:3C-18C; Farnier M, et al. Eur Heart J. 2005;26:897-905; Guyton JR, et al. Arch Intern Med. 2000;160:1177-1184; Hottelart C, et al. Nephron. 2002;92:536-541; Insua A, et al. Endocr Pract. 2002;8:96-101; Jellinger P, Handelsman Y, Rosenblit P, et al. Endocr Practice. 2017;23:479-497; Kockx M, et al. Thromb Haemost. 1997;78:1167-1172; Lopid (gemfibrozil) [PI] 2010; McKenney JM, et al. J Am Coll Cardiol. 2006;47:1584-1587; Syvänne M, et al. Atherosclerosis. 2004;172:267-272; Tricor (fenofibrate) [PI]; 2010; Trilipix (fenofibric acid) [PI]; 2016; Westphal S, et al. Lancet. 2001; 358:39-40. 45 Fibrates: Main Considerations • • • • • • • • • Gemfibrozil may ↑ LDL-C 10%-15% GI symptoms, possible cholelithiasis May potentiate effects of orally administered anticoagulants Gemfibrozil may ↑ fibrinogen level Gemfibrozil and fenofibrate can ↑ homocysteine independent of vitamin concentrations May cause muscle disorders; myopathy/rhabdomyolysis when used with statin Fibrates are associated with increased serum creatinine levels, which may not reflect renal dysfunction Fenofibrate dose should be cut by two-thirds and gemofibrozil by one-half when eGFR is 15-60, and fibrates should be avoided when eGFR is <15 Can improve diabetic retinopathy eGFR, estimated glomerular filtration rate; GI, gastrointestinal; LDL-C, low-density lipoprotein cholesterol. Jellinger P, et al. Endocr Practice. 2017;23:479-497. 46 Bile Acid Sequestrant Starting Dosages and Dosage Ranges Agent Cholestyramine Usual recommended daily dosage Dosage range Administration 8-16 g 4-24 g Oral 2g 2-16 g Oral 3.8 g 3.8-4.5 g Oral Colestipol Colesevelam Metabolic Effects • • Primarily ↓ LDL-C 15%-25% by binding bile acids and preventing their reabsorption in the ileum (causing hepatic cholesterol depletion and LDL-receptor upregulation) Colesevelam ↓ glucose and hemoglobin A1C (~0.5%); FDA-approved to treat T2D Main Considerations • May ↑ serum TG • Frequent constipation and/or bloating, which can reduce adherence • Many potential drug interactions (decreased drug absorption), less so with colesevelam (see product labeling) • May reduce absorption of folic acid and fat-soluble vitamins such as vitamins A, D, and K FDA, Food and Drug Administration; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; T2D, type 2 diabetes; TG, triglyceride. Colestid (colestipol hydrochloride) [PI]; 2014; Jellinger P, et al. Endocr Practice. 2017;23:479-497; Prevalite (cholestyramine for oral suspension, USP) [PI]; 2015; WelChol (colesevelam hydrochloride) [PI]; 2014; Zieve FJ, et al. Ther. 2007;29:74-839:74-83. 47 Cholesterol Absorption Inhibitor Starting Dosages and Dosage Ranges Agent Ezetimibe Ezetimibe/ simvastatin Usual recommended daily dosage Dosage range Administration 10 mg 10 mg Oral 10/20 mg 10/10 to 10/80 mg Oral Metabolic Effects • • • • Primarily ↓ LDL-C 10%-18% by inhibiting intestinal absorption of cholesterol and decreasing delivery to the liver, leading to upregulation of hepatic LDL receptors ↓ Apo B 11%-16% In combination with statins, additional ↓ LDL-C 25%, total ↓ LDL-C 34%-61% In combination with fenofibrate, ↓ LDL-C 20%22% and ↓ apo B 25%-26% without reducing ↑ HDL-C Main Considerations • Myopathy/rhabdomyolysis (rare) • When coadministered with statins or fenofibrate, risks associated with those drugs remain (e.g., myopathy/ rhabdomyolysis, cholelithiasis) Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. Bays HE, et al. Clin Ther. 2001;23:1209-1230; Bays HE, et al. Clin Ther. 2004;26:1758-1773; Bissonnette S, et al. Can J Cardiol. 2006;22:1035-1044; Brohet C, et al. Curr Med Res Opin. 2005;21:571-578; Denke M et al. Diab Vasc Dis Res. 2006;3:93-102; Dujovne CA, et al. Am J Cardiol. 2002;90:109-21097; Farnier M, et al. Eur Heart J. 2005;26:897-905; Gagne C, et al. Am J Cardiol. 2002;90:1084-1091; Jellinger P, et al. Endocr Practice. 2017;23:479-497; Knopp RH, et al. Int J Clin Pract. 2013. 57:363-368; McKenney JM, et al. J Am Coll Cardiol. 2006;47:1584-1587; Zetia (ezetimibe) [PI] 2013. 48 Omega-3 Fatty Acid Starting Dosages and Dosage Ranges Agent Omega-3-acid ethyl esters (Lovaza) Icosapent ethyl (Vascepa) • • Usual recommended daily dosage Dosage range Administration 4g 4g Oral 4g 4g Oral Metabolic Effects ↓ TG 27%-45%, TC 7%-10%, VLDL-C 20%-42%, apo B 4%, and non-HDL-C 8%14% in individuals with severe hypertriglyceridemia most likely by reducing hepatic VLDL-TG synthesis and/or secretion and enhancing TG clearance from circulating VLDL particles. Other potential mechanisms of action include: increased -oxidation; inhibition of acyl-CoA; 1,2-diacylglyceral acyltransferase; decreased hepatic lipogenesis; and increased plasma lipoprotein activity Icosapent ethyl ↓ LDL-C 5%, whereas, omega-3-acid ethyl esters ↑ LDL-C 45% Apo, apolipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides; VLDL, very low-density lipoprotein. Jellinger P, et al. Endocr Practice. 2017;23:479-497; Lovaza (omega-3-acid ethyl esters) [PI]; 2015; Vascepa (icosapent ethyl) [PI]; 2016. 49 50 Omega-3 Fatty Acids: Main Considerations • • • • • Assess TG levels prior to initiating and periodically during therapy Omega-3-acid ethyl esters can increase LDL-C levels. Monitor LDL-C levels during treatment May prolong bleeding time. Monitor coagulation status periodically in patients receiving treatment with omega-3 fatty acids and other drugs affecting coagulation Monitor ALT and AST levels periodically during treatment in patients with hepatic impairment. Some patients may experience increases in ALT levels only Exercise caution when treating patients with a known hypersensitivity to fish and/or shellfish AF, atrial fibrillation. Jellinger P, et al. Endocr Practice. 2017;23:479-497. • • • • The effect of omega-3 fatty acids on cardiovascular morbidity and mortality and the risk of pancreatitis has not been determined in patients with severe hypertriglyceridemia In patients with paroxysmal or persistent atrial fibrillation, therapy with omega-3-acid ethyl esters may be associated with increased frequency of symptomatic AF or flutter, especially within the first 2 to 3 months after initiation Most common adverse events include arthralgia (2.3%), eructation (4%), dyspepsia (3%), and taste perversion (4%). May also experience constipation, gastrointestinal disorders, vomiting, rash, or pruritus Should be used with caution in nursing mothers and only be used in pregnant women if the benefits of treatment outweigh the potential risk of fetal harm Niacin Starting Dosages and Dosage Ranges Usual recommended daily dosage Dosage range Administration Immediate release 250 mg 250-3000 mg Oral Extended release 500 mg 500-2000 mg Oral Agent Metabolic Effects • • • ↓ LDL-C 10%-25%, ↓ TG 20%-30%, ↑ HDL-C 10%-35% by decreasing hepatic synthesis of LDL-C and VLDL-C ↓ Lipoprotein (a) Transforms LDL-C to less atherogenic form by increasing average particle size and also decreases LDL particle concentration Main Considerations • • • Potential for frequent skin flushing, pruritus, abdominal discomfort, hepatoxicity (rare but may be severe), nausea, peptic ulcer, atrial fibrillation Deleterious effect on serum glucose at higher dosages Increases uric acid levels; may lead to gout HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride; VLDL-C, very low-density lipoprotein cholesterol. Guyton JR, et al. Arch Intern Med. 2000;160:1177-1184; Jellinger P, et al. Endocr Practice. 2017;23:479-497; Niaspan (niacin extendedrelease) [PI] 2015. 51 MTP Inhibitor Starting Dosage and Dosage Range Agent Lomitapide • • • • • Recommended starting dose Dosage range Administration 5 mg 5-60 mg Oral Metabolic Effects ↓ Up to LDL-C 40%, TC 36%, apo B 39%, TG 45%, and non-HDL-C 40% (depending on dose) in individuals with HoFH by binding and inhibiting MTP, which inhibits synthesis of chylomicrons and VLDL Main Considerations Can cause increases in transminases (ALT, AST); monitoring of ALT, AST, alkaline phosphatase, and total bilirubin prior to initiation, and of ALT and AST during treatment, is required per FDA REMS Causes increases in hepatic fat (steatosis) with or without concomitant elevated transminases, which may be a risk for progressive liver diseases Also causes steatosis of the small intestine with resulting abdominal pain and steatorrhea unless a very-low-fat diet is followed; may also cause fat-soluble vitamin deficiency unless vitamin supplements are taken Caution should be exercised when used with other drugs with potential hepatoxicity; because of hepatoxicity risk, only available through REMS program ALT, aspartate amino transferase; AST, amino alanine transferase; FDA, Food and Drug Administration; HDL-C, high-density lipoprotein cholesterol; HoFH, homozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; MTP, microsomal transfer protein; REMS, Risk Evaluation and Mitigation Strategy; TG, triglycerides; VLDL, very low-density lipoprotein. Jellinger P, et al. Endocr Practice. 2017;23:479-497; Juxtapid (lomitapide) [PI]; 2012. 52 Anti-sense Apolipoprotein B Oligonucleotide Starting Dosage and Dosage Range Agent Mipomersen • • • • Usual recommended dosage Dosage range Administration 200 mg once weekly 200 mg once weekly SC Metabolic Effects ↓ LDL-C 21%, TC 19%, apo B 24%, and non-HDL-C 22% in individuals with HoFH by degrading mRNA for apo B-100, the principal apolipoprotein needed for hepatic synthesis of VLDL (and subsequent intra-plasma production of IDL and LDL) Main Considerations Can cause increases in transminases (ALT, AST); monitoring of ALT, AST, alkaline phosphatase, and total bilirubin before initiation, and of ALT and AST during treatment is recommended Causes increases in hepatic fat (steatosis) with or without concomitant elevated transminases, which may be a risk for progressive liver diseases Caution should be exercised when used with other drugs with potential hepatoxicity; because of hepatoxicity risk, only available through REMS program ALT, aspartate amino transferase; apo, apolipoprotein; AST, amino alanine transferase; HDL-C, high-density lipoprotein cholesterol; HoFH, homozygous familial hypercholesterolemia; IDL, intermediate-density lipoprotein; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; mRNA, messenger RNA; SQ, subcutaneous; VLDL, very low-density lipoprotein. Jellinger P, et al. Endocr Practice. 2017;23:479-497; Kynamro (mipomersen sodium) Injection [PI]; 2016. 53 Benefits of Aggressive LDL-C Lowering in Diabetes Primary event rate (%) Aggressive Lipid Lowering Difference P value in LDL-C (mg/dL) Treatment Control Better Worse TNT Diabetes, CHD 13.8 17.9 0.026 22* ASCOT-LLA Diabetes, HTN 9.2 11.9 0.036 35† CARDS Diabetes, no CVD 5.8 9.0 0.001 46† HPS All diabetes 9.4 12.6 <0.0001 39† HPS Diabetes, no CVD 9.3 13.5 0.0003 39† 0.4 *Atorvastatin 10 vs 80 mg/day. †Statin vs placebo. 0.6 0.8 1.0 1.2 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. 1.4 54 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. 55 Treat Patients With the Greatest Absolute Risk the Most Aggressively Robinson JG, et al. Am J Cardiol. 2006;98:1405-1408. 56 Statin Benefits Across a Range of Baseline Levels Cholesterol Treatment Trialists’ Collaboration LDL-C 90-130 mg/dL shows same benefit as LDL-C 50-90 mg/dL Events (% per annum) Statin <2 mmol/L (<77 mg/dL) RR (CI) per 1 mmol/L reduction in LDL-C Control 910 (4.1%) 1,012 (4.6%) 0.78 (0.61-0.99) ≥2 to <2.5 mmol/L (77-96 mg/dL) 1,528 (3.6%) 1,729 (4.2%) 0.77 (0.67-0.89) ≥2.5 to <3.0 mmol/L (97-116 mg/dL) 1,866 (3.3%) 2,225 (4.0%) 0.77 (0.70-0.85) P=0.3 ≥3.0 to <3.5 mmol/L (117-135 mg/dL) 2,007 (3.2%) 2,454 (4.0%) 0.76 (0.70-0.82) ≥3.5 mmol/L (>136 mg/dL) 4,508 (3.0%) 5,736 (3.9%) 0.80 (0.76-0.83) 10,973 (3.2%) 13,350 (4.0%) 0.78 (0.76-0.80) Total 1 mmol/L = 38.6 mg/dL LDL-C, low-density lipoprotein cholesterol. Baigent C, et al. Lancet. 2010;376:1670-1681. 57 Effect on CHD and Diabetes Primary Prevention Cholesterol Treatment Trialists’ Collaboration Events (% per annum) Previous Vascular Disease CHD No CHD, vascular Statin RR (CI) per 1 mmol/L reduction in LDL-C Control 8,395 (4.5%) 10,123 (5.6%) 0.79 (0.76-0.82) 674 (3.1%) 802 (3.7%) 0.81 (0.71-0.92) 1,904 (1.4%) 2,425 (1.8%) 0.75 (0.69-0.82) Type 1 diabetes 145 (4.5%) 192 (6.0%) 0.77 (0.58-1.01) Type 2 diabetes 2,494 (4.2%) 2,920 (5.1%) 0.80 (0.74-0.86) No diabetes 8,272 (3.2%) 10,163 (4.0%) 0.78 (0.75-0.81) None P=0.3 Diabetes P=0.8 1 mmol/L = 38.6 mg/dL. CHD: coronary heart disease; CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; RR: relative risk. Baigent C, et al. Lancet. 2010;376:1670-1681. 58 Residual Cardiovascular Risk in Major Statin Trials CHD events still occur in patients treated with statins Secondary CARE 40 Placebo HPS CARDS Statin 30 20 15.9 12.3 13.2 10 0 N= LDL-C 9014 -25% 30 10.2 4159 -28% 11.8 8.7 20,536 -29% 5.5 3.6 2841 -40% 37.0 40 Patients with Diabetes (%) Total Population (%) LIPID Primary 29.0 23.0 20 19.0 25.1 20.2 5.5 10 3.6 0 N= 782 586 5963 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. 2841 59 IMPROVE-IT: Improved Reduction of Outcomes, Vytorin Efficacy International Trial Trial design: Patients with recent ACS were randomized 1:1 to either ezetimibe 10 mg + simvastatin 40 mg or simvastatin 40 mg and followed for a median of 6 years Primary composite CV endpoint Percent reduction 50% Results • Primary endpoint (CV death/MI/UA/coronary revasc/stroke/moderate/severe bleeding) for ezetimibe/simvastatin vs. simvastatin: 32.7% vs. 34.7% (HR 0.94, 95% CI 0.89-0.99; P=0.016) • MI: 13.1% vs. 14.8%, P=0.002; stroke: 4.2% vs. 4.8%, P=0.05; CVD/MI/stroke: 20.4% vs. 22.2%, P=0.003 • Median LDL follow-up average: 53.7 vs. 69.5 mg/dL (P=0.016) 32.7% 34.7% 25% Conclusions 0% Ezetimibe/simvastatin (n = 9,067) Simvastatin (n = 9,077) • In patients with high-risk ACS, ezetimibe 10 mg/simvastatin 40 mg was superior to simvastatin 40 mg alone in reducing adverse CV events • This is the first study powered for clinical outcomes to show a benefit with a non-statin agent Abbreviations: ACS, acute coronary syndrome; CV, cardiovascular; CVD, cardiovascular disease; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction. Cannon CP, et al. N Engl J Med. 2015;372:2387-2397. • Reaffirms the “lower is better” hypothesis with LDL-C 60 IMPROVE-IT Major Prespecified Subgroups Simvastatin EZE/Simvastatin (BL LDL-C: 69.5 mg/dL) (BL LDL-C: 53.7 mg/dL) P value for interaction Male Female 34.9 34.0 33.2 31.0 0.267 Age <65 years Age ≥65 years 30.8 39.9 29.9 36.4 0.098 No diabetes Diabetes 30.8 45.5 30.2 40.0 0.023 Prior LLT No prior LLT 43.4 30.0 40.7 28.6 0.272 LDL-C >95 mg/dL LDL-C ≤95 mg/dL 31.2 38.4 29.6 36.0 0.670 0.7 0.8 0.9 1 1.1 Ezetimibe/simvastatin better Simvastatin better EZE, ezetimibe; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy. Cannon CP, et al. N Engl J Med. 2015;372:2387-2397. 61 Lipid Effects of Adding a Fenofibrate to a Statin in Patients With T2D Action to Control Cardiovascular Risk in Diabetes (N=5518) ACCORD Study Group. N Engl J Med. 2010;362:1563-1574. 62 Effect of Fenofibrate Plus Statin on CV Events in Patients With T2D Action to Control Cardiovascular Risk in Diabetes (N=5518) ACCORD Study Group. N Engl J Med. 2010;362:1563-1574. 63 Benefits of Fenofibrate Plus Statin in Patients With T2D Action to Control Cardiovascular Risk in Diabetes (N=5518) ACCORD Study Group. N Engl J Med. 2010;362:1563-1574. 64 Fenofibrate Benefits Most Likely in Patients with High TG and Low HDL-C Major Fatal or Nonfatal CV Events (%) Action to Control Cardiovascular Risk in Diabetes (N=5518) 20 18 16 14 17.32% RR 31% (P=0.06) The benefit associated with fenofibrate treatment was confined to the high TG/low HDL-C subgroup (<18% of ACCORD-LIPID trial population) 12.37% 12 12.37% 10.11% 10 8 6 4 2 0 High TG / low HDL-C All others in cohort (TG>204 mg/dL; HDL-C <34 mg/dL; n=941) (n=4,548) CV, cerebrovascular; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; RR, risk reduction; TG, triglycerides. Elam M, et al, Clin Lipidol. 2011;6:9-20. ACCORD Study Group. NEJM. 2010; 362:1563-1574. 65 Effect of Fenofibrate on Progression of Coronary Atherosclerosis in Patients With Type 2 Diabetes Diabetes Atherosclerosis Intervention Study Fenofibrate Quantitative Coronary Angiography Placebo 4 Baseline Endpoint 2.59 -29% 2.42 +1% HDL-C (mmol/L) Baseline 1.01 1.05 Endpoint +7% +2% Change in Stenosis (%) Triglycerides (mmol/L) 3.7 3.5 3 * 2.5 2.1 2 1.5 1 0.5 0 Placebo (n=207) Fenofibrate (n=211) *P=0.02 vs placebo Diabetes Atherosclerosis Intervention Study. Lancet. 2001;357:905-910. 66 FIELD: Fenofibrate Intervention in Event Lowering in Diabetes Multinational, randomized controlled trial (N=9,795) of patients with T2D currently taking statin therapy assigned to add-on treatment with fenofibrate or placebo Outcome Fenofibrate % (n) Placebo % (n) HR 95% CI P value Coronary events 5% (256) 6% (288) 0.89 0.75-1.05 0.16 CHD mortality 2% (110) 2% (93) 1.19 0.90-1.57 0.22 Nonfatal MI 3% (158) 4% (207) 0.76 0.62-0.94 0.01 CHD, coronary heart disease; MI, myocardial infarction; T2D, type 2 diabetes. Keech A, et al. Lancet. 2005;366:1849-1861. 67 Fenofibrate and CV Events FIELD (N=9795 Patients With T2D) Baseline cholesterol (mg/dL): TC 194; TG 154; HDL-C 42; LDL-C 119; Non-HDL-C 152 Placebo Fenofibrate 200 mg 11% Reduction, P=0.035 16 Event Rate (%)* 14 12 10 8 6 13.9 11% Reduction P=0.16 5.9 5.2 12.5 24% Reduction P=0.01 4.2 4 3.2 2 19% Increase P=0.22 Nonfatal MI * Not corrected for large placebo-group statin drop-in rate. 7.4 5.9 1.9 2.2 0 CHD Events** (Primary Endpoint) 21% Reduction P=0.003 CHD Death Total CVD Events† (Secondary Endpoint) Coronary Revascularization ** Nonfatal MI and CHD death. † CHD events, stroke, CVD death, revascularizations. CHD, coronary heart disease; CV, cardiovascular; CVD, cardiovascular disease; HDL, high-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; T2D, type 2 diabetes; TC, total cholesterol; TG, triglycerides. Keech A, et al. Lancet. 2005;366:1849-1861. 68 Greatest Benefit of Fenofibrate Seen in Patients With Elevated TG and Low HDL-C FIELD Placebo RR 11% 5-Year Total CV Event Rate (%) 20 15 13.9 12.5 RR 14% Fenofibrate 17.2 RR 23% 17.8 RR 27% 15.1 13.5 13 13.4 Low HDL-C** TG >200 mg/dL Low HDL-C + TG >200 mg/dL 0.86 0.75-0.99 <0.01 0.77 0.63-0.94 <0.01 0.73 0.58-0.91 <0.05 10 5 0 Any MetS Criteria Hazard ratio 95% CI P value 0.89 0.80-0.99 <0.01 *Not corrected for large placebo group statin drop-in rate **HDL-C <40 mg/dL (men) and <50 mg/dL (women). CI, confidence interval; CV, cerebrovascular; FIELD, Secondary Endpoints from the Fenofibrate Intervention and Event Lowering in Diabetes trial; HDL-C, high-density lipoprotein cholesterol; MetS, metabolic syndrome; RR, risk reduction; TG, triglycerides. Scott R, et al. Diabetes Care 2009;32:493-498 69 Coronary Drug Project: 15-Year Follow-up Placebo (n = 2008) Niacin (n = 827) 60 11% Reduction P =0.0004 Event Rate (%) 55 50 45 12% Reduction P <0.05 40 35 30 Total Mortality CHD Mortality Canner PL, et al. J Am Coll Cardiol. 1986;8:1245-1255. Canner PL, et al. J Am Coll Cardiol. 2005;95:254-257. 70 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. 2017;23(suppl 2):1-87. 71 Management of Common Comorbidities in Diabetes HYPERTENSION 72 73 Meta-Regression Analysis of Major CV Events and BP Reduction 2.0 Relative risk 1.0 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. 74 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 30 25 20 CV Deaths P=0.005 24.4 18.6 15 51% 11.9 10 P=0.50 9.9 10 9.3 5 0 Events per 1000 Patient-years Events per 1000 Patient-years Major CV Events 15 DBP ≤ 90 DBP ≤85 DBP ≤ 80 P=0.016 11.1 11.2 10 67% 5 3.7 P=0.49 3.7 3.8 4.1 0 T2DM n=1501 All Patients n=18,790 T2DM n=1501 All Patients n=18,790 DBP, diastolic blood pressure, in mmHg. Hansson L, et al. Lancet. 1998;351:1755-1762. 75 Blood Pressure and Diabetic Complications in T2D 10 10 P<0.0001 1 13% Decrease per 10 mmHg reduction in SBP 0.5 110 120 130 140 150 Updated Mean A1C Adler Al, et al. BMJ. 2000;321:412-419. 160 170 Myocardial Infarction Hazard Ratio Microvascular Complications Hazard Ratio United Kingdom Prospective Diabetes Study P<0.0001 1 12% Decrease per 10 mmHg reduction in SBP 0.5 110 120 130 140 150 160 170 Updated Mean A1C 76 BP Reductions and Risk of Microvascular and Macrovascular Complications in T2D United Kingdom Prospective Diabetes Study (N=1148) Benefits of 144/82 vs. 154/87 mm Hg Risk Reduction (%) 0 Any diabetesMyocardial related infarction endpoint Diabetesrelated death Stroke Heart failure Renal failure Vision deteriorRetinopathy ation -10 -20 -30 -21 P=0.13 -24 P=0.005 -40 -50 -60 UKPDS Group. BMJ. 1998;317:703-713. -32 P=0.019 -42 P=0.29 -44 P=0.013 -56 P=0.004 -34 P=0.004 -47 P=0.004 77 Long-Term Follow-up After Tight Control of Blood Pressure in T2D UKPDS Post-monitoring Study Good BP control must be continued if benefits are to be maintained Any Diabetes-Related Endpoint • • 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: – – – – • Holman RR, et al. N Engl J Med. 2008;359;1565-1576. 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) 78 Intensive Blood Pressure Control in Type 2 Diabetes Action to Control Cardiovascular Risk in Diabetes (N=4733) ACCORD Study Group. N Engl J Med. 2010;362:1575-1585. 79 Effect of Intensive Blood-Pressure Control on CV Outcomes and Death in T2D Action to Control Cardiovascular Risk in Diabetes (N=4733) ACCORD Study Group. N Engl J Med. 2010;362:1575-1585. 80 Effect of Weight Loss on Blood Pressure in Type 2 Diabetes Look AHEAD Trial (N=5145) ILI DSE Systolic Blood Pressure Diastolic Blood Pressure 128 * 126 * * * * * * 124 Main effect: -1.9 (95% CI -2.6, -1.1) P<0.05 122 120 0 1 2 3 4 5 6 7 8 9 Estimated mean (mm Hg) Estimated mean (mm Hg) 130 71 70 69 68 67 66 65 64 10 Years Main effect: -0.1 (95% CI -0.5, 0.3) P=0.72 * * * 0 1 2 3 4 5 6 7 8 9 10 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. Look AHEAD Research Group. N Engl J Med. 2013;369:145-154. 81 Multiple Antihypertensive Agents Are Usually Required to Achieve BP Control RENAAL (BP <140/90) 3 IRMA-2 (BP <135/85) 3.1 IDNT (BP <135/85) 3 UKPDS (DBP <85) 2.7 ABCD (DBP <75) 2.8 HOT (DBP <80) 3.3 0 0.5 1 1.5 2 2.5 3 Number of Agents Required to Achieve Goal BP 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. 3.5 82 Compelling Indications for Individual Drug Classes Recommended Drugs Compelling Indication Diuretic Heart failure • Post-myocardial infarction BB • ACEI • • • ARB • High coronary disease risk • • • Diabetes • • • • • • Chronic kidney disease Recurrent stroke prevention • • CCB Aldo ANT Clinical Trial Basis • ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES, CHARM • ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS • ALLHAT, HOPE, ANBP2, LIFE, CONVINCE, EUROPA, INVEST • NKF-ADA Guideline, UKPDS, ALLHAT NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK PROGRESS Aldo ANT = aldosterone antagonist. Chobanian AV, et al. Hypertension. 2003;42:1206-1252. 83 The Renin Angiotensin System: ACE Inhibition ACEI Angiotensin I ACE-independent formation of ANG II ACE Bradykinin Angiotensin II AT1 AT2 Vasoconstriction Proliferation Antiproliferation Differentiation Aldosterone Sympathetic NS Regeneration Anti-inflammation NaCl retention Inflammation Apoptosis? B2 NO, PGI2 Vasodilation, etc NO Vasodilation Tissue protection Apoptosis ACE, angiotensin converting enzyme; ACEI, angiotensin converting enzyme inhibitor; ANG II, angiotensin II; AT 1, angiotensin II type 1; AT2, angiotensin II type 2; B2, bradykinin 2; NO, nitric oxide; PGI2, prostacyclin. Unger T, et al. Am J Cardiol. 2007;100:25J-31J. 84 The Renin Angiotensin System: AT1 Blockade Angiotensin I ARB ACE Angiotensin II AT1 AT2 Vasoconstriction Proliferation Antiproliferation Differentiation Aldosterone Sympathetic NS Regeneration Anti-inflammation NaCl retention Inflammation Apoptosis? B2 NO, PGI2 Vasodilation, etc NO Vasodilation Tissue protection Apoptosis ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; AT 1, angiotensin II type 1; AT2, angiotensin II type 2; B2, bradykinin 2; NO, nitric oxide; PGI2, prostacyclin. Unger T, et al. Am J Cardiol. 2007;100:25J-31J. 85 MI Risk With ACEIs and ARBs Events ARBs ACEIs Odds Ratio ARB vs ACEI ELITE 1997 ELITE II OPTIMAAL DETAIL VALIANT (val) ONTARGET (tel) Fixed effect model (I2=0.0%, p=0.884) Random effect model ARB + ACEI vs ACEI 2000 2002 2004 2003 2008 VALIANT (val + cap) 2003 ONTARGET (tel+ram) Fixed effect model (I2=0.0%, p=0.148) Random effect model Overall Effect 2008 Fixed effect model (I2=0.0%, p=0.759) 4/352 31/1578 384/2744 9/120 796/4909 440/8542 0.79 (0.17,3.54) 4/370 28/1574 379/2733 6/130 798/4909 413/8576 1.11 (0.66,1.85) 1.01 (0.87,1.18) 1.68 (0.58,4.86) 1.00 (0.90,1.11) 1.07 (0.94,1.23) 1663/18,245 1628/18,292 1.03 (0.95, 1.10) 1.03 (0.95,1.10) 756/4885 438/8502 0.94 (0.85,1.05) 798/4909 413/8576 1.07 (0.94,1.23) 1194/13,387 1211/13,485 0.99 (0.91,1.08) 1.00 (0.88,1.13) 2857/31,632 2839/31,777 Random effect model Heterogeneity between groups p=0.555 1.01 (0.96,1.07) 1.01 (0.96,1.07) 0.5 Favors 1st 1.0 Favors Odds Ratio listed 2nd listed 2.0 ACE, angiotensin converting enzyme; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; MI, myocardial infarction. Volpe M, et al. J Hypertension. 2009;27:941-946. 86 Not All Combinations Are Equal in High Risk Patients The ACCOMPLISH Trial Blood Pressure Reductions Time to Primary Endpoint* Benazepril plus hydrochlorothiazide Relative risk reduction: 20% Hazard ratio: 0.80 (95% CI , 0.72 to 0.90; P <0.001) Benazepril plus amlodipine By 1 year, 32.3% of patients in both treatment groups required a third antihypertensive agent to maintain target BP *Composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden, cardiac arrest, and coronary revascularization. ACCOMPLISH, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension. Jamerson K et al. N Engl J Med. 2008;359:2417-2428. 87 Hypertension Summary • In T2D, 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 mmHg • 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 ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; T2D, type 2 diabetes. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 88 Management of Common Comorbidities in Diabetes CHRONIC KIDNEY DISEASE 89 Prevalence of CKD in Diagnosed Diabetes Diabetic kidney disease is the leading cause of kidney failure in the United States CKD may be both a pre-existing comorbidity and a secondary complication of diabetes NKF Description Stage GFR 1 Kidney damage* with normal or GFR ≥90 2 Kidney damage* with mild GFR 60-89 3 Moderate GFR 30-59 4 Severe GFR 15-29 5 Kidney failure or ESRD <15 or dialysis *Pathologic abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. CKD, chronic kidney disease; ESRD, end-stage renal disease; GFR, glomerular filtration rate (mL/min/1.73 m 2); NKF, National Kidney Foundation. CDC. National diabetes statistics report, 2014. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2014. Plantinga LC, et al. Clin J Am Soc Nephrol. 2010;5:673-682. 90 Reducing A1C Reduces Nephropathy Risk in Type 2 Diabetes UKPDS ADVANCE ACCORD A1C reduction (%)* 0.9 0.8 1.3 Nephropathy risk reduction (%)* 30 21 21 New onset microalbuminuria (P=0.033) New or worsening nephropathy (P=0.006) New microalbuminuria (P=0.0005) *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. 91 Cardiovascular Outcomes Worsen With CKD Progression Valsartan in Acute Myocardial Infarction Trial (N=14,527*) † eGFR (mL/min/1.73 m2) Estimated Event Rate (%) 60 50 † † 40 75 60-74 45-59 <45 † 30 20 † 10 † 0 Composite End Point Death From CV Causes Reinfarction CHF Stroke Resuscitation *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. 92 CV Risk Increases With Comorbid Diabetes and CKD Incidence per 100 Patient-Years No diabetes/no CKD Diabetes/no CKD Diabetes/CKD 60 x 2.8 x 2.0 50 40 30 x 2.1 x 1.7 x 2.5 20 x 2.3 10 0 CHF AMI CVA/TIA PVD ASVD* Death 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. 93 Risk of Cardiovascular Mortality with Decreasing eGFR and Increasing Albuminuria 14 Relative Risk 12 10 8 6 4 2 ≥300 30-299 10-29 ACR (mg/g) 0 >105 90-105 75-90 60-75 45-60 eGFR (mL/min/1.73 <10 30-45 15-30 m2) ACR = albumin-creatinine ratio; eGFR = estimated glomerular filtration rate. NKF. Kidney Int Suppl. 2013;3:1-150. 94 Assessment of Diabetic Nephropathy • Annual assessments – Serum creatinine to determine eGFR – Urine AER • Begin annual screening – 5 years after diagnosis of T1D if diagnosed before age 30 years – At diagnosis of T2D or T1D in patients diagnosed after age 30 years AER, albumin excretion rate; eGFR, estimated glomerular filtration rate; T1D, type 1 diabetes; T2D, type 2 diabetes. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 95 KDIGO CKD Classification by Relative Risk Albuminuria stages (mg/g) A3 Optimal and high normal High Very high and nephrotic 10-29 30-299 300-1999 ≥2000 Very low Very low Low Moderate Very high Very low Very low Low Moderate Very high Mild to 45-59 moderate Low Low Moderate High Very high Moderate 30-44 to severe Moderate Moderate High High Very high High High High High Very high Very high Very high Very high Very high Very high High and optimal G2 Mild G5 A2 <10 G1 GFR stages (mL/min G3a per 1.73 m2 body surface G3b area) G4 A1 >105 90-104 75-89 60-74 Severe 15-29 Kidney failure <15 Levey AS, et al. Kidney Int. 2011;80:17-28. 96 Staging and Monitoring of CKD in Diabetes Persistent albuminuria categories Description and range GFR categories (mL/min/1.73 m2) Description and range Previous NKF CKD stage Guide to frequency of monitoring (number of times per year) by GFR and albuminuria category A1 A2 A3 Normal to mildly increased Moderately increased Severely increased <30 mg/g <3 mg/mmol 30-300 mg/g 3-30 mg/mmol >300 mg/g >30 mg/mmol 1 G1 Normal or high ≥90 1 if CKD 1 2 2 G2 Mildly decreased 60-89 1 if CKD 1 2 G3a Mild to moderately decreased 45-59 1 2 3 G3b Moderately to severely decreased 30-44 2 3 3 4 G4 Severely decreased 15-29 3 3 4+ 5 G5 Kidney failure <15 4+ 4+ 4+ 3 CKD = chronic kidney disease; GFR = glomerular filtration rate; NKF = National Kidney Foundation. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 97 DKD Risk Factor Management Risk Factor Goal Hyperglycemia Individualized A1C goals Avoid biguanide in moderate to severe CKD ≤6.5% for most (AACE) Consider need for dose reductions and/or risk of hypoglycemia and other renal-related AEs with other <7.0% (NKF) antidiabetic agents Hypertension BP ~130/80 mmHg Proteinuria Dyslipidemia Management Recommendation Use ACE inhibitor or ARB in combination with other antihypertensive agents as needed Use ACE inhibitor or ARB as directed LDL-C <100 mg/dL, <70 mg/dL an option for high risk Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179. Statin therapy recommended Fibrate dose reduction may be required 98 Management of Diabetic Nephropathy • Optimal control of blood pressure, glucose, and lipids • Smoking cessation • RAAS blockade – ACE inhibitor, ARB, or renin inhibitor – Do not combine RAAS blocking agents – Monitor serum potassium • Nephrologist referral – Atypical presentation – Rapid decline in eGFR or albuminuria progression – Stage 4 CKD ACE, angiotensin converting enzyme; ARB, angiotensin II receptor blocker; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; RAAS, renin angiotensin aldosterone system. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 99 Use of Antihyperglycemic Agents in Kidney Disease Class: Agent(s) Kidney Disease Recommendation Amylin analog: pramlintide Not recommended for CKD stage ≥4 Biguanide: metformin Contraindicated if SCr >1.5 (men) or 1.4 (women) mg/dL Bile acid sequestrant: colesevelam No dosage adjustment Dopamine-2 agonist: bromocriptine Use with caution DPP-4 inhibitors: alogliptin, linagliptin, saxagliptin, sitagliptin Reduce dosage for alogliptin, saxagliptin and sitagliptin if CrCl <50 mg/dL Glinides: nateglinide, repaglinide Start at lowest effective dose if GFR <30 mL/min/1.73 m2 GLP-1 receptor agonists: albiglutide, dulaglutide, exenatide, exenatide XR, liraglutide Exenatide and liraglutide not recommended with GFR <30 mL/min/ -Glucosidase inhibitors: acarbose, miglitol Avoid if GFR <25 (miglitol) or <30 (acarbose) mL/min/1.73 m2 Insulin: aspart, detemir, glargine, glulisine, inhaled, lispro, NPH, regular Adjust dose based on patient response SGLT inhibitors: canagliflozin, dapagliflozin, empagliflozin Ineffective if GFR <30 mL/min/1.73 m2 Sulfonylureas: glimepiride, glipizide, glyburide No dose adjustment for glipizide; start glimepiride conservatively; avoid glyburide and all other SUs Thiazolidinediones: pioglitazone, rosiglitazone No dosage adjustment Garber AJ, et al. Endocr Pract. 2017;23:207-238. ADA. Diabetes Care. 2017;40:S64-S74. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. National Kidney Foundation. Am J Kidney Dis. 2012;60:850-886. 100 Dietary Guidelines for DKD CKD Stage Macronutrient 1-2 1-4 Sodium <2.3 Total fat, % calories* <30 Saturated fat, % calories <10 Cholesterol, mg/day <200 Carbohydrate, % calories 50-60 Protein, g/kg/day (% calories) 3-4 0.8 (~10) 0.6-0.8 (~8-10) Phosphorus 1.7 0.8-1.0 Potassium >4 2.4 *Adjust so total calories from protein, fat, and carbohydrate are 100%. Emphasize such whole-food sources as fresh vegetables, whole grains, nuts, legumes, low-fat or nonfat dairy products, canola oil, olive oil, cold-water fish, and poultry. Tailor dietary counseling to cultural food preferences. National Kidney Foundation. Am J Kidney Dis. 2007;49(suppl 2):S1-S179. 101 Management of Common Comorbidities in Diabetes CARDIOVASCULAR DISEASE 102 Prevalence of CV Risk Factors in Diabetes Overweight / Obese Hyperlipidemia BMI <25 kg/m2 12.9% BMI 25-<30 kg/m2 25.9% Normal BMI ≥30 kg/m2 35% Hypertension 61.2% 65% Normal 29% LDL-C ≥100 mg/dL or using cholesterollowering medication BP ≥140/90 mmHg or taking antihypertensive medication 71% BMI, body mass index. Selvin S, et al. Ann Intern Med. 2014;160:517-525. CDC. National diabetes statistics report, 2014. Atlanta, GA: US Department of Health and Human Services, Centers for Disease Control and Prevention, 2014. 103 Coincidence of CV Comorbidities in Type 2 Diabetes NHANES 1999-2004 (N=984) Hypertension (BP ≥140/90 mm Hg or taking antihypertensive medication) 16.9% 17.7% 12.2% 20.6% Hyperlipidemia Obesity (BMI ≥30 kg/m2) 5.0% Suh DC, et al. J Diabetes Complications. 2010;24:382-391. 5.9% 7.4% (LDL-C ≥100 mg/dL, TC ≥200 mg/dL, or TG ≥150 mg/dL) 104 Cardiovascular Disease Risk Factors Major Additional Nontraditional • Advancing age • • Increased lipoprotein (a) • High total serum cholesterol level Obesity or abdominal obesity • Elevated clotting factors • Family history of hyperlipidemia • Inflammation markers (hsCRP; Lp-PLA2) • Elevated homocysteine levels • High non–HDL-C • High LDL-C • Small, dense LDL-C • Low HDL-C • Increased Apo B • Diabetes mellitus • • Apo E4 isoform • Hypertension Increased LDL particle concentration • Elevated uric acid • Cigarette smoking • Fasting/postprandial hypertriglyceridemia • • Family history of ASCVD Increased triglyceride-rich remnants • PCOS • Dyslipidemic triad* *Hypertriglyceridemia; low HDL-C; and small, dense LDL-C. Apo, apolipoprotein; ASCVD, atherosclerotic cardiovascular disease; HDL-C, high-density lipoprotein cholesterol; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; Lp-PLA2, lipoprotein-associated phospholipase A2; PCOS, polycystic ovary syndrome. Jellinger PS, et al. Endocr Pract. 2017;23(suppl 2):1-87. 105 7-Year Incidence of MI (%) Diabetes Is a Cardiovascular Disease Risk Equivalent P<0.001 50 45 40 30 P<0.001 18.8 20.2 Prior MI No prior MI 20 10 3.5 0 No prior MI Nondiabetic (n=1373) Prior MI Diabetic (n=1059) MI, myocardial infarction. Grundy SM, et al. Circulation. 2004;110:227-239. Haffner SM, et al. N Engl J Med. 1998;339:229-234. 106 Baseline Proteinuria Increases Cardiovascular Risk Systematic Review (RCTs: N=29; Patients with DM: N=116,790; ~518,611 patient-years of follow-up) ~6-fold higher Events/1,000 patient-years 40 No Proteinuria 39.9 Mixed Trials All Proteinuria 30 ~15-fold higher 18.7 18.6 20 ~13-fold higher ~12-fold higher 11.6 12.9 10 12.4 9.3 7.5 6.3 1.2 0 All-Cause Death CVD Death 0 0 MI Stroke CVD, cardiovascular disease; MI, myocardial infarction. Preiss D, et al. Am Heart J. 2011;161:210-219. 107 Risk of All-Cause and CV Mortality According to eGFR and Albuminuria CV, cerebrovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio. Chronic Kidney Disease Prognosis Consortium. Lancet. 2010;375:2073-2081 . 108 AACE ASCVD Risk Categories Low risk: Extreme risk: • • Progressive ASCVD, including unstable angina that persists after achieving an LDL-C less than 70 mg/dL, or established clinical ASCVD with diabetes, stage 3 or 4 CKD, and/or HeFH, or in those with a history of premature ASCVD (<55 years of age for males or <65 years of age for females) • This category was added in this CPG based on clinical trial evidence and supported by meta-analyses that further lowering of LDL-C produces better outcomes in individuals with ACS. IMPROVE-IT demonstrated lower rates of cardiovascular events in those with ACS when LDL-C levels were lowered to 53 mg/dL combining ezetimibe with statins. No risk factors Moderate risk: • 2 or fewer risk factors and a calculated 10year risk of less than 10% High risk: • An ASCVD equivalent including diabetes or stage 3 or 4 CKD with no other risk factors, or individuals with 2 or more risk factors and a 10-year risk of 10%-20% Very high risk: • Established or recent hospitalization for ACS; coronary, carotid or peripheral vascular disease; diabetes or stage 3 or 4 CKD with 1 or more risk factors; a calculated 10-year risk greater than 20%; or HeFH ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; CKD, chronic kidney disease; CPG, clinical practice guideline; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; IMPROVE-IT, Improved Reduction of Outcomes: Vytorin Efficacy International Trial. Jellinger PS, et al. Endocr Pract. 2017;23(suppl 2):1-87. Cannon, CP, et al. N Engl J Med. 2015;372(25):2387-239. 109 AACE ASCVD Risk Categories Risk Category Risk factors*/10-year risk† Extreme risk • Treatment goals (mg/dL) LDL-C Non-HDL-C Apo B Progressive ASCVD including unstable angina in patients after achieving LDL-C <70 mg/dL Established clinical CVD in patients with diabetes, stage 3 or 4 CKD, or HeHF History of premature ASCVD (age <55 male, <65 female) <55 <80 <70 Established or recent hospitalization for ACS or coronary, carotid, or peripheral vascular disease, or 10-year risk >20% Diabetes or stage 3 or 4 CKD plus ≥1 additional risk factor(s) HeHF <70 <100 <80 ≥2 risk factors and 10-year risk 10-20% Diabetes or stage 3 or 4 CKD with no other risk factors <100 <130 <90 Moderate risk ≤2 risk factors and 10-year risk <10% <100 <130 <90 Low risk <130 <160 NR • • Very high risk • • • High risk • • 0 risk factors *High LDL-C, PCOS, cigarette smoking, hypertension, low HDL-C, family history of CAD, stage 3 or 4 CKD, coronary calcification, and age ≥45 years in men and ≥55 years in women. †Framingham risk score. ASCVD, atherosclerotic cardiovascular disease; CAD, coronary artery disease; CKD, chronic kidney disease; HDL-C, high density lipoprotein cholesterol; HeHF, heterozygous familial hypercholesterolemia; LDL-C low density lipoprotein cholesterol; NR, not recommended; PCOS, polycystic ovary syndrome. Jellinger PS, et al. Endocr Pract. 2017;23(suppl 2):1-87. 110 Comprehensive Management of Cardiovascular Risk • Manage CV risk factors – Weight loss – Smoking cessation – Optimal glucose, blood pressure, and lipid control • Use low-dose aspirin for secondary prevention of CV events in patients with existing CVD – May consider low-dose aspirin for primary prevention of CV events in patients with 10-year CV risk >10% • Measure coronary artery calcification or use coronary imaging to determine whether glucose, lipid, or blood pressure control efforts should be intensified CV, cardiovascular; CVD, cardiovascular disease. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 111 Statin Use in Patients with Diabetes • Majority of patients with T2D • Use a statin regardless of LDLhave a high cardiovascular risk C level in patients with diabetes who meet the following criteria: • People with T1D are at – >40 years of age elevated cardiovascular risk – ≥1 major ASCVD risk factor • LDL-C target: <70 mg/dL—for • Hypertension the majority of patients with • Family history of CVD diabetes who are determined • Low HDL-C to have a high risk • Smoking ASCVD, atherosclerotic cardiovascular disease; CVD, cardiovascular disease; HDL-C, high density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 112 Management of Common Comorbidities in Diabetes DEPRESSION 113 Prevalence of Comorbid Depression and Diabetes Community Sample (N=506) Meta-analysis No diabetes 40 40 1.9 P=0.5 OR 2.1 30 22% 20 9.9% Patients (%) Patients (%) 30 10 Diabetes 26.1 20 14.4 9.0 10 5.0 0 Major Depressive Disorder 0 Likely Depression Diagnostic Interview Self-report Scale OR, odds ratio. Fisher L, et al. Diabetes Care. 2007;30:542-548; Anderson RJ, et al. Diabetes Care. 2001;24:1069-1078 114 Depression and Adherence to Diabetes Self-management (HANDS score <9) Unlikely major depression Mean Adherent Days/Week 7 (HANDS score ≥9) Probable major depression 6 5 P<0.001 4 P=0.001 P<0.001 P=0.006 P<0.001 3 P=0.348 P=0.241 2 1 0 General diet Carbohydrates Exercise Glucose monitoring Fruits and vegetables High fat foods Foot care 2.3-Fold increased risk of missing 1 or more prescribed medications over previous week with major depression HANDS, Harvard Department of Psychiatry/National Depression Screening Day Scale. Gonzales JS, et al. Diabetes Care. 2007;30:2222-2227. 115 Mental Health Referral for Patients With Diabetes • • Establish emotional well-being as a part of diabetes management Include psychological assessment and treatment in routine care – Do not wait for deterioration in psychological status – Utilize patient-provider relationship as a foundation for psychological management • Indications for referral – – – – – • Gross noncompliance with medical regimen Depression with the possibility of self-harm Debilitating anxiety (alone or with depression) Eating disorder Cognitive functioning that significantly impairs judgment Always refer to mental health specialist familiar with diabetes management Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 116 Management of Common Comorbidities in Diabetes SLEEP APNEA 117 Obstructive Sleep Apnea Mechanisms Feedback loop involving interplay between excess visceral adipose tissue, insulin resistance, and inflammatory cytokines Excess fat reduces diaphragm mobility and promotes soft tissue edema, which in turn lead to depression of ventilation Ventilation depression causes sleep apnea and poor sleep, which contributes to daytime sleepiness and fatigue Poor sleep promotes stress hormone and interleukin 6 production, which exacerbates insulin resistance Risk Factors Obesity Neck circumference >44 cm Narrowed airway Hypertension Smoking Male sex Age Family history Alcohol or sedatives Treatment Options Continuous positive airway pressure (CPAP) Adjustable airway pressure devices Oral appliances Surgery Uvulopalatopharyngoplasty (UPPP) Maxillomandibular advancement Tracheostomy Epstein LJ, et al. J Clin Sleep Med. 2009;5:263-276. NHLBI Working Group on Sleep Apnea. Am Fam Physician. 1996;53:247-253. Vgontzas AN, et al. J Intern Med. 2003;254:32-44 . 118 Prevalence of Sleep Apnea in Type 2 Diabetes Sleep AHEAD Study Obese Patients With T2D (N=305) No OSA 13.4% Severe OSA 22.6% Moderate OSA 30.5% Mild OSA 33.4% OSA, obstructive sleep apnea. Foster GD, et al. Diabetes Care. 2009;32:1017-1019. 119 Management of Common Comorbidities in Diabetes CANCER 120 Diabetes and Cancer Risk • Diabetes (especially T2D) may: – ↑ Cancer risk • • • • • • Liver Pancreas Endometrium Colon and rectum Breast Bladder – ↓ Cancer risk: prostate Giovannucci E, et al. Diabetes Care. 2010;33:1674-1685. • Hyperinsulinemia, hyperglycemia, and inflammation may directly increase cancer risk • Shared risk factors – – – – Aging Obesity Diet Physical inactivity 121 Insulin and Cancer Risk Study Hazard Ratio (95% CI) Outcome Reduction With an Initial Glargine Intervention (ORIGIN) N=12,537; prospective RCT Median follow-up: 6.2 years Any cancer: 1.00 (0.88-1.13); P=0.97 Death from cancer: 0.94 (0.77-1.15); P=0.52 Northern European Database Study N=447,821; observational Mean follow-up: Glargine users: 3.1 years Other insulin users: 3.5 years Breast cancer (women): 1.12 (0.99-1.27) Prostate cancer (men): 1.11 (1.00-1.24) Colorectal cancer (men and women): 0.86 (0.76-0.98) Kaiser-Permanente Collaboration N=115,000; observational Median follow-up: Glargine users: 1.2 years NPH users: 1.4 years Breast cancer (women): 1.0 (0.9-1.3) Prostate cancer (men): 0.7 (0.6-0.9) Colorectal cancer (men and women): 1.00 (0.8-1.2) All cancers (men and women): 0.9 (0.9-1.0) MedAssurant Database Study N=52,453; observational Mean follow-up: Glargine users: 1.2 years NPH users: 1.1 years No increased risk for breast cancer Gerstein HC, et al. N Engl J Med. 2012;367:319-328. Kirkman MS, et al. Presented at the American Diabetes Association 72nd Scientific Sessions. June 11, 2012. Session CT-SY13. Philadelphia, PA. 122 Diabetes and Cancer Risk Management • Conduct cancer screenings as recommended for age and sex • Encourage healthful diet, physical activity, and weight management • Evidence is inconclusive on effects of specific drugs on cancer risk due to limited data and confounding factors • Cancer risk should not be a major factor in the choice of antidiabetic agent unless the patient has a very high risk of cancer occurrence or recurrence Giovannucci E, et al. Diabetes Care. 2010;33:1674-1685. 123 Diabetes and Cancer: Summary • Screen obese individuals with diabetes more frequently and rigorously for certain cancers – Endometrial, breast, hepatic, bladder, pancreatic, colorectal cancers • Increased BMI (≥25 kg/m2) also increases risk of some cancers – Strong associations: endometrial, gall bladder, esophageal , renal, thyroid, ovarian, breast, and colorectal cancer – Weaker associations: leukemia, malignant and multiple melanoma, pancreatic cancer, non-Hodgkin lymphoma • To date, no definitive relationship has been established between specific hyperglycemic agents and increased risk of cancer or cancerrelated mortality – Consider avoiding medications considered disadvantageous to specific cancers in individuals at risk for or with a history of that cancer Handelsman YH, et al. Endocr Pract. 2015;21(suppl 1):1-87. 124