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  • 1. Hypertension in people with Type 2 diabetes: knowledge-based diabetes-specific guidelines. Diabet Med, 20 : 972-87, 2003. 2. Abbott, KC & Bakris, GL: What have we learned from the current trials? Med Clin North Am, 88 : 189-207, 2004. 3. Anderson, PW, McGill, JB & Tuttle, KR: Protein kinase C beta inhibition: the promise for treatment of diabetic nephropathy. Curr Opin Nephrol Hypertens, 16 : 397-402, 2007. 4. Baghdasarian, SB, Jneid, H & Hoogwerf, BJ: Association of dyslipidemia and effects of statins on nonmacrovascular diseases. Clin Ther, 26 : 337-51, 2004. 5. Bakris, GL, Weir, MR, Shanifar, S, Zhang, Z, Douglas, J, van Dijk, DJ & Brenner, BM: Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL study. Arch Intern Med, 163 : 1555-65, 2003. 6. Bando, Y, Ushiogi, Y, Okafuji, K, Toya, D, Tanaka, N & Miura, S: Non-autoimmune primary hypothyroidism in diabetic and non-diabetic chronic renal dysfunction. Exp Clin Endocrinol Diabetes, 110 : 408-15, 2002. 7. Berl, T, Hunsicker, LG, Lewis, JB, Pfeffer, MA, Porush, JG, Rouleau, JL, Drury, PL, Esmatjes, E, Hricik, D, Parikh, CR, Raz, I, Vanhille, P, Wiegmann, TB, Wolfe, BM, Locatelli, F, Goldhaber, SZ & Lewis, EJ: Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med, 138 : 542-9, 2003. 8. Brenner, BM, Cooper, ME, de Zeeuw, D, Keane, WF, Mitch, WE, Parving, HH, Remuzzi, G, Snapinn, SM, Zhang, Z & Shahinfar, S: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med, 345 : 861-9, 2001. 9. Chalmers, J: Comparison of various blood pressure lowering treatments on the primary prevention of cardiovascular outcomes in recent randomised clinical trials. Clin Exp Hypertens, 26 : 709-19, 2004. 10. de Zeeuw, D, Remuzzi, G, Parving, HH, Keane, WF, Zhang, Z, Shahinfar, S, Snapinn, S, Cooper, ME, Mitch, WE & Brenner, BM: Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation, 110 : 921-7, 2004. 11. Dussol, B & Berland, Y: [What do large clinical trials learn us about cardiovascular and renal prevention in patients with type 2 diabetes mellitus and hypertension?]. Nephrol Ther, 2 : 51-74, 2006. 12. Facchini, FS & Saylor, KL: A low-iron-available, polyphenol-enriched, carbohydrate-restricted diet to slow progression of diabetic nephropathy. Diabetes, 52 : 1204-9, 2003. 13. Fitchett, D: Have angiotensin receptor blockers lived up to expectations? Can J Cardiol, 21 : 569-75, 2005. 14. Folan, LA & Tuttle, KR: Diabetic nephropathy: implications for renal and cardiovascular outcomes. Minerva Med, 95 : 385-94, 2004. 15. Friedman, AN, Hunsicker, LG, Selhub, J & Bostom, AG: C-reactive protein as a predictor of total arteriosclerotic outcomes in type 2 diabetic nephropathy. Kidney Int, 68 : 773-8, 2005. 16. Gerstein, HC: Diabetes and the HOPE study: implications for macrovascular and microvascular disease. Int J Clin Pract Suppl : 8-12, 2001. 17. Gerstein, HC, Bosch, J, Pogue, J, Taylor, DW, Zinman, B & Yusuf, S: Rationale and design of a large study to evaluate the renal and cardiovascular effects of an ACE inhibitor and vitamin E in high-risk patients with diabetes. The MICRO-HOPE Study. Microalbuminuria, cardiovascular, and renal outcomes. Heart Outcomes Prevention Evaluation. Diabetes Care, 19 : 1225-8, 1996. 18. Grover, SA, Coupal, L & Lowensteyn, I: Estimating the cost effectiveness of ramipril used for specific clinical indications: comparing the outcomes in four clinical trials with a common economic model. Am J Cardiovasc Drugs, 7 : 441-8, 2007. 19. Hoogwerf, BJ & Young, JB: The HOPE study. Ramipril lowered cardiovascular risk, but vitamin E did not. Cleve Clin J Med, 67 : 287-93, 2000. 20. Hughes, DB & Britton, ML: Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers for prevention and treatment of nephropathy associated with type 2 diabetes mellitus. Pharmacotherapy, 25 : 1602-20, 2005. 21. Jungmann, E: Prevention and treatment of diabetic nephropathy in older patients. Drugs Aging, 20 : 419-35, 2003. 22. Leung, WY, So, WY, Tong, PC, Chan, NN & Chan, JC: Effects of structured care by a pharmacist-diabetes specialist team in patients with type 2 diabetic nephropathy. Am J Med, 118 : 1414, 2005. 23. Lewis, EJ, Hunsicker, LG & Rodby, RA: A clinical trial in type 2 diabetic nephropathy. Am J Kidney Dis, 38 : S191-4, 2001. 24. Maione, A, Nicolucci, A, Craig, JC, Tognoni, G, Moschetta, A, Palasciano, G, Pugliese, G, Procaccini, DA, Gesualdo, L, Pellegrini, F & Strippoli, GF: Protocol of the Long-term Impact of RAS Inhibition on Cardiorenal Outcomes (LIRICO) randomized trial. J Nephrol, 20 : 646-55, 2007. 25. Malik, RA: Can diabetic neuropathy be prevented by angiotensin-converting enzyme inhibitors? Ann Med, 32 : 1-5, 2000. 26. McCullough, PA, Bakris, GL, Owen, WF, Jr., Klassen, PS & Califf, RM: Slowing the progression of diabetic nephropathy and its cardiovascular consequences. Am Heart J, 148 : 243-51, 2004. 27. Palmer, AJ, Annemans, L, Roze, S, Lamotte, M, Rodby, RA & Bilous, RW: An economic evaluation of the Irbesartan in Diabetic Nephropathy Trial (IDNT) in a UK setting. J Hum Hypertens, 18 : 733-8, 2004. 28. Palmer, AJ & Rodby, RA: Health economics studies assessing irbesartan use in patients with hypertension, type 2 diabetes, and microalbuminuria. Kidney Int Suppl : S118-20, 2004. 29. Philips, JC, Weekers, L & Scheen, AJ: [Clinical study of the month. The CALM study assessing the combination of an angiotensin-converting enzyme inhibitor and an angiotensin II receptor antagonist in the treatment of diabetic nephropathy]. Rev Med Liege, 56 : 126-8, 2001. 30. Raij, L: Recommendations for the management of special populations: renal disease in diabetes. Am J Hypertens, 16 : 46S-49S, 2003. 31. Ravera, M, Re, M & Vettoretti, S: Economic evaluation of angiotensin receptor blockers in type 2 diabetes, hypertension, and nephropathy. J Am Soc Nephrol, 17 : S44-8, 2006. 32. Ruilope, LM & Segura, J: Losartan and other angiotensin II antagonists for nephropathy in type 2 diabetes mellitus: a review of the clinical trial evidence. Clin Ther, 25 : 3044-64, 2003. 33. See, S: Angiotensin II receptor blockers for the treatment of hypertension. Expert Opin Pharmacother, 2 : 1795-804, 2001. 34. Stojiljkovic, L & Behnia, R: Role of renin angiotensin system inhibitors in cardiovascular and renal protection: a lesson from clinical trials. Curr Pharm Des, 13 : 1335-45, 2007. 35. Taddei, S, Ghiadoni, L & Salvetti, A: Current treatment of patients with hypertension: therapeutic implications of INSIGHT. Drugs, 63 : 1435-44, 2003. 36. Thomas, GN, Chan, P & Tomlinson, B: The role of angiotensin II type 1 receptor antagonists in elderly patients with hypertension. Drugs Aging, 23 : 131-55, 2006. 37. Weber, MA: The angiotensin II receptor blockers: opportunities across the spectrum of cardiovascular disease. Rev Cardiovasc Med, 3 : 183-91, 2002. 38. Yamagishi, S & Nakamura, K: Revival of nifedipine, a dihydropyridine-based calcium blocker. Med Hypotheses, 68 : 565-7, 2007. 39. Zanella, MT & Ribeiro, AB: The role of angiotensin II antagonism in type 2 diabetes mellitus: a review of renoprotection studies. Clin Ther, 24 : 1019-34, 2002.    
  • 1. Hypertension in people with Type 2 diabetes: knowledge-based diabetes-specific guidelines. Diabet Med, 20 : 972-87, 2003. 2. Abbott, KC & Bakris, GL: What have we learned from the current trials? Med Clin North Am, 88 : 189-207, 2004. 3. Anderson, PW, McGill, JB & Tuttle, KR: Protein kinase C beta inhibition: the promise for treatment of diabetic nephropathy. Curr Opin Nephrol Hypertens, 16 : 397-402, 2007. 4. Baghdasarian, SB, Jneid, H & Hoogwerf, BJ: Association of dyslipidemia and effects of statins on nonmacrovascular diseases. Clin Ther, 26 : 337-51, 2004. 5. Bakris, GL, Weir, MR, Shanifar, S, Zhang, Z, Douglas, J, van Dijk, DJ & Brenner, BM: Effects of blood pressure level on progression of diabetic nephropathy: results from the RENAAL study. Arch Intern Med, 163 : 1555-65, 2003. 6. Bando, Y, Ushiogi, Y, Okafuji, K, Toya, D, Tanaka, N & Miura, S: Non-autoimmune primary hypothyroidism in diabetic and non-diabetic chronic renal dysfunction. Exp Clin Endocrinol Diabetes, 110 : 408-15, 2002. 7. Berl, T, Hunsicker, LG, Lewis, JB, Pfeffer, MA, Porush, JG, Rouleau, JL, Drury, PL, Esmatjes, E, Hricik, D, Parikh, CR, Raz, I, Vanhille, P, Wiegmann, TB, Wolfe, BM, Locatelli, F, Goldhaber, SZ & Lewis, EJ: Cardiovascular outcomes in the Irbesartan Diabetic Nephropathy Trial of patients with type 2 diabetes and overt nephropathy. Ann Intern Med, 138 : 542-9, 2003. 8. Brenner, BM, Cooper, ME, de Zeeuw, D, Keane, WF, Mitch, WE, Parving, HH, Remuzzi, G, Snapinn, SM, Zhang, Z & Shahinfar, S: Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med, 345 : 861-9, 2001. 9. Chalmers, J: Comparison of various blood pressure lowering treatments on the primary prevention of cardiovascular outcomes in recent randomised clinical trials. Clin Exp Hypertens, 26 : 709-19, 2004. 10. de Zeeuw, D, Remuzzi, G, Parving, HH, Keane, WF, Zhang, Z, Shahinfar, S, Snapinn, S, Cooper, ME, Mitch, WE & Brenner, BM: Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation, 110 : 921-7, 2004. 11. Dussol, B & Berland, Y: [What do large clinical trials learn us about cardiovascular and renal prevention in patients with type 2 diabetes mellitus and hypertension?]. Nephrol Ther, 2 : 51-74, 2006. 12. Facchini, FS & Saylor, KL: A low-iron-available, polyphenol-enriched, carbohydrate-restricted diet to slow progression of diabetic nephropathy. Diabetes, 52 : 1204-9, 2003. 13. Fitchett, D: Have angiotensin receptor blockers lived up to expectations? Can J Cardiol, 21 : 569-75, 2005. 14. Folan, LA & Tuttle, KR: Diabetic nephropathy: implications for renal and cardiovascular outcomes. Minerva Med, 95 : 385-94, 2004. 15. Friedman, AN, Hunsicker, LG, Selhub, J & Bostom, AG: C-reactive protein as a predictor of total arteriosclerotic outcomes in type 2 diabetic nephropathy. Kidney Int, 68 : 773-8, 2005. 16. Gerstein, HC: Diabetes and the HOPE study: implications for macrovascular and microvascular disease. Int J Clin Pract Suppl : 8-12, 2001. 17. Gerstein, HC, Bosch, J, Pogue, J, Taylor, DW, Zinman, B & Yusuf, S: Rationale and design of a large study to evaluate the renal and cardiovascular effects of an ACE inhibitor and vitamin E in high-risk patients with diabetes. The MICRO-HOPE Study. Microalbuminuria, cardiovascular, and renal outcomes. Heart Outcomes Prevention Evaluation. Diabetes Care, 19 : 1225-8, 1996. 18. Grover, SA, Coupal, L & Lowensteyn, I: Estimating the cost effectiveness of ramipril used for specific clinical indications: comparing the outcomes in four clinical trials with a common economic model. Am J Cardiovasc Drugs, 7 : 441-8, 2007. 19. Hoogwerf, BJ & Young, JB: The HOPE study. Ramipril lowered cardiovascular risk, but vitamin E did not. Cleve Clin J Med, 67 : 287-93, 2000. 20. Hughes, DB & Britton, ML: Angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers for prevention and treatment of nephropathy associated with type 2 diabetes mellitus. Pharmacotherapy, 25 : 1602-20, 2005. 21. Jungmann, E: Prevention and treatment of diabetic nephropathy in older patients. Drugs Aging, 20 : 419-35, 2003. 22. Leung, WY, So, WY, Tong, PC, Chan, NN & Chan, JC: Effects of structured care by a pharmacist-diabetes specialist team in patients with type 2 diabetic nephropathy. Am J Med, 118 : 1414, 2005. 23. Lewis, EJ, Hunsicker, LG & Rodby, RA: A clinical trial in type 2 diabetic nephropathy. Am J Kidney Dis, 38 : S191-4, 2001. 24. Maione, A, Nicolucci, A, Craig, JC, Tognoni, G, Moschetta, A, Palasciano, G, Pugliese, G, Procaccini, DA, Gesualdo, L, Pellegrini, F & Strippoli, GF: Protocol of the Long-term Impact of RAS Inhibition on Cardiorenal Outcomes (LIRICO) randomized trial. J Nephrol, 20 : 646-55, 2007. 25. Malik, RA: Can diabetic neuropathy be prevented by angiotensin-converting enzyme inhibitors? Ann Med, 32 : 1-5, 2000. 26. McCullough, PA, Bakris, GL, Owen, WF, Jr., Klassen, PS & Califf, RM: Slowing the progression of diabetic nephropathy and its cardiovascular consequences. Am Heart J, 148 : 243-51, 2004. 27. Palmer, AJ, Annemans, L, Roze, S, Lamotte, M, Rodby, RA & Bilous, RW: An economic evaluation of the Irbesartan in Diabetic Nephropathy Trial (IDNT) in a UK setting. J Hum Hypertens, 18 : 733-8, 2004. 28. Palmer, AJ & Rodby, RA: Health economics studies assessing irbesartan use in patients with hypertension, type 2 diabetes, and microalbuminuria. Kidney Int Suppl : S118-20, 2004. 29. Philips, JC, Weekers, L & Scheen, AJ: [Clinical study of the month. The CALM study assessing the combination of an angiotensin-converting enzyme inhibitor and an angiotensin II receptor antagonist in the treatment of diabetic nephropathy]. Rev Med Liege, 56 : 126-8, 2001. 30. Raij, L: Recommendations for the management of special populations: renal disease in diabetes. Am J Hypertens, 16 : 46S-49S, 2003. 31. Ravera, M, Re, M & Vettoretti, S: Economic evaluation of angiotensin receptor blockers in type 2 diabetes, hypertension, and nephropathy. J Am Soc Nephrol, 17 : S44-8, 2006. 32. Ruilope, LM & Segura, J: Losartan and other angiotensin II antagonists for nephropathy in type 2 diabetes mellitus: a review of the clinical trial evidence. Clin Ther, 25 : 3044-64, 2003. 33. See, S: Angiotensin II receptor blockers for the treatment of hypertension. Expert Opin Pharmacother, 2 : 1795-804, 2001. 34. Stojiljkovic, L & Behnia, R: Role of renin angiotensin system inhibitors in cardiovascular and renal protection: a lesson from clinical trials. Curr Pharm Des, 13 : 1335-45, 2007. 35. Taddei, S, Ghiadoni, L & Salvetti, A: Current treatment of patients with hypertension: therapeutic implications of INSIGHT. Drugs, 63 : 1435-44, 2003. 36. Thomas, GN, Chan, P & Tomlinson, B: The role of angiotensin II type 1 receptor antagonists in elderly patients with hypertension. Drugs Aging, 23 : 131-55, 2006. 37. Weber, MA: The angiotensin II receptor blockers: opportunities across the spectrum of cardiovascular disease. Rev Cardiovasc Med, 3 : 183-91, 2002. 38. Yamagishi, S & Nakamura, K: Revival of nifedipine, a dihydropyridine-based calcium blocker. Med Hypotheses, 68 : 565-7, 2007. 39. Zanella, MT & Ribeiro, AB: The role of angiotensin II antagonism in type 2 diabetes mellitus: a review of renoprotection studies. Clin Ther, 24 : 1019-34, 2002.    
  • Pharmaceutical therapies that inhibit ACE have shown efficacy, in previous studies, in slowing the deterioration of renal function in diabetic nephropathy. Maschio and colleagues performed a 3-year, double-blind, randomized study on 583 patients with renal insufficiency to compare the efficacy of the ACE inhibitor benazepril with placebo in slowing the progression of the disorder in patients with various underlying causes. Three hundred patients were randomized to benazepril, 283 to placebo. Patients ranged in age from 18 to 70 years and had CKD caused by glomerulopathies (192), interstitial nephritis (105), nephrosclerosis (97), polycystic kidney disease (64), diabetic nephropathy (21), and miscellaneous or unknown disorders (104). Inclusion criteria for CKD: SCr concentration of 1.5 to 4.0 mg/dL and 24-hour estimated Ccr of 30 to 60 mL/min. As shown in the above Kaplan-Meier curve showing estimates of renal survival among the evaluable patients, significantly more patients who received benazepril experienced renal survival than patients who received placebo ( P  0.001); overall risk reduction of progressive renal insufficiency was 71% among patients with mild insufficiency and 46% among patients with moderate insufficiency. Maschio G, Alberti D, Janin G, et al. Effect of the angiotensin-converting enzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med . 1996;334:939-945.
  • In patients with type 1 diabetes, antihypertensive treatment was associated with beneficial effects on proteinuria and the incidence of ESRD and cardiovascular mortality.

Diabetes Diabetes Presentation Transcript

  •  
  • Objectives
    • Educate physicians and nurses on practical management tips for diabetes control.
    • Identify goals for diabetes therapy in patients with CKD with emphasis on prevention and medication side effects
  • At the end of this online presentation you should
    • Understand the relationship between diabetes and kidney disease
    • Know the difference between type 1 and Type 2 diabetes
    • Be familiar with some of the clinical trials that have shaped our progress
    • List key management objectives for Diabetes as it relates to progressive CKD
    • Be familiar with therapy for diabetes
  • Incidence ESRD due to Diabetes in Network 14 is 206/million Each year in Texas 206/million patients start dialysis because of diabetic nephropathy. Texas has the highest incidence in the nation. Source: USRDS
  • Diabetes is the main cause of ESRD
  • Predicted and actual cost adjusted by diagnosis Dialysis management of diabetic ESRD patients, particularly with heart failure Source: USRDS
    • Type 1 – onset in youth, destruction of beta cells and a requirement for insulin
    • Type 2 – onset as adult or young adult, related to insulin resistance. May be treated with lifestyle modification, oral medications, and later may require insulin
  • Type 1 Diabetes
      • Insulin-dependent/Juvenile onset
      • 20 to 30% develop microalbuminuria after 15 years
        • Amin, R, Widmer, B, Dalton, N & Dunger, DB: Unchanged incidence of Microalbuminuria in Children with Type 1 Diabetes since 1986: A UK based inception cohort. Arch Dis Child : adc.2008.144337, 2009.
      • Of the ones who develop this less than half progress to diabetic nephropathy
      • Associated with microvascular disease – retina and kidney. The increased sugar is neurotoxic – hence neuropathy
      • 2.2 percent will develop ESRD in 20 years and 7.8 percent in 30 years
        • Finne P, Reunanen A, Stenman S, et al. Incidence of end-stage renal disease in patients with type 1 diabetes. JAMA 2005; 294: 1782-1787.
  • Type 1 Diabetes (Continued)
      • The microalbuminuria can regress – and it is not always related to the use of ACE or ARB therapy
        • Perkins, BA, Ficociello, LH, Silva, KH, Finkelstein, DM, Warram, JH & Krolewski, AS: Regression of Microalbuminuria in Type 1 Diabetes. N Engl J Med, 348 : 2285-2293, 2003
      • The risk of developing kidney failure after 20 to 25 years in patients who have no proteinuria is low
      • Labile swings in blood sugar because of autonomic insufficiency
      • Always requires insulin
      • If diabetic nephropathy develops, the patient will develop insulin resistance – metabolic syndrome due to kidney disease. Atherosclerosis and hypertension are not primary but secondary events
  • Type 2 Diabetes
    • Common in Hispanics, Native Americans and Pima Indians
    • Incidence of ESRD is lower, but the disease is more frequent – thus it is the most common cause of renal failure
    • United Kingdom Prospective Diabetes Study
      • UKPDS – large British study, (predominantly Caucasians)
      • Adler, AI, Stevens, RJ, Manley, SE, Bilous, RW, Cull, CA & Holman, RR: Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int, 63 : 225-32, 2003.
      • Incidence of microalbuminuria 25% but incidence of ESRD only 0.8%
      • Microlbuminuria patients spent an average of 11 years before progressing to overt proteinuria
      • Only 2.3% progress from macroalbuminuria to ESRD
  • Type 2 Diabetes (Continued)
    • Disease progresses slowly over many years and is associated with proteinuria. The urine should show more than just red cells.
    • In the elderly, it is impossible to clinically distinguish the hypertensive and atherosclerotic effects from the diabetic effects without a kidney biopsy.
    • Not associated with labile blood sugar swings
    • Insulin resistance
  • Incidence of Type 2 Diabetes
    • Doubled in past 20 years
    • Framingham Offspring Study
    • Related to Lifestyle Change and Obesity
    • BMI Increase confirmed by NHANES Dataset
      • Source: American Heart Association
    • Prevalence of Diagnosed and Undiagnosed Diabetes in the United States, All Ages, 2007
      • Total: 23.6 million people
        • 7.8 percent of the population—have diabetes.
        • Diagnosed: 17.9 million people
        • Undiagnosed: 5.7 million people
      • Source: NIDDK
  • Metabolic Syndrome
    • Characterized by insulin resistance – 50 to 75 million Americans
      • High blood pressure
      • High blood sugars
      • High levels of triglycerides
      • Low levels of HDL
      • Increased waist line
    • It is associated with
      • Diabetes, Hypertension, stroke, cardiovascular disease
    • Dominant Features
      • Obesity, lack of exercise
  • Diet Plays a Major Role
    • The Sugar Fix
      • High fructose corn syrup
        • Decreases the ATP in cells – this decreases cell respiration and causes hypoxia in cells
        • Releases cytokines that impair nitrous oxide synthesis
        • Releases uric acid which increases blood pressure
        • Causes leptin resistance (Leptin turns off the appetite) continue to be hungry
        • Supersized – HFCS is in many soft drinks and other products
        • Americans eat more sugar, now have an epidemic of obesity, the metabolic syndrome, heart disease and diabetes
  • Management Objectives
    • Lifestyle
      • An aspirin a day
      • Smoking and Exercise
      • Weight/cholesterol
    • Blood Pressure
    • ACE and ARB
    • Vitamin D
    • Diabetes Control
  • Lifestyle - An aspirin a day - Smoking and Exercise - Weight/cholesterol
    • Can be a rewarding way to keep diabetes under control.
    • Requires a lifelong strategy
    • Diet: Avoid fructose, excess salt, trans fats and excess carbohydrates
    • Two alcoholic beverages at most/day
    • 25% incident diabetics are smokers
      • Potentiates kidney disease
      • Increases inflammation
    • Gentle aerobic exercise
    • Aspirin a day to reduce cardiovascular risk
  • ACE and ARB
  • Blood pressure goal in CKD < 130/80
    • Any person with abnormal kidneys is at risk for heart disease
    • Most patients will require two or more medications to control their blood pressure
    • Lowering the systolic blood pressure to <130 mm Hg is usually associated with a reduction in diastolic blood pressure to <80 mm Hg
    Adapted from American Journal of Kidney Diseases, Vol 43, No 5, Suppl Suppl 1 (May), 2004: pp S14-S15
  • Many blood pressures medications may be needed to control severe blood pressure
  • Blood pressure is poorly controlled in patients with kidney disease
  •  
  •  
  •  
  • ACES & ARBS are the two major classes of medications used to treat high blood pressure
  • Effect of ACE Inhibitors on Progression of CKD Maschio. N Engl J Med . 1996;334:939.
  • Proteinuria is a powerful determinant of renal deterioration. Source: The New England Journal of Medicine -- November 12, 1998 -- Vol. 339, No. 20 Mechanisms of Disease: Pathophysiology of Progressive Nephropathies Giuseppe Remuzzi, Tullio Bertani
  • Collaborative Study Group – Reduction of proteinuria in Type 1 DM with ACE 20% -40% 37% 22% 7% 4% -60 -40 -20 0 20 40 60 Changes in proteinuria Incidence of ESRD Incidence of mortality Percent Placebo Captopril Lewis EJ, et al. N Engl J Med . 1993;329:1456-1462.
  • ARBS in Diabetes – The RENAAL Trial
      • (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan)
        • Brenner. BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G,Snapinn SM, Zhang Z, Shahinfar S; RENAAL Study InvestigatorsEffects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001 Sep 20;345(12):861-9.
      • Randomized, double-blind, multicenter, placebo-controlled
      • Losartan Vs Placebo and conventional BP medications
      • 1513 patients
      • Outcome: Composite of doubling creatinine, ESRD, Death
      • Followup 3.4 years
      • RESULT: Reduced doubling of creatinine by 25% and ESRD by 28%
  • ARBS in Diabetes - IRMA
    • IRMA (Irbesartan Microalbuminuria) study
      • Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P;Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group.The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001 Sep 20;345(12):870-8
    • multicenter, randomized, double-blind, placebo-controlled trial, randomized
    • 590 patients with type 2 diabetic nephropathy (albuminuria)
    • Randomized to irbesartan, 150 mg, 300 mg (Avapro) or placebo
    • Blood pressure medications allowed
    • Endpoint was overt nephropathy – a urine albumin at least 30% greater than baseline
      • 10/194 (300 mg group) – reached endpoint
      • 19/195 (150 mg group) – reached endpoint
      • 30/201 (Placebo group) – reached endpoint
      • Blood pressure unchanged
  • ARBS in Diabetes IDNT
    • IDNT (Irbesartan Diabetic Nephropathy Trial)
      • Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851-860.
    • Randomized, double-blind, placebo-controlled
    • 1715 patients to irbesartan,amlodipine or placebo
    • 2.6 years
    • BP therapy allowed (with exception on study drugs)
    • Result:
      • Lowered risk of developing ESRD by 23%
  • What slows progression?
    • Proven interventions
      • Control blood sugar in diabetics
      • Strict blood pressure control
      • Certain meds: ACES (Angiotensin-converting enzyme inhibition) and ARBS (angiotensin-2-receptor blockade)
    • Studied, but inconclusive
      • Dietary protein restriction
      • Lipid lowering therapy
      • Partial correction of anemia
      • Vitamin D administration
  • How are we doing?
    • Elderly diabetic patients
    • Medical insurance claims
    • 65 years and older
    • 30,750 patients studied (58.7% also had high blood pressure and/or protein in the urine)
    • Of these only 50.7% (CI 50.0-51.4) received an ACE or ARB
    Am J Kidney Dis. 2005 Dec;46(6):1080-7.
  • ACCOMPLISH TRIAL
    • Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial
    • Has been stopped early – accomplished its goal
    • benazepril plus amlodipine better than benazepril plus hydrochlorothiazide
    • Study group – Hypertensives at risk secondary to previous events or diabetes
    • 11,464 patients
      • ≥ 55 years old
      • BP ≥ 160
      • 60.4% with diabetes
      • Obese
      • Cardiovascular, renal disease or target damage
    • 70% treated with two or more agents
    • Only 37.5% had blood pressure les than 140/90
    • Endpoints – cardiovascular morbidity MI, (stroke, unstable angina, bypass) or death
    • ACE/amlodipine Risk reduced by 20% compared with ACE/diuretic
      • SOURCE: Presented by KA Jamerson, American College of Cardiology, March 31, 2008
  •  
  • Vitamin D
    • Type 1 Diabetes in children might be prevented with vitamin D supplements and 5 – 10 minutes of noon sunlight
    • Epidemiology study
    • UCSD
      • SOURCE: University of California - San Diego. &quot;Sun Exposure And Vitamin D Levels May Play Strong Role In Risk Of Type 1 Diabetes In Children.&quot; ScienceDaily 5 June 2008. 10 March 2009 <http://www.sciencedaily.com­ /releases/2008/06/080605073804.htm>.
  •  
    • Sulfonylureas
    • Biguanides
    • Thiazolidinediones “Glitazones”
    • Meglitinides
    • DPP-4 Inhibitors
    • Incretin Memetics
    • Insulin
  • ADA Guidelines
  • TYPE NAME MECHANISM ROUTE, TIME Sulfonylureas Glimepiride Glipizide Glyburide Increases insulin production through K channels of beta cells Po qd or bid Biguanides Metformin (Glucophage) Reduce hepatic glucose output and increase its muscle uptake Po bid – tid XR – po qd Thiazolidinediones “Glitazones” Rosiglitazone (Avandia) Pioglitazone (Actos) PPAR gamma ligand – improves glucose utilization Po qd Meglitinides Repaglinide (Prandin) Nateglinide (Starlix) Close K channel and open Ca channel in Beta cell – increasing insulin Po 5 – 30 min AC DPP-4 Inhibitors Sitagliptin (Januvia) Blocks, DPP-4 which catalyzes enzyme breaking down insulin 100 mg po qd Incretin Memetics Exenatide (Byetta) Stimulates beta cells and slows digestion 10 mcg sc 60 min AC AM and PM meal
  • SULFONYUREAS
    • First category of oral agents for diabetes – now in third generation
    • Mainly for type 2 diabetes – work on existing beta cells
    • Increase secretion of insulin by binding to potassium channels and opening calcium channels
    • Can cause hypoglycemia and weight gain
  • BIGUANIDES
    • Metformin used in obese type 2 diabetics
    • Maximum reduction in HgbA1c after 6 months
    • Action lasts additional 9 months with thiazolidinedione
    • With sulfonureas HgbA1C tends to increase
    • Reduced cardiovascular risks
      • Pharmacotherapy. 2007 Aug;27(8):1102-10.Loss of glycemic control in patients with type 2 diabetes mellitus who werereceiving initial metformin, sulfonylurea, or thiazolidinedione monotherapy.Riedel AA, Heien H, Wogen J, Plauschinat CA.
  • ROSIGLITAZONE
    • Controversy regarding risk of causing MI
      • Odds ratio 1.43
    • ADOPT – increased fractures
    • Associated with macular edema
    • Stimulates the PPARγ receptor
    • Not to be used in heart failure
      • Nissen SE, Wolski K. Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes. N Engl J Med . 2007;356(24):2457-2471.
  • INCRETIN MIMETICS
    • Exenatide (Byetta)
    • From the saliva of the gila monster
    • Incretin – mimetic
      • Enhances beta cell insulin
      • Blocks glucagon
      • Delays gastric emptying
    • Injection sub cutaneously 30 to 60 minutes before first and last meal – adjunctive therapy
    • Side effects – Gastrointestinal symptoms
    • FDA warning – pancreatitis – may be fatal
  • WHEN TO START INSULIN
    • Start with oral agents (metformin) and proceed to insulin if goal is not achieved
    • May be able to manage for up to 6 years
    • HgbA1C – use a target
    • In kidney patients and those who may be operating heavy machinery – because of the risk of hypoglycemia – may want to have a higher goal
    • Mono-duo-triple therapy – disease has advanced
  • HgbA1C
    • American Diabetic Association 7.0%
    • American Society of Clinical Endocrinologist 6.5%
    • Many local endocrinologist 6.0%
    • CONTROVERSY: The lower the HgbA1C the lower the risk of microvascular disease, but the higher the risk of hypoglycemia
  •  
  • Adapted from Hirsch IB, Edelman SV Practical Management of Type 1 Diabetes, PCI Book,, West Islip Ny (2005) PREPARATION ONSET PEAK DURATION MAX DURATION RAPID ACTING Lispro (Humalog) 5 – 15 min .5-1.5 hr 5 hr 4-6 hr Aspart (Novolog) Glulisine (Apidra) SHORT Regular .5 – 1 hr 2 – 3 hr 5 – 8 hr 6 – 10 hr INTERMEDIATE NPH (isophane) 2 – 4 hr 4-10 hr 10-16 hr 14-18 hr Lente (zinc) 2 – 4 hr 4-12 hr 12-18 hr 16-20 hr LONG Ultralente 6 – 10 hr 10-16 hr 18-24 hr 20-14 hr LONG ANALOGUE Glargine (Lantus) 2 – 4 hr No Peak 20-24 hr 24 hr COMBINATIONS 70/30 NPH/Reg .5 to 1 hr Dual 10 -16 hr 14-18 hr 50/50 NPH/Reg CONBINATION ANALOGUES 75/25 NPL/lispro 5 – 15 min Dual 10 -16 hr 14-18 hr 70/30 NPL/aspart
  • INSULIN
    • Glucose homeostasis declines –
      • Loss of post prandial glycemic control
      • Decline in control around breakfast
      • Nocturnal Hyperglycemia
    • Consider prandial insulin before starting basal insulin
    • Basal insulin typically started in type 2
  • Diabetes and the eye
    • Type 1
      • Almost always have retinopathy and neuropathy by the time they develop nephropathy, but many patients with retinopathy do not have nephropathy
      • Detected clinically by the doctor or opthalmologist
    • Type 2
      • Retinopathy will likely be accompanied by nephropathy
      • If no retinopathy is present, they may have something other than diabetic nephropathy
  • Background Diabetic Retinopathy NORMAL BDR
  • ADOPT A Diabetes Outcome Progression Trial
    • 4360 Patients with type 2 diabetes
    • Rosiglitazone, metformin, glyburide
    • Double blind randomized
    • Treated 4 years
    • Outcome – time to medial failure
    • Results
      • Monotherapy at five years – when compared with metformin
      • 32% risk reduction with rosiglitazone
      • 63% risk reduction with glyburide
      • Better blood sugar control with glitazone
    • N Engl J Med. 2006 Dec 7;355(23):2427-43. Epub 2006 Dec 4..Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy.Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, LachinJM, O'Neill MC, Zinman B, Viberti G; ADOPT Study Group.
  • DREAM
    • Lancet. 2006 Sep 23;368(9541):1096-105.
    • Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial.
    • DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators, Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N, Hanefeld M, Hoogwerf B, Laakso M, Mohan V, Shaw J, Zinman B, Holman RR.
    • Multicenter – RCT – Rosiglitazone v placebo – follow up median of 3 years
    • Primary Outcome – Composite – incident diabetes or death
    • Type Intent to treat
    • GOAL: prevent type 2 diabetes in high risk patients
    • 5269 adults ≥ 30 years old with abnormal glucose tolerance, no prior CV diease
    • Composite reached
      • Rosiglitazone 11.6%
      • Placebo 26%
    • Euglycemic
      • Rosiglitazone 50.5%
      • Placebo 30.3%
      • Cardiovascular
    • Heart Failure
      • Rosiglitazone 0.5%
      • Placebo 0.1%
  • Common Medications to avoid in CKD
    • NSIADS
      • Ibuprofen (Motrin)
      • Indomethacin (Indocin)
      • Naproxen (Aleve, Anaprox, Naprosyn)
      • (Celecoxib) Celebrex
      • (Rofecoxib) Vioxx
    • METFORMIN
      • Glucophage, Diaformin
  • DRUGS THAT RAISE POTASSIUM
    • Beta blockers like propanolol
    • ACES
    • ARBS
    • Renin inhibitors
    • NSAIDS
    • Potassium sparing diuretics
  • Lowering Potasium
    • Glucose and insulin
    • Albuterol
    • Kayexalate
    • Loop diuretics
    • Thiazide diuretics
  • Hardening of the Arteries
    • Vascular Calcification
      • Potentiated by metabolic syndrome and kidney disease
      • Accumulation of phosphorus with decreased bone turnover in CKD associated with the metabolic syndrome potentiates changes in cells inside blood vessel walls
      • These vessels accumulate phosphorus and calcium – leading to vascular calcification
      • Common in diabetes and in CKD
  • Diabetes Complications
    • Vascular Disease
      • Peripheral vascular disease
      • Amputations
    • Autonomic insufficiency
      • Gastroparesis
      • Postural hypotension
      • Bladder dysfunction
    • Neuropathy
      • Charcot Joints
      • Burning Neuropathy
  • Impact of diabetes on dialysis blood pressure management
    • Autonomic insufficiency
      • BP drops and very labile
    • Medial Calcification
      • Wide Pulse Pressure
    • Hypertensive cardiomyopathy
      • Preload
      • Cardiac function
      • Afterload
  • Summary of prevention
    • Lifestyle Modification
    • ACE inhibitor therapy
    • ARB therapy
    • Control Blood sugar
    • Control Blood pressure
    • Vitamin D
    • Titrate proteinuria
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