Impact of declining renal function on treatment choice in diabetes           林 文 玉 醫師         台中市大里區大里仁愛醫院           內分泌新陳...
Causes of Declining Renal Function1)   Diabetic Nephropathy2)   Hypertension3)   Vascular Disease4)   Polycystic Kidney Di...
Diabetes:                            The Most Common Cause of ESRD                       Primary Diagnosis for Patients Wh...
Quality of Diabetes Management             Glycemic Control, A1c           Declining renal functionBlood pressure control ...
Definition of Diabetic Nephropathy Diabetic nephropathy has been classically defined by the presence of proteinuria >0.5 g...
Microalbuminuria and Macroalbuminuria                             DIABETES CARE, VOLUME 28, NUMBER 1, JANUARY 2005 165
We conclude that microalbuminuria in patients with Type IIdiabetes is predictive of clinical proteinuria and increasedmort...
DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011
Epidemiology1.     Approximately 7% of Diabetes naive pts already have microalbuminuria       (Adler et al., 2003). Howeve...
Albuminuria May Precede the Development of Diabetes                                 Modern Pathology 2004
Change of Glomerular Basement Membrane at             Pre-diabetes stage         Blood tests for diabetes were positive in...
Diabetic Nephropathy   Not all DM patients in ESRD suffer from classic    Kimmelstiel-Wilson syndrome ( enlarged kidney a...
Prevalence of the different stages of nephropathy with           increasing duration of diabetesUKPDS 64
UKPDS 64, Development and Progression of DN
UKPDS 74 Progression38 % of 4031 developed MAU at 15 yrs • 64 % had eCrCl > 60 ml/min/1.73m2 • 24 % had eCrCl < 60 ml/min...
UKPDS 74 Conclusions Strong evidence of effectiveness of glycaemic and BP  control in prevention of increases in albuminu...
Hypothetical example of change in GFR and proteinuria               over duration of kidney disease.Stevens L A et al. CJA...
金魚草
Target A1c withoutHypoglycemia in CKD
Hypoglycaemia―The major limiting factor to achievingintensive glycaemic control for people         with type 2 diabetes‖  ...
Elderly subjects with CKD stage 3-5 prone to         severe hypoglycemia, esp. SU related57/6276 ER p’t ( 0.9% )48/57, dru...
Declining renal function increases risk of                 severe hypoglycaemia                                           ...
Reason for developing hypoglycemia in CKD1. Altered insulin metabolism2. Decreased appetite3. Decreased renal gluconeogene...
9.0                           8.0Serum Creatinine (mg/dl)   7.0                           6.0                           5....
Counter regulatory hormone response82 mg/dl                                        Inhibition of endogenous insulin secret...
Hypoglyecmia Unawareness25 folds risk of hypoglycemia
Effect of experimental hypoglycaemia on                QT interval                 A                                    B ...
Intervention Works...but at a                                   Price: DCCT and UKPD                                      ...
Survival as a function of HbA1c in people with type 2diabetes: a retrospective cohort studyMethods: Two cohorts of patient...
Relative Risk of Hypoglycemia between Sulphonylureas   UKPDS 33, in which the mean percentage of patients per year   with ...
Hypoglycemia with sulphonylureas versus                           insulin(UKPDS)                           Any            ...
燈籠花
Treating Diabetes withoutIncreased Risk of CHF and       Cardiac Event
ADOPT study
The ACCORD Trial: Prescribed Glucose                  Lowering Drugs—Single Class            Lower A1C in the intensive-th...
The ACCORD Trial:             Adverse Events and Clinical Measures            The intensive-therapy group had significantl...
PROactive: Heart-failure events End point                    Pioglitazone, n     Placebo,                              (%)...
Triad of fluid retention, edema and weight gain;and Acute pulmonary edema  Kermani and Garg, in their recently published a...
Renal Dysfunction – Frequent Comorbidity in CHF% of patients with renal dysfunction                                       ...
Renal Dysfunction – A Strong Predictor of Poor                      Outcome in HF                      1.0                ...
AHA/ADA consensus in December 2003:              In patients with NYHA class III or IV HF, TZDs              should not be...
June 14, 2007; Miserable Day of Avandia
Effect of Pioglitazone on Cardiovascular Outcome in                  Diabetes and CKD Post hoc analysis from PROactive stu...
天使花
Approximately 40% of type 2 diabetes            patients have renal complications†     CKD prevalence was greater among pe...
Cardiovascular risk is greatest when          both diabetes and nephropathy are present1                                  ...
Patients at risk of declining renal function (e.g. microalbuminuria)                have an increased cardiovascular riskT...
At least 67% of all patients with type 2 diabetes have        cardiovascular risk factors that also affect the kidneys   P...
There is a close relationship between cardiac and renal                pathophysiology in type 2 diabetesConcomitant cardi...
Treating Diabetes withoutLife-threatening Lactic Acidosis          ( esp. MALA )
Metformin (Activates the AMP-Activated Protein Kinase)Mode of Action    Decreases hepatic gluconeogenesis, decreases gluco...
MALA Incidence: 0.03 cases/1000 patient-years Mortality: about 50% of cases Sign and symptoms: non-specific (nausea, vo...
西印度櫻桃
Metabolism and Elimination of Acarbose
Acarbose and Possible Toxicity1. Elderly use: 1.5x AUC than normal health2. Severe renal impairment: 5x peak plasma   conc...
Contraindication when Creatinine ≧ 2.0                      J Am Soc Nephrol 16: S7–S10, 2005
美國凌霄
Incretin base therapy
Incretin effect on insulin secretion                 80       Control subjects (n=8)                            80   Peopl...
Two Incretins: GLP-1 and GIP
Glucose-dependent Effects of GLP-1 Infusion on Insulin and Glucagon Levels in T2DM Patients                               ...
GLP-1—Effects in Humans                                                              Central nervous system               ...
Because of its short half-life, native GLP-1 haslimited clinical value   DPP-IV                                          i...
GLP-1 enhancement                   GLP-1 secretion is impaired in Type 2 diabetes                     Natural GLP-1 has e...
DPP-IV inhibitor: Mechanism of Action                                                   Glucose-                          ...
Linagliptin – a DPP-4 inhibitor with a unique                    xanthine-based structure     DPP-4 inhibitors mimicking d...
Pharmacokinetic Properties of DPP-4 Inhibitors                            Sitagliptin                Vildagliptin         ...
Prescribing characteristics of DPP-4 inhibitors                                           Renal Impairment*               ...
Linagliptin provides long-lasting DPP-4 inhibition in patients                     with type 2 diabetes  Steady-state plas...
Current treatments for type 2 diabetes have limitations                           when renal function declinesInjectables ...
Linagliptin CV meta-analysis            Cardiovascular risk with linagliptin in            patients with type 2 diabetes: ...
Linagliptin CV meta-analysis: Existing morbidity and CV                risk characteristics at baseline                   ...
In a prospective, pre-specified meta-analysis, Linagliptinwas not associated with an increased CV risk Individual componen...
Linagliptin CV meta-analysis: Time to onset of first                  primary endpoint   Kaplan Meier plot for time to pri...
In a prospective, pre-specified meta-analysis, Linagliptin          was not associated with an increased CV risk  Incidenc...
Linagliptin restores ß-cell survival in isolated human islets With linagliptin, less apoptosis is seen under stress condit...
Why DPP-4 Inhibitors?   Excellent in patients with mild hyperglycemia    requiring insulin secretagogue   No contraindic...
Should DPP-4 Inhibitors Be First-line Agents?   If β-cell-sparing effect shown in rats proves to be true in    humans, DP...
Summary: Kidneys matter in type 2 diabetes• Many patients with type 2 diabetes face an inevitable decline in renal  functi...
ADA/EASD Consensus 20091. Sulfonylurea other than Glyburide2. TZD: kicking out Rosiglitazone
ADA/EASD Position Statement 2012Safety first: primum non nocere (first, do no harm); SU, TZD, pre-mixed insulin and non-an...
ADA/EASD Position Statement 2012
Thanks for Your Attention
Impact of declining renal function on treatment choice in diabetes
Impact of declining renal function on treatment choice in diabetes
Impact of declining renal function on treatment choice in diabetes
Impact of declining renal function on treatment choice in diabetes
Impact of declining renal function on treatment choice in diabetes
Impact of declining renal function on treatment choice in diabetes
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  1. 1. Impact of declining renal function on treatment choice in diabetes 林 文 玉 醫師 台中市大里區大里仁愛醫院 內分泌新陳代謝科
  2. 2. Causes of Declining Renal Function1) Diabetic Nephropathy2) Hypertension3) Vascular Disease4) Polycystic Kidney Disease/Genetics5) Chronic pyelonephritis6) Obstruction ( ureteral stone, LUT obstruction)7) Glomerular Disorders/ Glomerulonephritis
  3. 3. Diabetes: The Most Common Cause of ESRD Primary Diagnosis for Patients Who Start Dialysis Other Glomerulonephritis 10% 13% No. of patients 700 Projection Diabetes Hypertension 95% CINo. of dialysis patients 600 50.1% 27% (thousands) 500 400 300 520,240 281,355 200 243,524 100 r2=99.8% 0 1984 1988 1992 1996 2000 2004 2008 2010
  4. 4. Quality of Diabetes Management Glycemic Control, A1c Declining renal functionBlood pressure control Lipid control, LDL-C
  5. 5. Definition of Diabetic Nephropathy Diabetic nephropathy has been classically defined by the presence of proteinuria >0.5 g/24 h. This stage has been referred to as overt nephropathy, clinical nephropathy, proteinuria, or macroalbuminuria Diabetes Care 28:176–188, 2005
  6. 6. Microalbuminuria and Macroalbuminuria DIABETES CARE, VOLUME 28, NUMBER 1, JANUARY 2005 165
  7. 7. We conclude that microalbuminuria in patients with Type IIdiabetes is predictive of clinical proteinuria and increasedmortality. (N Engl J Med 1984; 310:356–60.) 76 ( 30 to 140 μ/ml )vs 75 ( <15 μ/ml ) + 53 ( 16-29 μ/ml )vs 28 ( > 140 μ/ml ) Follow 9 years
  8. 8. DIABETES CARE, VOLUME 34, SUPPLEMENT 2, MAY 2011
  9. 9. Epidemiology1. Approximately 7% of Diabetes naive pts already have microalbuminuria (Adler et al., 2003). However, the prevalence of microalbuminuria before 5 years can reach 18% esp. in pts with poor glycemic and lipid control and high normal BP.2. Albuminuria: roughly 10% of the general population including patients with diabetes.3. USRDS report: diabetes accounted for 54% of new CKD patients in 2007; and affects 40% of type 1 and type 2 diabetic patients (USRDS, 2003).4. Admission for renal replacement therapy: 49% diabetes ( Heidelberg )Table derived from: Maduka Ignatius C, European Journal of Scientific Research, ISSN 1450-216X Vol.26 No.2 (2009), pp.255-259
  10. 10. Albuminuria May Precede the Development of Diabetes Modern Pathology 2004
  11. 11. Change of Glomerular Basement Membrane at Pre-diabetes stage Blood tests for diabetes were positive in 20% of patients at biopsy. In 44% of 6 months and 70% at 24 months follow-up.
  12. 12. Diabetic Nephropathy  Not all DM patients in ESRD suffer from classic Kimmelstiel-Wilson syndrome ( enlarged kidney and heavy proteinuria, 70% ).  Terminal renal failure without major proteinuria and with small kidney: 11%  DM in the presence of primary kidney disease: 19%Classic glomerulosclerosis is characterized by increased glomerular basement membrane width,diffuse mesangial sclerosis, hyalinosis, microaneurysm, and hyaline arteriosclerosis. NDT ( 2010 ) 25:2044-2047
  13. 13. Prevalence of the different stages of nephropathy with increasing duration of diabetesUKPDS 64
  14. 14. UKPDS 64, Development and Progression of DN
  15. 15. UKPDS 74 Progression38 % of 4031 developed MAU at 15 yrs • 64 % had eCrCl > 60 ml/min/1.73m2 • 24 % had eCrCl < 60 ml/min/1.73m2 after MAU • 12 % had eCrCl < 60 ml/min/1.73m2 pre MAU29 % of 5032 developed reduced eCrCl < 60 ml/min/1.73m2 at 15 yrs • 51 % had UAC < 50 mg/L • 16 % had UAC > 50 mg/L after reduced eCrCl • 33 % had UAC > 50 mg/L pre reduced eCrCl Thus MAU does not always precede declining renal function DIABETES, VOL. 55, JUNE 2006
  16. 16. UKPDS 74 Conclusions Strong evidence of effectiveness of glycaemic and BP control in prevention of increases in albuminuria Significant reduction in those doubling plasma creatinine (albeit small numbers) Demonstration of poor prognosis for those with worsening renal function Relatively slow progression of albuminuria toward renal impairment in T2DM Discordance between eCrCl and UAC
  17. 17. Hypothetical example of change in GFR and proteinuria over duration of kidney disease.Stevens L A et al. CJASN 2006;1:874-884©2006 by American Society of Nephrology
  18. 18. 金魚草
  19. 19. Target A1c withoutHypoglycemia in CKD
  20. 20. Hypoglycaemia―The major limiting factor to achievingintensive glycaemic control for people with type 2 diabetes‖ Briscoe VJ, et al. Clin Diab 2006;24:115-121.
  21. 21. Elderly subjects with CKD stage 3-5 prone to severe hypoglycemia, esp. SU related57/6276 ER p’t ( 0.9% )48/57, drug induced60.4% > 70y/oIn above, >60% CKD 3-5 Masakazu Haneda et. NDT ( 2009 ) 24
  22. 22. Declining renal function increases risk of severe hypoglycaemia 9 Risk for severe hypoglycaemia 8 (incidence rate ratio) 7 6 5 4 3 2 1 0 + CKD +CKD / + –– CKD + CKD / + CKD / – + CKD – CKD – CKD / – + Diabetes Diabetes +Diabetes Diabetes Diabetes – Diabetes – Diabetes Around 74% of sulphonylurea-induced severe hypoglycaemic events (loss of consciousness) occur in patients with reduced renal functionMoen MF, et al. Clin J Am Soc Nephrol. 2009 Jun;4(6):1121–1127
  23. 23. Reason for developing hypoglycemia in CKD1. Altered insulin metabolism2. Decreased appetite3. Decreased renal gluconeogenesis4. Impaired release of counter-regulatory hormones like epinephrine due to autonomic neuropathy5. Concurrent hepatic disease6. Decreased metabolism of drugs that might promote a reduction in plasma glucose concentrations such as alcohol, nonselective β blockers, and disopyramide++++ sustained insulin secretion related to K channel closing and impaired counter-regulatory hormone response.
  24. 24. 9.0 8.0Serum Creatinine (mg/dl) 7.0 6.0 5.0 4.0 3.0 2.0 1.0 0 0 20 40 60 80 100 120 140 160 180 Inulin Clearance (ml/min per 1.73m2)
  25. 25. Counter regulatory hormone response82 mg/dl Inhibition of endogenous insulin secretion Counterregulatory hormone release 70 mg/dl GLUCAGON, CATECHOLAMINES: failed in type 1 DM or advanced type 2 DM 50-60 mg/dl Onset of autonomic and neuroglycopenic symptoms < 50 mg/dl Cognitive dysfunction Coma, convulsion McCrimmon and colleagues report that application of urocortin I (a corticotrophin-releasing factor receptor–2 agonist) to the ventromedial hypothalamus reduces the glucose counterregulatory response to hypoglycemia in rats. Thus, hypothalamic urocortin I release during antecedent hypoglycemia is, among other possibilities, a potential mechanism of HAAF ( hypoglycemia-associated autonomic failure ).
  26. 26. Hypoglyecmia Unawareness25 folds risk of hypoglycemia
  27. 27. Effect of experimental hypoglycaemia on QT interval A B QTc= 456 ms QTc= 610 ms HR= 66 bpm HR= 61 bpm 5.0mM 2.5mM International Diabetes Monitor 2009; 21(6): 234-241.
  28. 28. Intervention Works...but at a Price: DCCT and UKPD Severe Hypoglycemia 100 DCCT (Type 1) UKPDS (Type 2) Major Episodes 5 80 Major Episodes Incidence (%) Rate/100 Patient Years 4 60 Intensive 3 Intensive 40 2 20 1 Conventional Conventional 0 0 56 78 9 10 11 12 13 14 0 3 6 9 12 15 HbA1c (%) During Study Years from RandomizationDCCT Research Group, Diabetes. 1997;46:271-286 UKPDS Group (33), Lancet. 352: 837-853, 1998 Stratton IM et al. BMJ. 2000;321:405-412.
  29. 29. Survival as a function of HbA1c in people with type 2diabetes: a retrospective cohort studyMethods: Two cohorts of patients aged 50 years and older with type 2 diabetes were generated from theUK General Practice Research Database from November 1986 to November 2008. We identified 27 965patients whose treatment had been intensified from oral monotherapy to combination therapy with oralblood-glucose lowering agents, and 20 005 who had changed to regimens that included insulin.... Lancet 2010; 375: 481–89
  30. 30. Relative Risk of Hypoglycemia between Sulphonylureas UKPDS 33, in which the mean percentage of patients per year with one of more episodes of hypoglycemia was 17.7% for glyburide and 11.0% for chlorpropamide (RR 1.61), and the mean percentage of patients per year with one or more major hypoglycemic episodes was 0.6% for glyburide and 0.4% for chlorpropamide. DIABETES CARE, VOLUME30, NUMBER2, FEBRUARY2007
  31. 31. Hypoglycemia with sulphonylureas versus insulin(UKPDS) Any Severe 40 3.0 36.5 2.5 2.3 30 Mean (%)Mean (%) 2.0 20 17.7 1.5 11 1.0 10 0.6 0.5 0.4 1.2 0.1 0 0.0 Diet Chlorpropamide Glibenclamide Insulin UKPDS 33. Lancet 1998;352:837-853.
  32. 32. 燈籠花
  33. 33. Treating Diabetes withoutIncreased Risk of CHF and Cardiac Event
  34. 34. ADOPT study
  35. 35. The ACCORD Trial: Prescribed Glucose Lowering Drugs—Single Class Lower A1C in the intensive-therapy group was associated with greater exposure to drugs from every class Intensive Standard Therapy Therapy n=5128 n=5123 Metformin 4856 (94.7) 4452 (86.9) Secretagogue 4443 (86.6) 3779 (73.8) Glimepiride 4010 (78.2) 3465 (67.6) Repaglinide 2574 (50.2) 908 (17.7) Thiazolidinedione 4702 (91.7) 2986 (58.3) Rosiglitazone 4677 (91.2) 2946 (57.5)Data are n (%).The ACCORD Study Group. N Engl J Med. 2008;358(24):2545-2559. 3
  36. 36. The ACCORD Trial: Adverse Events and Clinical Measures The intensive-therapy group had significantly higher rates of hypoglycemia, weight gain, and fluid retention Intensive Therapy Standard Therapy Variable n=5128 n=5123 P Value Hypoglycemia, n (%) Requiring medical assistance 538 (10.5) 179 (3.5) <0.001 Requiring any assistance 830 (16.2) 261 (5.1) <0.001 Fluid retention, n/total no. (%) 3541/5053 (70.1) 3378/5054 (66.8) <0.001 Weight gain >10 kg since baseline, 1399/5036 (27.8) 713/5042 (14.1) <0.001 n/total no. (%) Fatal or nonfatal heart failure, n (%) 152 (3.0) 124 (2.4) 0.10 Systolic blood pressure, mm Hg 126.4 ± 16.7 127.4 ± 17.2 0.002 Diastolic blood pressure, mm kg 66.9 ± 10.5 67.7 ± 10.6 <0.001The ACCORD Study Group. N Engl J Med. 2008;358(24):2545-2559.
  37. 37. PROactive: Heart-failure events End point Pioglitazone, n Placebo, (%) n (%) Reported HF 281 (10.8) 198 (7.5) (nonadjudicated) HF leading to 149 (5.7) 108 (4.1) hospitalization HF leading to death 25 (0.96) 22 (0.84) Dormandy J et al. European Association for the Study of Diabetes; September 10-15 2005; Athens, Greece.
  38. 38. Triad of fluid retention, edema and weight gain;and Acute pulmonary edema Kermani and Garg, in their recently published article, discussed 6 patients with CHF and acute pulmonary edema, which developed because of the use of TZDs. In their risk evaluation, all of the patients were older than 65 years, 4 patients had chronic renal failure, 1 patient had ischemic cardiomyopathy, and 1 patient had no predisposing factor. Use of TZDs is associated with a triad of fluid retention, edema, and weight gain. Fluid retention generally is considered mild and reversible and may result from a reduction in renal excretion of sodium and an increase in sodium and free water retention. TZDs may interact synergistically with insulin to cause arterial vasodilatation, leading to sodium reabsorption with a subsequent increase in extracellular volume, thereby resulting in pedal edema. Increased sympathetic nervous system activity, altered interstitial ion transport, alterations in endothelial permeability, and PPAR-mediated expression of vascular permeability growth factor represent other possible mechanisms for edema with these agents Kermani A, Garg A Mayo Clin Proc. 2003;78:1088-1091
  39. 39. Renal Dysfunction – Frequent Comorbidity in CHF% of patients with renal dysfunction Clinical trials ‘Real life’ 60% (patients with severe RD excluded) 62% GFR 40% 30−59 GFR 34% <60 36% GFR GFR 60−75 60−90 20% GFR GFR <60 45−60 GFR <30 21% GFR <45 GFR >90 SOLVD-P SOLVD-T VALIANT ADHERE NYHA I–II NYHA II–III (post AMI, CHF / LVD) (acute, decompensated HF) (n=3673)1 (n=2161)1 (n=14,527)2 (n=118,465)3 1. Dries DL et al. J Am Coll Cardiol 2000;35:681−689 2. Anavekar NS et al. N Engl J Med 2004;351:1285−1295 GFR, glomerular filtration rate 3. Heywood JT et al. J Card Fail 2007;13:422−430
  40. 40. Renal Dysfunction – A Strong Predictor of Poor Outcome in HF 1.0 • 1708 CHF patientsProportion Survival 0.9 (NYHA III–IV) from PRIME II Trial 0.8 >76 mL/min 0.7 59−76 mL/min • GFR was the most predictive of 0.6 survival at multivariate analysis 44−58 mL/min 0.5 <44 mL/min • GFR <60 mL/min, 2.1 risk 0.4 of mortality 0.3 0 250 500 750 1000 1250 • Surpassed LVEF, NYHA class, Days hypotension concomitant meds,RR (for mortality) 3.0 2.85 diabetes mellitus, tachycardia 1.91 2.0 1.32 1.0 >76 59–76 44–58 <44 GFR Hillege HL et al. Circulation 2000;102:203−210
  41. 41. AHA/ADA consensus in December 2003: In patients with NYHA class III or IV HF, TZDs should not be used.Circulation December 9, 2003
  42. 42. June 14, 2007; Miserable Day of Avandia
  43. 43. Effect of Pioglitazone on Cardiovascular Outcome in Diabetes and CKD Post hoc analysis from PROactive study Secondary: Individual components of primary outcome, CV mortality J Am Soc Nephrol 19: 182-187, 2008
  44. 44. 天使花
  45. 45. Approximately 40% of type 2 diabetes patients have renal complications† CKD prevalence was greater among people with diabetes than among those without diabetes (40.2% versus 15.4%) 2.3 Data missing 9.5 no CKD CKD stage 1 17.7 CKD stage 2 50.8 CKD stage 3 CKD stage 4/5 11.1 CKD Stage eGFR (mL/min) 8.6 No CKD ≥90* 1 ≥90** 2 60–89 3 30–59 4 15–29* Normal kidney function, no sign of kidney damage 5 <15 or dialysis** Albuminuria – kidney damage†Based on data from 1462 patients aged ≥20 years with T2DM who participated in the Fourth NationalHealth and Nutrition Examination Survey (NHANES IV) from 1999 to 2004.1. Koro CE, et al. Clin Ther. 2009;31:2608–17; 2. Coresh J, et al. JAMA. 2007;298(17) 2038-2047
  46. 46. Cardiovascular risk is greatest when both diabetes and nephropathy are present1 x 2.1 Incidence per 100 patient-years x 1.7 x 2.5 x 2.2CKD chronic kidney diseaseAMI acute myocardial infarctionCVA/TIA cerebrovascular accident/transient ischemic attackPVD peripheral vascular diseaseDeath all-causesFoley RN, et al. J Am Soc Nephrol. 2005;16:489–95.
  47. 47. Patients at risk of declining renal function (e.g. microalbuminuria) have an increased cardiovascular riskThe risk of CV outcomes according to degree of albuminuria in patients with T2DM:The HOPE Study ACR clinical threshold for 30 microalbuminuria (2.0 mg/mmol)* 20Cardiovascular events (%) 10 0 20 All-cause mortality (%) 10 0 1+2 3 4 5 6 7 8 9 10 Categorical increase in albuminuria (deciles)*The 8th decile includes ACR of 2 mg/mmol, which is the current threshold for a diagnosis of microalbuminuriaDeciles 1 and 2 are combined due to very low incidence rates in these two deciles mcg/mg ÷ 8.84 = mcg/mmol4.5 year median follow-up (1994 – 1999) The ACR values 17 to 250 μg/mg in men and 25 to 355 μg/mg in women corresponded to 30 to 300 μg/min of urine albumin excretion measured in a timed urine specimenn = 3498 patients with T2DCardiovascular events = composite (myocardial infarction, stroke, or CV death)HOPE Study Investigators. JAMA. 2001;286:421-426. ACR = urine albumin/creatinine ratio
  48. 48. At least 67% of all patients with type 2 diabetes have cardiovascular risk factors that also affect the kidneys Prevalence of risk factors for declining renal function: Prevalence in T2DM Risk factor patients 1 Arterial 67%1 Hypertension 2 Poor glycemic 63%2 control* 3 Microalbuminuria** 30%3 4 Dyslipidemia† 24%** 4,5Risk range is likely to be significantly higher than 67% due to overlap of risk factors in individuals*Defined as not reaching the target HbA1c of 7.0%2. **Defined as defined as a urinary albumin-to-creatinine ratio ≥ 30 ug/mg† defined as hypertriglyceridemia in male subjects1. CDC National Diabetes Fact Sheet 2011. http://www.cdc.gov/diabetes/pubs/factsheet11.htm (Accessed Sept 2011)2. Saydah SH, et al. JAMA. 2004;291:335–342; 3. Cheung BMY, et al. Am J Med. 2009;122:443–53.4. Mooradian A, Nat Clin Pract Endocrinol Metab. 2009:5;150–15; 5. Kannel WB. Am Heart J. 1985;110;1100–7.
  49. 49. There is a close relationship between cardiac and renal pathophysiology in type 2 diabetesConcomitant cardiorenal dysfunction in type 2 diabetes1 Acute or chronic dysfunction of one organ may induce acute or chronic dysfunction of the other Cardiorenal Risk factors Heart Disease CKD Stage 1-2 Glomerular/Interstitial Type 2 diabetes Increased ischaemic risk damage Smoking Left ventricular hypertrophy Obesity Hypertension Dyslipidemia Genetic risk factors Acquired risk factors1. Ronco C, et al. J Am Col Cardiol. 2008;52(19):1527–1539; 2. AACE. Endocr Pract. 2007;13 Suppl 1:1-683;3. Afghahi H et al. Nephrol Dial Transplant. 2011;26(4):1236-43;4. Radbill B et al. Mayo Clin Proc. 2008;83(12):1373-1381; 5. UKPDS Group. BMJ. 2000;321:405-412.
  50. 50. Treating Diabetes withoutLife-threatening Lactic Acidosis ( esp. MALA )
  51. 51. Metformin (Activates the AMP-Activated Protein Kinase)Mode of Action Decreases hepatic gluconeogenesis, decreases glucose absorption in the intestines, and increases sensitivity to insulin by increasing peripheral glucose uptake and utilization.Contraindications Hypersensitivity Renal disease (males with serum creatinine >1.5 mg/dL, females with serum creatinine >1.4 mg/dL) AMI, CHF exacerbation, surgery, or shock Acute or chronic metabolic acidosisHebel SK, Katstrup EK (eds): Drug Facts and Comparisons. St. Louis, Mo. 2001For conversion of creatinine expressed in conventional units to SI units, multiply by 88.4
  52. 52. MALA Incidence: 0.03 cases/1000 patient-years Mortality: about 50% of cases Sign and symptoms: non-specific (nausea, vomiting, altered consciousness, fatigue, abdominal pain, and thirst).
  53. 53. 西印度櫻桃
  54. 54. Metabolism and Elimination of Acarbose
  55. 55. Acarbose and Possible Toxicity1. Elderly use: 1.5x AUC than normal health2. Severe renal impairment: 5x peak plasma concentration and 6X AUC3. In 1117 subjects ( phase III trial ): 14%, 6%, 3% liver transaminase elevation ( woman, black, obese, DM of >5 years )4. Dosage > 300 mg/d: 15% abnormal liver function5. Animal study: increased risk of renal tumor; but nil in human beings. 內科學誌 2009;20: 434-439
  56. 56. Contraindication when Creatinine ≧ 2.0 J Am Soc Nephrol 16: S7–S10, 2005
  57. 57. 美國凌霄
  58. 58. Incretin base therapy
  59. 59. Incretin effect on insulin secretion 80 Control subjects (n=8) 80 People with Type 2 diabetes (n=14) 60 60Insulin (mU/l) Insulin (mU/l) 40 Incretin 40 effect 20 20 0 0 0 60 120 180 0 60 120 180 Time (min) Time (min) Oral glucose load Intravenous glucose infusion Nauck et al. Diabetologia. 1986
  60. 60. Two Incretins: GLP-1 and GIP
  61. 61. Glucose-dependent Effects of GLP-1 Infusion on Insulin and Glucagon Levels in T2DM Patients 15.0 mmol/L 250 12.5 Placebo mg/dL 200 Glucose 10.0 7.5 * * * 150 GLP-1 * * 5.0 * * 100 *P<0.05 2.5 50 Patients with T2DM 0 (N=10) 0 250 40 pmol/L 200 mU/L 30 Insulin 150 20 When glucose levels approach normal values, 100 * * * * 10 insulin levels decrease. 50 * * * * 0 0 20 20 pmol/L pmol/L 15 15 When glucose levels Glucagon 10 * 10 approach normal * * * values, glucagon levels 5 5 rebound. 0 Infusion 0 –30 0 60 120 180 240 MinutesAdapted from Nauck MA et al. Diabetologia. 1993;36:741-744.
  62. 62. GLP-1—Effects in Humans Central nervous system Promotes satiety and The most smart way to regulate plasma reduction of appetite sugar, increased insulin secretion and inhibited glucagon release when the blood Liver  Glucagon reduces sugar rises;output vice versa. The risk of of and hepatic glucose β cell Enhances secretion hypoglycemia is low. glucose-dependent insulin Potential increase in β-cell mass α cell  Glucagon Stomach secretion post-meal Regulates gastric emptyingFlint A et al. J Clin Invest. 1998;101:515-520. Larsson H et al. Acta Physiol Scand.1997;160:413-422. Nauck MA et al. Diabetologia. 1996;39:1546-1553. Drucker DJ. Diabetes.1998;47:159-169.
  63. 63. Because of its short half-life, native GLP-1 haslimited clinical value DPP-IV i.v. bolus GLP-1 (15 nmol/l) 1000 Healthy individuals Intact GLP-1 (pmol/l) His Ala Glu Gly Thr Phe Thr Ser Asp Val Type 2 diabetes 7 9 Ser 500 Lys Ala Ala Gln Gly Glu Leu Tyr Ser Glu Phe 37 0 Ile Ala Trp Leu Val Lys Gly Arg Gly –5 5 15 25 35 45 Time (min) Enzymatic t½ = 1.5–2.1 minutes cleavage (i.v. bolus 2.5–25.0 High clearance nmol/l) (4–9 l/min) Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88: 220–224.
  64. 64. GLP-1 enhancement GLP-1 secretion is impaired in Type 2 diabetes Natural GLP-1 has extremely short half-life Add GLP-1 analogues Block DPP-4, the enzyme with longer half-life: that degrades GLP-1: • Sitagliptin • Exenatide ( Byetta ) • Saxagliptin • Liraglutide ( Victoza ) • Vildagliptin • Linagliptin Injectables • Alogptin Oral agentsDrucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003
  65. 65. DPP-IV inhibitor: Mechanism of Action Glucose- dependent  Insulin  Glucose Ingestion (GLP-1and uptake by of food Pancreas GIP) peripheral tissue Release of Beta cells active incretinsGI tract Alpha cells  Blood glucose GLP-1 and GIP in fasting and postprandialSitagliptin DPP-4 Glucose- states (DPP-4inhibitor) X enzyme dependent  Glucagon  Hepatic glucose (GLP-1) production Inactive Inactive GLP-1 GIP Incretin hormones GLP-1 and GIP are released by the intestine throughout the day, and their levels  in response to a mealGLP-1=glucagon-like peptide-1; GIP=glucose-dependent insulinotropic polypeptide.
  66. 66. Linagliptin – a DPP-4 inhibitor with a unique xanthine-based structure DPP-4 inhibitors mimicking dipeptides DPP-4 inhibitors directly binding to the active site of the enzyme O N N N N N Sitagliptin N O N NH2 Linagliptin Xanthine-based structure Saxagliptin Alogliptin Vildagliptin Peptidomimetic DPP-4 inhibitors Non-peptidomimetic DPP-4 inhibitorsAdapted from Deacon CF. Diabetes Obes Metab. 2011; 13: 7–18.
  67. 67. Pharmacokinetic Properties of DPP-4 Inhibitors Sitagliptin Vildagliptin Saxagliptin Alogliptin Linagliptin (Merck)1 (Novartis)2 (BMS/AZ)3 (Takeda)5 (BI)6–9Absorption tmax 2 h (4 h for active 1–4 h 1.7 h 1–2 h 1.34–1.53 h(median) metabolite)Bioavailability ~87% 85% >75 %4 N/A 29.5%Half-life (t1/2) at 2.5 h (parent) 12.4–21.4 h 113–131 hclinically relevant 12.4 h ~2–3 h 3.1 h (metabolite) (25–800 mg) (1–10 mg)dose Prominent concentration- dependent proteinDistribution 38% protein bound 9.3% protein bound Low protein binding N/A binding: <1 nM: ~99% >100 nM: 70%–80% 69% metabolized HepaticMetabolism ~16% metabolized mainly renal (active metabolite) <8% metabolized ~10% metabolized (inactive metabolite) CYP3A4/5 Feces 81.5% Renal 75% Renal (74.1% unchanged); Renal 87% Renal 85%Elimination (24% as parent; 36% as (60%–71% (79% unchanged) (23% unchanged) Renal 5.4% active metabolite) unchanged) (3.9% unchanged)DPP-4=dipeptidyl peptidase-4.1. EU-SPC for JANUVIA, 2010. 2. EU-SPC for Galvus, 2010. 3. EU-SPC for Onglyza, 2010. 4. EPAR for Onglyza.http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001039/WC500044319.pdf. Accessed May 4, 2011. 5. 73Christopher R et al. Clin Ther. 2008;30:513–527. 6. Heise T et al. Diabetes Obes Metab. 2009;11:786–794. 7. Reitlich S et al. Clin Pharmacokinet. 2010;49:829–840.8. Fuchs H et al. J Pharm Pharmacol. 2009;61:55–62. 9. Blech S et al. Drug Metab Dispos.2010;38:667–678.
  68. 68. Prescribing characteristics of DPP-4 inhibitors Renal Impairment* Hepatic Impairment Inhibitor Linagliptin      Not recommended (EU) Not recommended (EU) Sitagliptin  ½ dose (US)1 ¼ dose (US)1  Not recommended1 Vildagliptin2  Not recommended1 Not recommended1 Not recommended Not recommended ½ dose (EU) ½ dose (use with caution)  Saxagliptin3  ½ dose (US)1 not recommended in ESRD (EU) (Moderate: use with Not recommended1 ½ dose (US)1 caution) Alogliptin  ½ dose ¼ dose  Not recommended1CrCl = Creatinine clearance; ESRD = end-stage renal disease* Assessment of renal function recommended prior to initiation of treatment and periodically thereafter1. Not studied/no clinical experience2. Assessment of hepatic function recommended prior to initiation of vildagliptin and periodically thereafter3. Dose reduction (2.5 mg) when saxagliptin co-administered with strong CYP450 3A4/5 inhibitors (e.g. ketoconazole)Adapted from Deacon CF. Diabetes, Obes Metab. 2011;13(1):7–18.
  69. 69. Linagliptin provides long-lasting DPP-4 inhibition in patients with type 2 diabetes Steady-state plasma levels are already reached after the third dosing interval providing >91% of DPP-4 inhibition at peak levels 100 80 DPP-4 Inhibition [%] 60 40 20 0 0 4 8 12 16 20 24 Time after administration (h) Steady State linagliptin 5mg once daily – oral Tablet taken application Tablet taken linagliptin 5 mg linagliptin 5 mgAdapted from Heise T et al. Diabetes Obes Metab. 2009;11(8):786–94
  70. 70. Current treatments for type 2 diabetes have limitations when renal function declinesInjectables Dose Reduction Insulin Liraglutide Dose Reduction Exenatide Linagliptin Sitagliptin Vildagliptin Dose Reduction Saxagliptin Oral drugs Metformin Acarbose Dose Reduction Repaglinide Glimepiride Dose Reduction Dose Reduction Gliclazide Pioglitazone >60 30 – 60 <30 Hemodialysis Declining GFRAdapted from: Schernthaner G, et al. Nephrol Dial Transplant. 2010;25(7):2044–2047 and respective EMEA SmPCs
  71. 71. Linagliptin CV meta-analysis Cardiovascular risk with linagliptin in patients with type 2 diabetes: A pre- specified, prospective, and adjudicated meta-analysis from a large phase 3 programJohansen O-E., et al. ADA 2011 Late breaker 30-LB
  72. 72. Linagliptin CV meta-analysis: Existing morbidity and CV risk characteristics at baseline Linagliptin Placebo Active Total Comparator Comparator (n = 3319) (n = 977) (n = 943) (n = 1920) CV risk factors (%) • Metabolic syndrome 60.3 55.9 67.8 61.7 • Previous coronary artery disease 10.4 10.1 11.9 11.0 • Previous cerebrovascular disease 2.9 3.6 4.1 3.9 • Previous peripheral artery disease 2.3 2.7 3.3 3.0 • Hypertension 63.8 60.2 72.1 66.0 • Ex-/current smoker 22.6/14.4 19.1/16.1 29.5/15.7 24.2/15.9 eGFR (based on MDRD),% • Normal 55.4 58.3 52.3 55.4 • Mildly impaired 37.3 34.9 41.4 38.1 • Moderately impaired 4.3 4.5 4.1 4.3 • Severely impaired 0.1 0.1 0.0 0.1 Framingham 10 year CV risk score • Framingham risk score (%) 9.8 ±8.2 9.1 ±8.1 11.6 ±8.6 10.3 ±8.4 • Framingham risk > 15% (%) 27.8 24.7 37.8 31.1Johansen O-E., et al. ADA 2011 Late breaker 30-LB
  73. 73. In a prospective, pre-specified meta-analysis, Linagliptinwas not associated with an increased CV risk Individual components of composite primary endpoint* Linagliptin n = 3,319 12 Total comparators n = 1,920 11 10 Number of events 8 7 6 6 4 3 2 2 2 2 1 0 Non-fatal Non-fatal MI Hospitalization CV death stroke due to unstable angina Hazard ratio 0.11 0.52 0.24 0.74 95% CI 0.02/0.51 0.17/1.54 0.02/2.34 0.10/5.33*Individual components are tertiary endpointsJohansen O-E., et al. ADA 2011 Late breaker 30-LB
  74. 74. Linagliptin CV meta-analysis: Time to onset of first primary endpoint Kaplan Meier plot for time to primary endpoint (Linagliptin vs Combined comparator) 3.0 Linagliptin 2.7 Combined comparator 2.4 2.1 1.8 1.5 1.2 0.9 0.6 0.3 0.0 0 10 20 30 40 50 60 70 80 90 100Patients at risk: Time (weeks)Linagliptin 3319 3218 2988 798 715 670 440 223 49 0 0Combined 1920 1820 1601 729 690 650 421 213 48 0 0comparatorNote: Patient numbers decline as only patients are depicted that participated in any of the studies included in the meta-analysis at the specific time points.Most studies ended after 24 weeks and patients were therefore not examined further.Johansen O-E., et al. ADA 2011 Late breaker 30-LB
  75. 75. In a prospective, pre-specified meta-analysis, Linagliptin was not associated with an increased CV risk Incidence rate of CV events1 Number and percentage of patients Risk ratio 0.34 95% CI (0.15/0.74) p<0.05 Out of Out of 3,319 patients 1,920 patients = 0.3% = 1.2% Linagliptin Comparator2 Years of exposure 2,060 1,3721. CV events as defined as primary endpoint; 2. 977 patients receiving placebo, 781 glimepiride, 162 vogliboseJohansen O-E., et al. ADA 2011 Late breaker 30-LB
  76. 76. Linagliptin restores ß-cell survival in isolated human islets With linagliptin, less apoptosis is seen under stress conditions. The study provides evidence of a direct protective effect of linagliptin on ß-cell survival and insulin secretion 5 Vehicle Linagliptin * Example of TUNEL Staining * Insulin (ß-cell marker) 4 ** % TUNEL +β-cells TUNEL (marker for apoptosis) 3 * * * Vehicle 2 ** ** ** ** 1 Linagliptin (100 nM) 0 Oxidative Physiological Glucotoxicity Glucotoxicity Lipotoxicity Inflammatory stress condition stressNote: Human isolated islets were exposed for 48 h. ß-cell apoptosis was analyzed by double labeling for the TUNEL assay and insulin. Resultsare means from 3 independent experiments from 3 donors *P<0.05 to 5.5 mM glucose alone, **P<0.05 to vehicleSource: Shah P, et al. ADA 2010, Poster 1742-P
  77. 77. Why DPP-4 Inhibitors? Excellent in patients with mild hyperglycemia requiring insulin secretagogue No contraindication in heart failure and no risk of edema or lactic acidosis Can be used in renal insufficiency without risk of hypoglycemia or lactic acidosis No weight gain Immediate activity without causing hypoglycemia
  78. 78. Should DPP-4 Inhibitors Be First-line Agents? If β-cell-sparing effect shown in rats proves to be true in humans, DPP-4 inhibitors could become the preferred first-line agents Appropriate for patients with mild elevation of glucose with contraindications to other agents that cause hypoglycemia Should be considered early in overweight patients Should be considered in patients with heart failure Strongly considered in patients with renal failure
  79. 79. Summary: Kidneys matter in type 2 diabetes• Many patients with type 2 diabetes face an inevitable decline in renal function• CKD doubles the risk of cardiovascular events and death in patients with type 2 diabetes• Patients with poor glycaemic control, high blood pressure and/or microalbuminuria are at high risk for declining renal function• Renal function should be considered when choosing a glucose- lowering therapy• Declining renal function in type 2 diabetes: Effective glycemic control slows progression of CKD
  80. 80. ADA/EASD Consensus 20091. Sulfonylurea other than Glyburide2. TZD: kicking out Rosiglitazone
  81. 81. ADA/EASD Position Statement 2012Safety first: primum non nocere (first, do no harm); SU, TZD, pre-mixed insulin and non-analogue insulin were highlighted, especially as that concept has been shaped by results of theACCORD,4 ADVANCE,5 and VADT6 trials.Proceed with caution: affordability; but the real cost of diabetes management is controlling thecost of complications, not just the price of the pillsTZD: pioglitazone viable only. Many negative issues ( edema, weight gain, heart failure, fracture etc )against modest CV benefits. Bladder cancer issue: not clarified yet.Premixed insulin and NPH/RHI: It is difficult to titrate pre-mixed insulins to maximumeffectiveness without causing hypoglycemia or weight gain. The later: not physiologically met withinadvertent hypoglycemia.DPP4i: weight neutrality, freedom from hypoglycemia, and a very favorable adverse-effect profile(primum non nocere )GLP-1RA: robust reduction of A1C and weight—two prized properties of any antidiabetic agent.Pancreatitis might be a part of disease itself.Basal insulin: place value on it, adding on after MF with low risk of hypoglycemia and weight gain.
  82. 82. ADA/EASD Position Statement 2012
  83. 83. Thanks for Your Attention

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