MANAGEMENT OF DIABETIC PATIENTS WITH CKD. Roberto Pecoits-Filho, MD, PhD, FASN, FACP PUCPR, Curitiba, BRAZIL

Size: px

Start display at page:

Download "MANAGEMENT OF DIABETIC PATIENTS WITH CKD. Roberto Pecoits-Filho, MD, PhD, FASN, FACP PUCPR, Curitiba, BRAZIL"

Cory Summers
5 years ago
Views:

1 MANAGEMENT OF DIABETIC PATIENTS WITH CKD Roberto Pecoits-Filho, MD, PhD, FASN, FACP PUCPR, Curitiba, BRAZIL

2 Disclosure of Interests Honoraria Astra Zeneca, Novartis Trial participation and research grants Amgen, Genzyme, Jansen, Astra Zeneca Consultoria Jansen, Astra Zeneca, Abbvie KDIGO Diabetes Conference February 5-8, 2015 Vancouver, Canada

Retinopathy (18.9%) Cerebrovascular Disease Myocardial infarction (9.8%) Angina (9.

8%) Neuropathy Peripheral Vascular Disease 1. International Diabetes Federation.

Accessed January 2, 2014. 2. Gilmer TP, O Connor PJ.

3 Retinopathy (18.9%) Cerebrovascular Disease Myocardial infarction (9.8%) Angina (9.5%) Coronary heart disease (9.1%) Nephropathy (27.8%) Neuropathy Peripheral Vascular Disease 1. International Diabetes Federation. IDF Diabetes Atlas. 6th ed. Published Accessed January 2, Gilmer TP, O Connor PJ. Strategies to reduce the cost of renal complications in patients with type 2 diabetes. Diabetes Care. 2011;34: Ulceration/amputation (22.9%)

4 GFR (ml/min/1.73 m 2 ) Natural history of diabetic nephropathy I Hyperfiltration II Silent DN III Incipient DN IV Overt DN GFR UAE V ESRD Log UAE (g/24h) Duration of diabetes (years) DN, diabetic nephropathy; ESRD, end-stage renal disease; GFR, glomerular filtration rate; UAE, urinary albumin excretion Pugliese G. Acta Diabetol 2014;51:

5 Prevalence (%) Non-albuminuric renal impairment in Type 2 diabetes The Third National Health and Nutrition Examination Survey (NHANES III) A total of 1197 patients with Type 2 diabetes % 40 36% 20 13% 19% 0 Renal impairment* Normo Micro Macro Albuminuria Kramer HJ, et al. JAMA 2003;289:

6 Patients (%) Risk of progression to proteinuria in the STENO-2 trial 60 Multifactorial intervention failed to eliminate the risk of new-onset diabetic nephropathy in patients with Type 2 diabetes RR: 0.44 (95% CI: 0.25, 0.77) P= Conventional treatment 40 P= Intensive treatment Residual risk Duration of follow-up (years) CI, confidence interval; RR, relative risk Fioretto P, et al. Nat Rev Endocrinol 2010;6:19 25

7 Events per 10,000 adult population with diagnosed diabetes Trends in diabetes-related complications among US adults with diagnosed diabetes Acute myocardial infarction Stroke Amputation ESRD Year Death from hyperglycaemic crisis ESRD, end-stage renal disease Gregg EW, et al. N Eng J Med 2014;370:

8 Number of patients (in thousands) Rate per million population Incident counts and adjusted rates of ESRD, by primary diagnosis USRDS annual data report Counts Diabetes 200 Rates Diabetes Hypertension GN Cystic kidney Hypertension GN Cystic kidney Year Year ESRD, end-stage renal disease; GN, glomerulonephritis; USRDS, United States Renal Data System

9 CKDopps protocol and countries (2016) Germany 32 clinics (target=30) United States 29 clinics (target=40) France 40 clinics (target=40) Study design Target 12,000 CKD patients Japan 30 clinics (target=30) Brazil 20 clinics (target=20) Census CKD stage 3b to 5 (non dialysis, non-renal transplant) patients 18 yrs old All causes of CKD Inclusion per clinic with egfr <60 ml/min/1.73 m 2 Follow-up 3 years (up to 5 years in France) Before and after starting RRT Data collection (longitudinal) CKD, chronic kidney disease; egfr, estimated glomerular filtration rate; RRT, renal replacement therapy. Abstraction from medical records Nephrologist survey Patient questionnaire

10 % of patients Prevalence of hypertension and diabetes Brazil France Germany USA Hypertension * Diabetes * Among sampled patients PRELIMINARY: From CKDopps census (all clinic patients); N=14,769 (France), 925 (Germany), 1897 (Brazil), 3221 (USA); egfr <60 ml/min/1.73m 2

11 % of patients Age distribution Median age Brazil France Germany USA 44 Brazil Germany France USA 68 yrs 74 yrs 73 yrs 71 yrs PRELIMINARY: From CKDopps census (all clinic patients); N=14,769 (France), 26,093 (Germany), 1328 (Brazil), 2851 (US); egfr <60 ml/min/1.73m 2 egfr, estimated glomerular filtration rate Age (years)

12 % of patients Reported causes of chronic kidney disease 100 Other Hypertension Glomerulonephritis Diabetes Brazil France Germany USA Number of patients:

13 J Am Coll Cardiol 2008; 52:

14 Hypoglicemia Hyperglicemia Anorexia induced decrease in cfood intake Diabetes mellitus Dietary restriction-induced food intake Decrease in renal glucose excretion Increase in insulin half life Decrease in insulin metabolization Interferance in pharmacokinetics of hypoglicemic drugs Uremic toxicity induced insulin resistance Inflammation-induced insulin resistance Decreased renal gluconeogenesis Accumulation ofvcounterbalance hormones Insulin resistance Pecoits-Filho et al. Diabetology & Metabolic Syndrome, 2016

15 Hazard Ratio Risk of severe hypoglycaemia is increased in CKD 2 < > ACCORD study * 0.8 * Creatinine (µmol/l) *P<0.001 Miller ME, et al. BMJ 2010;340:b5444

17 egfr (ml/min) > <15 dialysis) Metformin Glimepiride Gliblenclamide Pioglitazone Vildagliptin Sitagliptin Saxagliptin Linagliptin Exenatide Liraglutide Insulin Dapagliflozin Canagliflozin Empagliflozin

18 Figure 2 HbA 1c levels and mortality in patients on dialysis Permission obtained from Wiley Rhee, C. M. et al. Semin. Dial. 27, (2014) Abe, M. & Kalantar-Zadeh, K. (2015) Haemodialysis-induced hypoglycaemia and glycaemic disarrays Nat. Rev. Nephrol. doi: /nrneph

19 Questions and Answers Which of the following clinical presentation in diabetes were not significantly improved over the last 3 decades? a. Myocardial infarction b. Stroke c. End stage kidney disease d. Amputation

20 Questions and Answers Which of the following clinical presentation in diabetes were not significantly improved over the last 3 decades? a. Myocardial infarction b. Stroke c. End stage kidney disease d. Amputation

21 Clinical case 70 years old man, type 2 DM for 12 years PA 150/90mmHg (Amlodipine 10mg/day) LDL 120mg/dL (Simvastatin 20mg/day) TG 245mg/dL BMI 29 Metformin 1.5g/day and gliblencamide 5mg/day HbA1C 7.9

24 24 Presentation Title Presenter Name Date Subject Business Use Only

26 Questions and Answers How would you best stratify the risk(s) of this patient? a. Patient at low risk of progression to end stage kidney disease b. Patient at high risk for a cardiovascular event c. Patient at high risk of progression to end stage kidney disease d. Patient at very high risk of progression to end stage kidney disease and cardiovascular disease

27 Questions and Answers How would you best stratify the risk(s) of this patient? a. Patient at low risk of progression to end stage kidney disease b. Patient at high risk for a cardiovascular event c. Patient at high risk of progression to end stage kidney disease d. Patient at very high risk of progression to end stage kidney disease and cardiovascular disease

28 Lifestyle & Dietary Potential Dietary Restrict dietary salt Fruit and vegetables Mediterranean diet Dietary fibre Calorie control Limited cola beverages Physical exercise Weight reduction Smoking cessation Alcohol reduction Increase fitness Improve blood pressure Improve glycemic control Reduce albuminuria What should we do? What can we do? Improve survival, vascular health, etc. KDIGO Diabetes Conference February 5-8, 2015 Vancouver, Canada

29 Modulators of the lipid pattern Proteinuria & Nephrotic syndrome Peritoneal dialysis & uremic toxins & NS Hemodialysis & Heparin administration Immunosuppression & polypharmacy Insulin resistance KDIGO Diabetes Conference February 5-8, 2015 Vancouver, Canada

30 Pattern of dyslipidemia TC LCL-C HDL-C TG Lp(a) 4D AURORA SHARP ALERT mg/dl KDIGO Diabetes Conference February 5-8, 2015 Vancouver, Canada

31 PLANET I Prospective EvaLuation of ProteinuriA and KidNey Function in diabetic (PLANET I) and non-diabetic (PLANET II) Patients with progressive Kidney Disease Renal effects of atorvastatin and rosuvastatin in patients with diabetes who have progressive renal disease (PLANET I): a randomised clinical trial The Lancet Diabetes & Endocrinology, Available online 4 February 2015, KDIGO Diabetes Conference February 5-8, 2015 Vancouver, Canada

32 Protein/creatinine (mg/g) on-treatment/baseline ratio Primary Endpoint: Proteinuria patients with T1- or T2-Diabetes Rosuvastatin 10 mg Rosuvastatin 40 mg Atorvastatin 80 mg Weeks LOCF No. of patients R R A KDIGO Diabetes Conference 92 February 5-8, 2015 Vancouver, 81 Canada 102

33 Change from baseline egfr Secondary Endpoint: Change in egfr 12 8 ml/min/1,73m * Weeks LOCF No. of patients R R A KDIGO Diabetes Conference 92 February 5-8, 2015 Vancouver, 84 Canada 101 * Atorvastatin 80 mg Rosuvastatin 10 mg Rosuvastatin 40 mg

34 egfr ml/min/1.73m 2 Fibrates in CKD VA-HIT ( ), p=0.529 FIELD ( ), p=0.028 Overall ( ), p=0.032 (I² = 0.0%, p for hetero=0.443) egfr 60 ml/min/1.73m 2 p=0.11 VA-HIT ( ), p=0.002 FIELD 122 Fibrate Placebo 4676 Favours Favours 1.23 ( ), p=0.07 P for hetero b/t Overall Events 159 Total 4909 Events Total Fibrate Placebo1.01 Risk ( ), Ratio; 95% p=0.966 CI egfr subgroups (I² = 70.3%, p for hetero=0.066) Cardiovascular Stroke events egfr ml/min/1.73m 2 VA-HIT ( ), ( ), p=0.04 p=0.054 FIELD ( ), ( ), p=0.04 p= ( ), p=0.004 Overall ( ), p=0.250 (I² (I² = 48.7%, 0.0%, p for hetero=0.72) hetero=0.163) egfr 60 ml/min/1.73m 2 p=0.44 p=0.12 VA-HIT ( ), ( ), p=0.002 FIELD ( ), ( ), p= ( ), p=0.009 Overall ( ), p=0.178 (I² = 40.4%, 0.0%, p for for hetero=0.868) hetero=0.195) Cardiovascular All-cause mortality death egfr ml/min/1.73m 2 VA-HIT ( ), ( ), p=0.529 p=0.986 FIELD ( ), ( ), p=0.028 p=0.254 Overall ( ), ( ), p=0.032 p=0.355 (I² = 0.0%, p for hetero=0.443) hetero=0.503) egfr 60 ml/min/1.73m 2 p=0.43 p=0.11 VA-HIT ( ), ( ), p=0.002 p=0.218 FIELD ( ), ( ), p=0.07 p=0.129 Overall ( ), ( ), p=0.966 p=0.948 (I² (I² = = 70.3%, 72.9%, p p for for hetero=0.066) hetero=0.055) Stroke Kidney egfr Disease: ml/min/1.73m Improving Global Outcomes J Am Coll Cardiol. 2012;60:

36 Questions and Answers What would be your preferred approach to the dyslipidemia in the case presented? a. Keep the treatment with simvastatin b. Add a fibrate c. Associate ezetimibe to simvastatin d. Change to rosuvastatin

37 Questions and Answers What would be your preferred approach to the dyslipidemia in the case presented? a. Keep the treatment with simvastatin b. Add a fibrate c. Associate ezetimibe to simvastatin d. Change to rosuvastatin

38 Lipid control LDLc <70 mg/dl or a 50% reduction Statins are safe and efficient for CV protection - SHARP Atorvastatin e fluvastatin don t require adjustment Sinvastatin, pravastatin, rosuvastatin, pitavastatin require Fibrates may be important in a subgroup of patients

39 AFIB/CKD/ATRIA Study Crude rates of thromboembolism OFF warfarin therapy by category of egfr among adults with nonvalvular AF. Copyright American Heart Association Go A S et al. Circulation 2009;119:

40 Hazard ratio (95% CI) HOT- bleeding by Kidney function Any bleeding HR 1.77 ( ) per halving of GFR p for trend = egfr (ml/min/1.73 m 2 ) * Reference *

41 Bleeding with warfarin in AF Jun et al, BMJ 2015

42 Major Regulatory Agency Recommendations for Novel Oral Anticoagulants in Patients with CKD Hart RG et al. Nat Rev Nephrol. 2012; 8(10):569-78

43 Anticoagulation and platelet antiaggregation therapy Progressive increased risk of bleeding individualize treatment

45 Relationship Between Achieved BP and Decline in Kidney Function from Primary Renal Endpoint Trials Nondiabetes MDRD. N Engl J Med AIPRI. N Engl J Med REIN. Lancet AASK. JAMA Hou FF, et al. N Engl J Med Parsa A et.al. NEJM 2013 Diabetes Captopril Trial. N Engl J Med Hannadouche T, et al. BMJ Bakris G, et al. Kidney Int Bakris G, et al. Hypertension IDNT. NEJM RENAAL. NEJM ABCD. Diabetes Care (Suppl) Normal decline in GFR Update from Kalaitzidis R and Bakris GL In: Handbook of Chronic Kidney Disease Daugirdas J (Ed.) 2011 KDIGO Diabetes Conference February 5-8, 2015 Vancouver, Canada

46 Data from the ADVANCE trial Zoungas S, et.al. Diabetes Care 2009;32 (11): KDIGO Diabetes Conference February 5-8, 2015 Vancouver, Canada

47 Summary of Guideline Goal BP and Initial Therapy in Kidney Disease to Reduce CKD Progression? Group 2014 Expert Panel (2014) ADA (2015) KDIGO/KDOQI (NKF) (2012) Goal BP (mmhg) <140/90 <140/90 <140/90 (130/80 if proteinuric) Initial Therapy ACE Inhibitor/ARB ACE Inhibitor/ARB* ACE Inhibitor/ARB ESH ( ) <130/80 ACE Inhibitor/ARB* KDOQI (NKF) (2004) <130/80 ACE Inhibitor/ARB* JNC 7 (2003) <130/80 ACE Inhibitor/ARB* Am. Diabetes Assoc (2003) <130/80 ACE Inhibitor/ARB* Canadian HTN Soc. (2002) <130/80 ACE Inhibitor/ARB* Natl. Kidney Foundation (2000) <130/80 ACE Inhibitor* JNC VI (1997) <130/85 ACE Inhibitor KDIGO Diabetes Conference February 5-8, 2015 Vancouver, Canada

48 Hipertension Risk factor for the progression of diabetic kidney diasease KDIGO recomendation: <130/90mmHg if albuminuria Unique features in diabetes: Volume related (diuretics and sodium restriction often needed) Frequent nocturnal and mask hypertension Consider ABPM SPRINT / ACCORDEON ACEs or ARBs mandatory

49 Glycemic control No important comorbidities, GFR higher than %. Longer diabetes duration, egfr lower than 60ml/min 7-8%.

50 Questions and Answers What is the degree of kidney dysfunction currently recommended for metformin discontinuation? a. Serum creatinine higher that 1.5mg/dL b. Creatinine clearance lower then 30ml/min c. egfr lower than 45ml/min d. egfr lower than 30ml/min

51 Questions and Answers What is the degree of kidney dysfunction currently recommended for metformin discontinuation? a. Serum creatinine higher that 1.5mg/dL b. Creatinine clearance lower then 30ml/min c. egfr lower than 45ml/min d. egfr lower than 30ml/min

52 egfr (ml/min) > <15 dialysis) Metformin Glimepiride Gliblenclamide Pioglitazone Vildagliptin Sitagliptin Saxagliptin Linagliptin Exenatide Liraglutide Insulin Dapagliflozin Canagliflozin Empagliflozin

53 Questions and Answers Which of the following hypoglycemic drugs have shown a reduction in the risk of progression to ESRD a. Insulin b. Metformin c. Pioglitazones d. SGLT2 inhibitors

54 Questions and Answers Which of the following hypoglycemic drugs have shown a reduction in the risk of progression to ESRD a. Insulin b. Metformin c. Pioglitazones d. SGLT2 inhibitors

55 Patients with an event (%) LEADER: Time to first renal event Macroalbuminuria, doubling of serum creatinine, ESRD, renal death HR: % CI (0.67, 0.92) P=0.003 Placebo Liraglutide Time since randomisation (months) Patients at risk Liraglutide Placebo The cumulative incidences were estimated with the use of the Kaplan Meier method, and the hazard ratios with the use of the Cox proportional-hazard regression model; the data analyses are truncated at 54 months because less than 10% of the patients had an observation time beyond 54 months CI, confidence interval; ESRD, end-stage renal disease; HR, hazard ratio Marso SP, et al. N Eng J Med 2016; June 13 [Epub ahead of print]

56 Vlado Perkovic et al (2015): Renal effects of canagliflozin in type 2 diabetes mellitus, Current Medical Research and Opinion

57 Adjusted mean (SE) egfr (ml/min/1.73m 2 ) EMPA-REG: Change in egfr over time After initial decrease, long term weekly changes of: EMPA (10 mg): +0.48±0.04 ml/min EMPA (25 mg): ±0.04 ml/min PBO: 0.04 ± Empagliflozin 10 Empagliflozin Weeks P<0.001 for both EMPA groups vs placebo Placebo Placebo Empagliflozin mg Empagliflozin mg egfr, estimated glomerular filtration rate; SE, standard error Wanner C. N Engl J Med 2016; June 14 [Epub ahead of print]

58 EMPA-REG: New onset or worsening of nephropathy New onset or worsening of nephropathy N with event/n analysed Empagliflozin Placebo HR (95% CI) 525/ / (0.53, 0.70) P value < New-onset macroalbuminuria 459/ / (0.54, 0.72) < Doubling of serum creatinine Initiation of renal replacement therapy 70/ / (0.39, 0.79) 13/ / (0.21, 0.97) Favours empagliflozin Favours placebo CI, confidence interval; HR, hazard ratio Wanner C. N Engl J Med 2016; June 14 [Epub ahead of print]

59 Patients with event (%) EMPA-REG: Doubling of serum creatinine, initiation of renal replacement therapy or death due to renal disease 7 6 Placebo 5 4 HR: 0.54 (95% CI: 0.40, 0.75) P= Empaglifloz No. of patients Empagliflozin Months Placebo Wanner C. N Engl J Med 2016; June 14 [Epub ahead of print]

60 Sodium glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis Kidney International, Volume 89, Issue 3, 2016,

61 Back to our patient: what changes in the management when kidney disease is present? Start an ACEi or ARB target <130/90mmHg Aspirin Warfarin Simvastatin/Ezetimibe target LDLc 70mg/dL Reduce the metformin dose to half Add a SGT2i target HbA1C 7% Weight, BP, albuminuria, egfr

63 GLP-1 agonist DPP inhibitors PPARγ agonist SGL2i Glucose lowering Glucose Blood pressure AGE inhibitors RAGE antagonists PKC inhibitors e.g. ruboxistaurin AGEs and RAGE PKCα and PKC β Other All ET-1 Other Antihypertensives ACE inhibitors Or ARBs Endothelin Receptor blockers e.g. atrasentan TGF-β or CTGF Antibodies Pirfenidone Growth factors CTGF TGF-β VEGF VEGF antibodies Fibrosis Inflammation Albuminuria Diabetic nephropathy Fineberg D, et al. Nat Rev Endocrinol 2013;9:

Kidney Disease, Hypertension and Cardiovascular Risk

1 Kidney Disease, Hypertension and Cardiovascular Risk George Bakris, MD, FAHA, FASN Professor of Medicine Director, Hypertensive Diseases Unit The University of Chicago-Pritzker School of Medicine Chicago,