1. (potentiële) Belangenverstrengeling Geen Voor bijeenkomst mogelijk relevante relaties met bedrijven Geen Sponsoring of onderzoeksgeld Honorarium of andere (financiële) vergoeding Aandeelhouder Andere relatie, namelijk Geen De transportkosten en een honorarium voor deze voordracht wordt voorzien door Baxter; er is geen direct verband tussen Baxter en de huidige voordracht Renal Highlights 2016 Disclosure belangen Prof.dr. W. van Biesen

2. ERBP Guideline on management of diabetics with advanced CKD

3. ERBP Mission improve the outcome of patients with kidney disease in a sustainable way, through enhancing the accessibility of knowledge on patient care, in a format that stimulates its use in clinical practice.

4. Outline Is intensive glycemic control as measured by HbA1C advantageous in diabetic patients with CKD 3b-5d? What oral agent should be preferred as first line agent in patients with CKD 3b-5d with impaired glucose tolerance/diabetes

5. HbA 1c is significantly correlated to eGFR K. Shima; Ann Clin Biochem; 2012, vol. 49, 68-74 With thanks to Rikke Borg

6. Hb, EPO & Hb A1C Inaba JASN 18:896 2007

8. Adjusted mortality rate in ESRD and DM: HbA1c

9. - Observational data - interfering factors in HbA1C measurement

10. CKD and Glycaemic Control Kovesdy AJKD 52:766 2008

11. CKD and Glycaemic Control Kovesdy AJKD 52:766 2008

12. CKD and Glycaemic Control Kovesdy AJKD 52:766 2008

13. 1,25-Vitamin D improves Insulin Sensitivity E 16 Insulin resistant HD patients PTH 798 pg/ml did not change during study RCT 1.8 µg 1,25-vitamin D X3/week for 4 weeks vs. Control (group 2) Triglycerides 198  148 mg/dL Oral glucose tolerance test Before:  and after:  Euglycaemic clamp study A: Insulin stimulated glucose metabolism B: Insulin concentration Mak KI 53,1353 1998

14. Incretins

15. Idorn KI 2013; 83:915

16. Considerations in advanced CKD patients Increased risk of hypoglycemia Decreasing renal mass leads to impaired gluconeogenesis and glycenolysis Decreased renal clearance of insulin Decreased clearance of hypoglycemic drugs comorbidity and co-medication Increasing impaired glucose tolerance Peripheral insulin resistance in CKD from counter-regulatory hormones, electrolyte abnormalities, uremic acidosis, and accumulation of uremic toxins Shortened life expectancy Increased cardiovascular risk +++

17. Cochrane review Hemmingsen et al, BMJ, 2011

20. Non fatal myocardial infarction

21. Cochrane review Hemmingsen et al, BMJ, 2011

23. Conclusions Hard evidence for LACK of impact on all cause mortality by actively lowering HbA1C Insufficient evidence for a 10% relative risk reduction in cardiovascular mortality and non-fatal myocardial infarction Insufficient evidence for reduction in microvascular disease (combination of retinopathy, nephropathy STRONG evidence for increased risk of severe hypoglycaemia

24. Conclusions Hard evidence for LACK of impact on all cause mortality by actively lowering HbA1C Insufficient evidence for a 10% relative risk reduction in cardiovascular mortality and non-fatal myocardial infarction Insufficient evidence for reduction in microvascular disease (combination of retinopathy, nephropathy At least in studies with an overwhelming majority of non advanced CKD patients!!!!!!

26. Conclusions First concern: avoid hypoglycemia If no hypoglycemia’s and HbA1C>7%: try to intensify hypoglycemic treatment Take into consideration comorbidity and age of patients

29. Why do you always have to be different?

30. Arnouts NDT 2014 Oral antidiabetics in CKD

31. Metformin Method of Action Increases insulin sensitivity Reduces glucose absorption from intestine Increases peripheral glucose uptake in cells Reduces gluconeogenesis in the liver Reduces weight Hypoglycaemia rare

32. UKPDS Study 4209 patients with Type 2 DM Creatinine <175 mmol/l Randomised to Diet or Insulin-sulphonylurea (normal weight) Metformin (Body weight >120% IBW) Holman NEJM 359:1577 2008

33. Scheen AJ. Metformin and lactate acidosis. Acta Clin Belg 2011, 66 (5): 329-331 METFORMIN in advanced CKD: ?

35. METFORMIN First drug of choice in all current guidelines Cheap No hypoglycemic risk Weight-neutral or reducing effect Lipid- lowering effect Well characterized efficacy and safety profile Impressive preventive effects with prevention of: – Diabetes – Micro- and macrovascular complications – Major events in patients with heart failure – Apoptotic neuron death – Cancer – Osteopenie – Mortality in lactic acidosis not related to to metformin

36. Scheen AJ. Metformin and lactate acidosis. Acta Clin Belg 2011, 66 (5): 329-331 METFORMIN: LACTIC ACIDOSIS

37. Herrington WG, Levy JB. Metformin: effective and safe in renal disease. Int Urol Nephrol 2008; 40: 411-417 A coctail of risk aversion and WYSIATI effects

38. Herrington WG, Levy JB. Metformin: effective and safe in renal disease. Int Urol Nephrol 2008; 40: 411-417 A coctail of risk aversion and WYSIATI effects

39. METFORMIN: LACTIC ACIDOSIS – No firm data that lactic acidosis is more frequent in patients on metformin (Salpeter, Cochrane review) – Evidence that outcome of lactic acidosis is BETTER in patients on vs not on metformin – We have to distinguish Lactic acidosis type A: caused by tissue hypoxia/liver damage Lactic acidosis type B: caused by intoxication, eg metformin – We have to to distinguish: Metformin as CAUSE of the lactic acidosis Metformin as a drug in a patient who develops lactic acidosis because of other reasons Mixed forms

40. Recommendations We recommend metformin in a dose adapted to renal function as a first line agent when lifestyle measures alone are insufficient to get HbA1C in the desired range (1B) We recommend to add on to meformin a drug with a low risk for hypoglycaemia as a second agent when improvement of glycaemic control is deemed appropriate according to guideline (1D) There is insufficient evidence to support insulin over an additional oral agent as add on second line treatment We recommend instructing patients to withhold metformin in conditions of pending dehydration, when undergoing contrast media investigations, or when there is a risk for AKI

41. advice for clinical practice Consider to provide patients with credit-card type flyers with instructions on when to temporarily withdraw methformin drugs with low risk for hypoglycaemia: (figure) – Metformin – Alpha glucosidase inhibitors – DPP-IV inhibitors – Incretin mimetics – SGLT-2 inhibitors drugs with moderate risk for hypoglycaemia: – Short acting SU derivates or SU derivates with inactive metabolites – meglitinides drugs with high risk for hypoglycaemia: – Insulin – Long acting SU derivates or derivates with active metabolites in patients with diabetes and eGFR <45 who are on metformin, the decision to withhold the drug 48 hours before and after administration of contrast media should be taken by the treating physician, balancing the probability for emergence of contrast induced nephropathy (type and amount of contrast, intravenous vs intra-arterial), and presence of other co- existing factors that might cause sudden deterioration of kidney function (dehydration, use of NSAID, use of inhibitors of the RAAS system) against the potential harms by stopping the drug (which should be considered low in view of the short period that it should be withheld).

42. When to start dialysis?

43. Study Publicatio n Year Time Frame Location Characteristi cs Study design N % DM Modality (% HD) Methods Outcomes Inclusion criteria Exclusion criteria Patients’ characteristic s Intervention (n=) Comparator(n=) Duration Outcom e(s) Results Quality of evidenc e Newcastle- Ottawa Score (Cochrane risk of bias for the RCT's) Notes Cooper et al.(7) 2010 2000- 2008 Australia/ New Zealand RCT (IDEAL study) N = 828 34% DM 44% HD Cox regression Mortality Patients were eligible for inclusion in the study if they had progressive chronic kidney disease (patients with a failing kidney transplant were eligible) and an estimated GFR between 10.0 and 15.0 ml per minute per 1.73 m2 Exclusion: < 18 years of age, eGFR< 10.0 ml/min, planned living donation within 12 months, cancer that was likely to affect mortality Age: 60.3 yrs Gender: 65% male DM (as PRD): 34% eGFR at start: 9.9 ml/min/1.73 m 2 Late start of dialysis group (eGFR CG between 5-7 ml) (n=424) Early start of dialysis group (eGFR CG between 10-14 ml)(n=404) FU until November 2009 Mortalit y HR 1.04 (0.83- 1.30) p=0.75. P for interaction for early or late start of dialysis with diabetes = 0.63. High selection bias: low performance bias: unclear detection bias: low attrition bias: low reporting bias: low other bias: unclear Randomized controlled trial with proper subgroup analysis for interaction in diabetics.

44. When to start dialysis?

45. Lipid lowering strategies?

47. Sharp trial

49. Lipid lowering strategies?