1. These slides were sponsored by Janssen and developed in conjunction with the BRS CKD Strategy Group, following an advisory board that was organised by Janssen. Bedrock Healthcare Communications provided editorial support to members of the advisory board in developing the slides. Janssen reviewed the content for technical accuracy. The content is intended for a UK professional audience only. JOB CODE PHGB/VOK/0914/0018d Date of preparation: February 2015 SECTION E Prevention of diabetic kidney disease

2. Objectives and background for this learning resource Introduction: This learning resource has been developed as part of a medical education initiative supported by Janssen. The content of this slide kit has been developed by an advisory board of renal physicians, GPs and specialist nurses. The panel of experts includes members of the British Renal Society Chronic Kidney Disease (CKD) Strategy Group. Bedrock Healthcare, a medical communications agency, has provided editorial support in developing the content; Janssen has reviewed the content for technical accuracy. Educational objectives: To provide clear and applicable clinical guidance on chronic kidney disease (CKD) in people with type 2 diabetes to primary care healthcare professionals To advise primary healthcare professionals on what people with diabetes need to know about their own condition with relation to CKD Usability objectives: To provide essential, relevant and up to date information in concise presentations To enable primary healthcare professionals to locate, select and use the content of the learning resource, as appropriate to their needs To enable secondary care experts in CKD to refer their primary care colleagues to the resource 1

3. Contents overview This learning resource comprises the following 10 sections (A-E): 2 Section A Introduction and overview of chronic kidney disease (CKD) in people with diabetes Section B Long-term impact of diabetes and the importance of optimal management of the condition Section C Pathophysiology of diabetic nephropathy & risk factors for the development of CKD Section D Appropriate monitoring for complications of diabetes in primary care – CKD as one of these complications Section EPrevention of diabetic kidney disease

4. Contents overview (cont.) This learning resource comprises the following 10 sections (F-J): 3 Section F Optimal management of diabetic kidney disease: hypertension and glycaemia Section G How to involve people with diabetes and CKD in their own care – what information must they have to manage their own condition effectively? Section H What does the future hold for a person with well-managed diabetes and CKD? Section I What do the guidelines say and what do they mean in terms of the day-to-day management of CKD in people with diabetes? Section JSources of further information and reading list

5. Section E – 3 key learning objectives Early optimal blood glucose control and blood pressure control may substantially reduce the risk of developing CKD (and other microvascular complications) The benefits of early optimal blood glucose control continue in the long term Patient engagement in lifestyle changes may reduce the risk of diabetic kidney disease 4

6. Hyperglycaemia causes macrovascular complications Macrovascular complications are: –Cerebrovascular disease 1 –Coronary artery disease 1 –Peripheral vascular disease 1 Proposed pathological mechanisms include: –Atherosclerosis causing a response that results in the formation of a lipid-rich atherosclerotic lesion with a fibrous cap; rupture of this lesion leads to acute vascular infarction 1 –Increased platelet adhesion and hypercoagulability in type 2 diabetes increasing the risk of vascular occlusion and cardiovascular events 1 5 Reference: 1. Fowler MJ. Clinical Diabetes 2008;26(2):77-82 2. International Diabetes Federation. What is diabetes. Available at: https://www.idf.org/node/23538. Accessed: 22/01/2014.https://www.idf.org/node/23538 Brain Cerebrovascular disease 1,2 Stroke 1,2 Dementia (stroke- related) 1 Brain Cerebrovascular disease 1,2 Stroke 1,2 Dementia (stroke- related) 1 Heart Cardiovascular disease 2 Angina 2 Myocardial infarction 2 Congestive heart failure 2 Heart Cardiovascular disease 2 Angina 2 Myocardial infarction 2 Congestive heart failure 2 Extremities Peripheral vascular disease 2 Ulceration 2 Gangrene 2 Amputation 2 Extremities Peripheral vascular disease 2 Ulceration 2 Gangrene 2 Amputation 2

7. Hyperglycaemia causes microvascular complications Microvascular complications are: –Diabetic retinopathy 1 –Diabetic kidney disease 1 –Diabetic neuropathy 1 Proposed pathological mechanisms leading to development of these conditions as a result of hyperglycaemia include: –The formation of glycoproteins 1 –Increased protein kinase C activity 2 –Polyol accumulation 1,2 –Oxidative stress 1,2 –Involvement of growth factors, including VEGF, growth hormone, and transforming growth factor β 1,2 –Increased osmotic stress caused by sorbitol accumulation 1 6 References: 1. Fowler MJ. Clinical Diabetes 2008;26(2):77-82. 2. Dronavalli S, Duka I and Bakris GL. Nat Clin Pract Endocrinol Metab. 2008;4(8):444-52. 3. International Diabetes Federation. What is diabetes. Available at: https://www.idf.org/node/23538. Accessed: 22/01/2014.https://www.idf.org/node/23538 Eye Retinopathy 3 Cataracts 3 Glaucoma 3 Eye Retinopathy 3 Cataracts 3 Glaucoma 3 Kidney Albuminuria 1 Kidney disease 3 Kidney Albuminuria 1 Kidney disease 3 Nerves Neuropathy 3 Peripheral 3 Autonomic 1 Nerves Neuropathy 3 Peripheral 3 Autonomic 1

8. The benefits of glycaemic control in diabetic kidney disease Individual HbA1c targets are typically in the range of 48-59 mmol/mol (6.5-7.5%) 1 The benefits of good glycaemic control are summarised in the table below: 7 Benefits of good glycaemic control Renal function effects: Reduces the rate of renal function decline, particularly if combined with blood pressure control 2 Can normalise glomerular filtration rate 3 Lower risk of albuminuria development 4 Reduces risk for development of renal failure 5 Effects on complications of diabetic kidney disease: Reduces incidence of autonomic neuropathy 6 Impact on outcomes: Delays the need for dialysis 7 Increased survival rate in patients undergoing hemodialysis 8 Improves the chances of a successful kidney transplant 9 Financial outcomes: Reduces costs - The cost of implementing UK guidelines for a practice of 10,000 patients would be recouped by delaying dialysis for one year in one person 10 References: 1. NHS Diabetes. HbA1c Standardisation For Clinical Health Care Professionals leaflet. Available at: https://www.diabetes.org.uk/upload/Professionals/Key%20leaflets/ 53130HbA1cHCPleaflet.pdf. Accessed 09 January. 2. American Diabetes Association. Nephropathy in diabetes. Diabetes Care 2004:27;S79-83. 2015. 3.Wiseman MJ et al. Effect of Blood Glucose Control on Increased Glomerular Filtration Rate and Kidney Size in Insulin-Dependent Diabetes. N Engl J Med 1985;312:617–21. 4. Fioretto P et al. Renal Protection in Diabetes: Role of Glycemic Control. J Am Soc Nephrol 2006 17:S86 –S89. 5.UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).Lancet 1998;352:837-53. 6.Ziegler D et al. The natural history of somatosensory and autonomic nerve dysfunction in relation to glycaemic control during the first 5 years after diagnosis of Type 1 (insulin-dependent) diabetes mellitus. Diabetologica 1991;34:822-829. 7. Ruggenenti P et al. Progression, remission, regression of chronic renal diseases. Lancet 2001;357: 1601–08. 8.Morioka T et al. Glycemic Control Is a Predictor of Survival for Diabetic Patients on Hemodialysis. Diabetes care 2001;24:909-913. 9. Wiesbauer F et al. Glucose control is associated with patient survival in diabetic patients after renal transplantation. Transplantation. 2010;89:612-9. 10. Klebe et al. The cost of implementing UK guidelines for the management of chronic kidney disease. Nephrol Dial Transplant 2007;22:2504-2512..

9. Blood glucose management can reduce the risk of death in patients with type 2 diabetes This graph shows a 21% decrease in death related to diabetes per 1% reduction in HbA1c 1 8 Hazard ratio 4 1 0.5 p<0.0001 6578910 Updated mean haemoglobin A 1C concentration (%) Reference: 1. Stratton IM, Adler AI, Neil HAW, et al. UKPDS35. BMJ 2000;321:405–12. Death related to diabetes Adapted from Stratton IM, Adler AI, Neil HAW, et al. UKPDS35. BMJ 2000;321:405–12.

10. Intensified multifactorial intervention has sustained beneficial effects 1 In patients with type 2 diabetes and albuminuria, intensified multifactorial intervention* had sustained beneficial effects on vascular complications and on rates of death 1 After a mean of 13.3 years † there was an absolute risk reduction for death from any cause of 20% among patients who received intensive therapy compared with those who received conventional therapy 1 * tight glucose regulation and the use of renin–angiotensin system blockers, aspirin, and lipid-lowering agents † 7.8 years of multifactorial intervention and an additional 5.5 years of follow-up CABG=coronary artery bypass graft, PCI=Percutaneous Coronary Intervention Number of cardiovascular disease events among patients on intensive vs. conventional therapy 1 9 Reference: 1. Gæde P, Lund-Anderson H, Parving H-H, et al. N Engl J Med 2008;358:580-91. 0 20 25 30 35 40 15 10 5 Death from cardiovascular causes Stroke Myocardial infarction CABGPCI Revascul- arisation Amputation Intensive therapyConventional therapy No. of cardiovascular events Adapted from Gæde P, Lund-Anderson H, Parving H-H, et al. N Engl J Med 2008;358:580-91..

11. This graph shows a 37% decrease in microvascular end points (predominantly retinal photo-coagulation) per 1% reduction in HbA1c 1 Microvascular end points 10 1 0.5 p<0.0001 Blood glucose management can reduce the risk of microvascular complications 10 65789 Updated mean haemoglobin A 1C concentration (%) 0.5 Hazard ratio Adapted from Stratton IM, Adler AI, Neil HAW, et al. UKPDS35. BMJ 2000;321:405–12. Reference: 1. Stratton IM, Adler AI, Neil HAW, et al. UKPDS35. BMJ 2000;321:405–12. *Microvascular complications were retinopathy requiring photocoagulation, vitreous haemorrhage, and or fatal or non-fatal renal failure

12. Blood glucose control is a predictor of kidney health The incidence of kidney disease for patients on insulin therapy was significantly lower than that for patients not on insulin 1 HbA1c was not significantly associated with progression of renal failure, possibly because all patients in the study had renal insufficiency/failure at baseline 1 11 60 Cumulative ratio Patients without insulin therapy n=44 Patients on insulin therapy n=41 50403020100 Follow-up period (months) 0.0 0.2 0.4 0.6 0.8 1.0 Cumulative incidence ratio for kidney failure* determined by Kaplan-Meier curves p=0.0022 *Kidney failure defined as a doubling of serum creatinine in type 2 diabetic patients with chronic renal insufficiency/failure Reference: 1. Ueda H, Ishimura E, Shoji T, Emoto M, et al. UKPDS36. Diabetes Care 2003;26:1530-1534 Patients without insulin therapy baseline HbA1c (%) 8.2±2.0 Patients on insulin therapy baseline HbA1c (%) 7.3±1.7 Adapted from Ueda H, Ishimura E, Shoji T, Emoto M, et al. UKPDS36. Diabetes Care 2003;26:1530-1534.

13. There may be potential hazards of tight glycaemic control in some patient groups The ACCORD study identified a previously unrecognised harm of intensive glucose lowering in high-risk patients with type 2 diabetes and high glycated haemoglobin levels 1 Study findings: 257 patients in the intensive-therapy group died, compared with 203 patients in the standard therapy group (hazard ratio, 1.22; 95% CI, 1.01 to 1.46; p=0.04) 1 After reviewing mortality trends for several months the intensive regimen was discontinued for safety reasons 1 Hypoglycemia requiring assistance and weight gain of more than 10 kg were more frequent in the intensive-therapy group (p<0.001) 1 –This harm may be due either to the approach used for rapidly lowering glycated haemoglobin levels or to the levels that were achieved 1 12 Reference: 1. The Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med 2008;358:2545-59.

14. Blood pressure management can reduce the risk of death Death related to diabetes was decreased by 17% per 10mm Hg reduction in systolic blood pressure 1 13 4 1 p<0.0001 120110130140150170160 0.5 Death related to diabetes Hazard ratio Updated mean systolic blood pressure (mm Hg) Reference: 1. Adler AI, Stratton IM, Neil HAW, et al. UKPDS36. BMJ 2000;321:412–9. Adapted from Adler AI, Stratton IM, Neil HAW, et al. UKPDS36. BMJ 2000;321:412–9.

15. Blood pressure management reduces the risk of microvascular complications* and MI The risk of microvascular complications and myocardial infarction (MI) are strongly associated with increasing blood pressure 1 14 Reference: 1. Adler AI, Stratton IM, Neil HAW, et al. UKPDS36. BMJ 2000;321:412–9. 50 10 0 20 30 40 110120130140150160170 Myocardial infarction Microvascular end points (predominantly retinal photocoagulation). Updated mean systolic blood pressure (mm Hg) Adjusted incidence per 1,000 person years (%) Adapted from Adler AI, Stratton IM, Neil HAW, et al. UKPDS36. BMJ 2000;321:412–9. *Microvascular complications were retinopathy requiring photocoagulation, vitreous haemorrhage, and or fatal or non-fatal renal failure

16. Tight blood pressure management needs to be continued in order to maintain benefits In the UKPDS study, tight blood pressure control in patients with hypertension and type 2 diabetes achieved a clinically important reduction in: 1 –the risk of deaths related to diabetes 1 –complications related to diabetes 1 –progression of diabetic retinopathy 1 –deterioration in visual acuity 1 However, it appears that blood pressure control must be continued if the benefits are to be maintained 2 15 Reference: 1. UKPDS Group UKPDS 38. BMJ 1998;317(7160);703-13. 2. Holman RR, et al. N Engl J Med. 2008;359:1563-76.

17. Lifestyle modifications to prevent development/progression of diabetic kidney disease The following lifestyle modifications should be discussed with your patient to optimise their health and reduce the chances of disease development and progression: –Smoking cessation 1 –Weight reduction 1 –Alcohol intake 1 –Increase physical activity 1 –Reduce sodium intake (no more than 2.3 grams per day, equivalent to 1 tsp) 1 –Reduce fat intake 1 16 Reference: 1. National Health Institute. National Kidney Disease Education Program: Diet and Lifestyle Changes. Available at: http://nkdep.nih.gov/living/diet-lifestyle-changes.shtml. Accessed 09 January 2015.

18. Section E – summary CKD development and progression can be prevented through blood glucose control and blood pressure control The benefits of early optimal glycaemic control continue in the long term –Reducing renal function decline –Reducing complications –Delaying dialysis –Reducing financial costs Lifestyle modification reduces risk factors for the development and progression of diabetic kidney disease 17