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Highlights

Highlights. Dr Mick Kumwenda MSc FRCP (London) Consultant Nephrologist and Clinical Director (Medicine) Glan Clwyd Hospital Rhyl Denbighshire UK Mick.kumwenda@wales.nhs.uk. PACD18 2014.

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Highlights

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  1. Highlights Dr Mick Kumwenda MSc FRCP (London) Consultant Nephrologist and Clinical Director (Medicine) Glan Clwyd Hospital Rhyl Denbighshire UK Mick.kumwenda@wales.nhs.uk

  2. PACD18 2014 We are delighted to present you with the highlights this year from yet again a very successful congress attended by 2003 multidisciplinary delegates from around the globe. We wish to thank all those who attended and hope you left the congress full of knowledge that made a difference when you returned back to your home base. We also thank all the speakers that contributed, the quality of all the papers was exceptional and we have selected a few slides with the kind permission of the presenters to summarise key messages from the congress.

  3. PACD18 2014 The PACD continues to serve the diabetes health care providers in the Middle East as an academic forum for the exchange of knowledge, training and experience. Conference chair : Sherif Hafez Vice chairs: Mohamed Fahmy Abdel-Aziz Megahed Abou El-Magd Assistant Secretary General: Gamela Nasr Hyam Refaat Tantawi

  4. Message from molecular metabolism workshops

  5. Type 2 diabetes Type 2 diabetes (T2D) is a complex disorder that is affected by multiple genetic and environmental factors. Existing genetic markers explain only a modest (15%) part of the heritability of T2D.

  6. Epigenetics Epigenetics has been defined as heritable changes in gene function that occur without a change in the nucleotide sequence. i e Non -sequence dependent inheritance

  7. Key Enzymes in epigenetics • It has recently been suggested that glucose availability can affect histone acetylation in an ATP-citrate lyase-dependent manner, further linking energy metabolism to epigenetic regulation

  8. Mitochondrial disease and diabetes

  9. Immune cells and Modulation of Energy Balance • The effectors of innate and adaptive immune cells implicated in maintaining energy balance include: • - Macrophages(MQ) • - T cells • - Neutrophils • - Dendritic cells(DCs) • - Mast cells (MCs) • - Eosinophil's • - Natural Killer (NK ) cells • - Natural killer T(NKT) cells

  10. Cooperation between brain and islet in glucose homeostasis and diabetes (Schwartz, M.W. et al., 2013)

  11. Message from obesity workshop

  12. Obesity and life expectancy • January 2003 Life Table analysis of Framingham Data • Obese at 40 live 6 to 7 years less than normal • Overweight at 40 live 3 years less than normal • Obese smoker live 14 years less than normal

  13. HEALTHY DIET RECOMMENDATIONS

  14. Understanding natural history of type 2 diabetes and targeted therapies

  15. b-cell Dysfunction Insulin Resistance Type 2 Diabetes Dual defect of type 2 diabetes: treating a moving target Hyperglycaemia Insulin Action b-cell Failure Insulin Concentration Insulin Resistance Euglycaemia Diagnosis oftype 2 diabetes Progression oftype 2 diabetes Normal IGT ± Obesity DeFronzo et al. Diabetes Care 1992;15:318-68

  16. Guiding principles for nutrition education Patients are responsible Patients are therefore the final decision-makers Knowing what is best for diabetes, is not the same as knowing what is best for that patient These principles have re-defined how we provide education Both structured education and one to one approach benefits patients.

  17. Trials to Prevent / Delay Progression From IGT to Type 2 Diabetes Lifestyle Changes • Malmo Study • Da Qing Study • Finnish Diabetes Prevention Study • Diabetes Prevention Program Medications • Diabetes Prevention Program: metformin • TRIPOD: troglitazone • PIPOD: pioglitazone • STOP-NIDDM: acarbose • NAVIGATOR: nateglinide and valsartan • DREAM: rosiglitazone and ramipril • XENDOS: orlistat • ORIGIN: glargine insulin • ACT NOW:pioglitazone TRIPOD=Troglitazone in Prevention of Diabetes Study; PIPOD= Pioglitazone in Prevention of Diabetes Study; STOP-NIDDM=Study to Prevent Non–Insulin-Dependent Diabetes Mellitus; NAVIGATOR=Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research; DREAM=Diabetes Reduction Approaches with Ramipril and Rosiglitazone; XENDOS=Xenical in the Prevention of Diabetes in Obese Subjects; ORIGIN=Outcomes Reduction with Initial Glargine Introduction.

  18. ADA/EASD position statement 2012 Towardspersonalizedglycaemic targets

  19. ADA. V. Diabetes Care. Diabetes Care 2014;37(suppl 1):S27. Figure 2;adapted with permission from Inzucchi SE, et al. Diabetes Care 2012;35:1364–1369

  20. The A1C and ABCDE of glycaemia management in type 2 diabetes: a physician's personalized approach. AGE (years) 15-40 40-70 >70 COMPLICATIONS DURATION>10yrs - + - + - + HbA1c(%) <6 <6.5 <6.5 6.5-7 <7 7-8 HbA1c≥ 9% Insulintreatment HbA1c< 9% METFORMIN Pozzilli P, Leslie RD, Chan J, De Fronzo R, Monnier L, Raz I, Del Prato S. The A1C and ABCD of glycaemia management in type 2 diabetes: a physician's personalized approach.Diabetes Metab Res Rev. 2010 May;26(4):239-44.

  21. Insulin initiation is often delayed in type 2 diabetes despite high HbA1c 9.9% 10.0 9.7% 9.5% 9.5 9.2% 9.2% 9.1% 9.0 8.5 Baseline HbA1c (%) 8.0 7.5 7.0 6.5 A1chieve Egypt sub-group 0.0 INITIATEplus4 17075 EuroMix2 INITIATE1 IMPROVETM 3 8.6 - - 9.5 10.3 7.4 7.7 Diabetes duration (years) • Raskin et al. Diabetes Care 2005;28:260–5 • Kann et al. Exp Clin Endo Diab 2006; 114:527–32 • Valensi et al. Int J Clin Pract 2009;63:522–31 • Oyer et al. Am J Med 2009;122:1043–9 • Yang et al. Diabetes Care 2008;31:852–6

  22. Improvement of glycaemic control in combination therapy Regime • Insulin and SU – 7 studies • Insulin and metformin – 4 studies • Insulin and TZD – 2 studies Glycated Hb reduction vs insulin alone • - 0.4% • - 1.3% • - 1.3% Yki Jarvinen H Diabetes Care 2001 24 : 738-67

  23. Be aware of hypoglycemia • <3.5-4 mmol/L (<63-72 mg/dL) • Whipple’s triad: • Symptoms • Low blood glucose • Relief of symptoms when blood glucose raised

  24. COUNTER REGULATORY HORMONES: GLUCAGON, EPINEPHRINE, CORTISOL, GROWTH HORMONE

  25. Hypoglycemia unawareness • Glucagon response often lost after five years with type 1 diabetes • Epinephrine response may be blunted and delayed • Adrenergic symptoms blunted • Reliance on recognizing neuroglycopenic symptoms

  26. Metformin: multiple mechanisms for vascular protection Improved Reduced All refs Diabetes Metab (2003): 1Gianarelli R vol. 29:6S28-35; 2Després JP 29:6S53-61; 3Grant PJ ;29:6S44-52; 4Wiernsperger N 29:6S77-8; 5Schäfers RF 29:6S62-70;6Beisswenger 29:6S95-103; 7Leverve XM 29:6S88-94; 8Mamputu JC 29:6S71-6;

  27. The proposed pathways by which GLP-1 may exert its cardiovascular Effects .

  28. Cardio protective potentials of DPP-4 inhibitors beyond their glucose-lowering action Balakumar P, et al. Cell Signal. 2013 Sep;25(9):1799-803

  29. 197 studies identified Metformin was well tolerated, albeit with a trend towards increased hypoglycaemia. Formal estimates of combined effects from the five trials which reported appropriate data indicated a significant reduction in insulin dose (6.6 U/day, p<0.001) but no significant reduction in HbA1c (absolute reduction 0.11%, p=0.42). No reported trials included cardiovascular outcomes 12

  30. Alpha Glucosidase Inhibitors in Type 1 DM • Prevention of nocturnal hypoglycemia? • Reduce postprandial hyperglycemia Raju B, et al. J Clin Endocrinol Metab. 2006 Jun;91(6):2087-92. Riccardi G, et al. Diabet Med. 1999 Mar;16(3):228-32. 13

  31. Thiazolidinediones in Type 1 DM • Potential insulin sparing role in overweight patients with type 1 diabetes. • Mixed effects on progression of diabetes reported Strowig SM, Raskin P. Diabetes Care. 2005 Jul;28(7):1562-7. Shimada A, et al. Diabetes Metab Res Rev. 2011 Nov;27(8):951 Yang Z, et al. Diabetes Res Clin Pract. 2009 Jan;83(1):54-60. 14

  32. Incretin-based Therapies in Early Type 1 DM 2 Hari Kumar KV, Shaikh A, Prusty P. Diabetes Res Clin Pract. 2013 May;100(2):e55-8

  33. Ramadan and glycaemic control Oral hypoglycemic agents SUs Unsuitable for use during fasting because of the inherent risk of Hypoglycemia, use with caution. Consider dose adjustment. TZDs No treatment adjustment required 2–4 weeks to exert substantial antihyperglycemic effects DPP4 inhibitors The best tolerated drugs, Consider DPP4i as an alternative to SUs if the risk of hypoglycemia is high Metformin Modify timing of doses: Two thirds of dose at Iftar • One third at suhur. Short acting insulin SUs Take twice daily at suhur and iftar E Hui et al , BMJ, 26 june 2010 , Volume 340; Al-Arouj M. et al, Recommendations for management of diabetes during Ramadan. Diabetes Care. 2010;33: 1895-1902.

  34. Don’t miss MODY!Genetic Testing for MODY • Who should be tested? • MODY misdiagnosed as type 2 diabetes and sometimes type 1 diabetes. • Mutations can be inherited (commonly) or de novo (rarely). • What genes should be tested? • Most common causes of MODY are mutations in GCK, HNF1A and HNF4A. • Is genetic testing good healthcare policy? • Change from expensive therapy to cheaper therapy – saves money. • If you have a GCK mutation, you DO NOT have type 2 diabetes and you do not need any drugs or a diabetes doctor! MonogenicDiabetes.org

  35. MODY – Treatment Decisions • HNF1A • Low-dose sulfonylurea (pills) • GCK • No therapy except during pregnancy • HNF4A • Low-dose sulfonylurea (pills) • HNF1B • Insulin?

  36. MANAGING DIABETES RELATED COMPLICATIONS

  37. OASIS Study Mortality by Diabetes and CVD Status Diabetes/CVD (n=1,148) RR=2.88 (2.37-3.49) No Diabetes/CVD (n=3,503) Diabetes/No CVD (n=569) No Diabetes/No CVD (n=2,796) RR=1.99 (1.52-2.60) Event rate RR=1.71 (1.44-2.04) RR=1.00 6 12 15 3 9 18 21 24 Months OASIS=Organization to Assess Strategies for Ischemic Syndromes Malmberg K, et al. Circulation. 2000;102:1014-1019.

  38. State of the art lecture in memory of Prof Zakarya El BAZ Diabetic Nephropathyby Prof Sherif HafezDr Mick Kumwenda

  39. Definitions – based on quantification • Micro albuminuria - dipstick negative > 2.5 mg/mmol males > 3.5 mg/mmol females 30 - 300mg/day • Macrolbuminuria – dipstick positive > 25 mg/mmol both males and females > 300mg/day – diabetic nephropathy (low serum albumin = nephrotic syndrome • Can be proteinuria negative in type 2 • +/- e GFR < 60ml/min

  40. Diabetic Nephropathy: pathological classification Class 1 – EM proven GBM thickening Class 2a – Mild mesangial expansion Class 2b – Severe mesangial expansion Class 3 - Nodular sclerosis ( KW lesions) Class 4 - Advanced sclerosis ( > 50% glomeruli) Tervaert TC et al J Am Soc Nephrol 2010 online

  41. CURRENT CHRONIC KIDNEY DISEASE (CKD) NOMENCLATURE USED BY KDIGO • CKD is defined as abnormalities of kidney structure or function, present for >3 months, with implications for health and CKD is classified based on cause, GFR category, and albuminuria category (CGA). Persistent albuminuria categories Description and range Prognosis of CKD by GFR and Albuminuria Categories: KDIGO 2012 Previously micro-albuminuria Previously macro-albuminuria GFR categories (ml/min/ 1.73 m²) Description and range Green: low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk; Orange: high risk; Red, very high risk. KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3:136-150. http://www.kdigo.org/clinical_practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf Accessed February 26, 2013

  42. Although we understand the natural history of diabetic kidney disease some patients with type 2 diabetes progress to end stage kidney disease without developing proteinuria

  43. Nonalbuminuric Renal Insufficiency in Type 2 Diabetes, MacIsaac 2004 • A cross-sectional survey of 301 outpatients attending a single tertiary referral center using the plasma disappearance of isotopic 99mTc-diethylene-triamine-penta-acetic acid to measure GFR and at least two measurements of urinary albumin excretion rate (AER) over 24 h to determine albuminuria. Conclusion: patients with type 2 diabetes can commonly progress to a significant degree of renal impairment while remaining normoalbuminuric. MacIsaac et al, Diabetes Care. 2004 Jan;27(1):195-200

  44. Blood Pressure Target Goals in CKD patients • CHEP 2014 (BP target)¹ • Target Blood pressure Should be less than 140/90 mmHg in most patients, including those with chronic kidney disease. • ESC 2013 (BP target)² • Target Blood pressure <140/90 mmHg should be considered in patients with diabetic or non-diabetic CKD. • JNC IV (BP target)³ • In patients with CKD, initiate treatment at SBP ≥140 mmHg or DBP ≥90 mmHg, and treat to achieve SBP <140 mmHg and DBP <90 mmHg. 1: Canadian Hypertension Education Program (CHEP) 2014 Recommendation, adopted from: https://www.hypertension.ca/chep. Accessed at 5/2/2014 2: Mancia G, et al. J Hypertens. 2013 Jul;31(7):1281-357 3: James PA, et al. JAMA. 2013 Dec 18. [Epub ahead of print]

  45. ACE inhibitors in Hypertensive diabetic patients

  46. Intensive group n=80 Weight loss Exercise Smoking cessation BP & Lipid targets Aspirin, Statin, ACEI CV morbidity & mortality -50% Compared to usual diabetic care 8 years follow up Progression to proteinuria -60% Progression to Retinopathy -60% Gaede P et al. Multifactorial intervention , N Engl J Med 2003; 348: 383 -93

  47. Steno-2: Number needed to treat Number of microalbuminuric patients with type 2 diabetes needed to treat for 13 years to prevent one ….. Death 5 patients Cardiovascular death 8 patients Major cardiovascular event 3 patients Progression to nephropathy 5 patients Dialysis 16 patients Laser treatment 7 patients Steno-2 Trial: multiple risk factor intervention in T2DM

  48. RAS MANAGEMENT CAUTION:avoid combined therapies

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