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GP Time In Time Out Session

GP Time In Time Out Session. Dr K R Narayanan. 69 ♂ T2 DM since 1995 Alcohol excess (15 U/W) 74 Kg [BMI=32] Ex-smoker, BP=122/80 HbA1c=8.8%, TC=6.0 GGT=113. Rx Bezalip MR 400mg OD Gliclazide 160mg BD MF MR 500 mg BD Amitriptyline 10mg OD Refuses Insulin Cannot tolerate statins.

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GP Time In Time Out Session

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  1. GP Time In Time Out Session Dr K R Narayanan

  2. 69 ♂ T2 DM since 1995 Alcohol excess (15 U/W) 74 Kg [BMI=32] Ex-smoker, BP=122/80 HbA1c=8.8%, TC=6.0 GGT=113 Rx Bezalip MR 400mg OD Gliclazide 160mg BD MF MR 500 mg BD Amitriptyline 10mg OD Refuses Insulin Cannot tolerate statins Case 1

  3. South of Tyne Type 2 Diabetes Management Guidelines 2010

  4. Acknowledgements • Dr Colin Bradshaw GP and PBC Diabetes Lead South Tyneside • Dr Henry Choi GP and PBC Diabetes Lead Sunderland • Helen Ramsey Nurse Practitioner and PBC Diabetes Lead Gateshead • Anne-Marie Bailey Prescribing Advisor NHS SoTW Medicines Management Team • Dr Terence Aspray Care of the Elderly Consultant City Hospitals Sunderland • Dr John Parr Consultant Diabetologist South Tyneside District General Hospital • Dr Shahid Wahid Consultant Diabetologist South Tyneside District General Hospital • Dr Rahul Nayar Consultant Diabetologist City Hospital Sunderland • Dr Peter Carey Consultant Diabetologist City Hospital Sunderland • Dr Kilimangalam Narayanan Consultant Diabetologist Gateshead Health Foundation Trust • Gillian Johnson Regional Programme Manager NHS Diabetes

  5. South of Tyne Guidance

  6. GLIPTINS Inhibit DPP IV Prolong action of native GLP 1 GLP 1 MIMETICS Resistant to cleavage by DPP IV Half life prolonged Liraglutide vs Exenatide OD Better S/E profile Better homology to human GLP 1 INCRETINS

  7. GLP-1 effects in humans GLP-1 secreted upon the ingestion of food 5.Brain: promotes satiety and reduces appetite4,5 2.α-cell: suppresses postprandialglucagon secretion1 3.Liver:reduces hepatic glucose output2 1.-cell:enhances glucose-dependent insulin secretion in the pancreas1 4.Stomach: slows the rate of gastric emptying3 7

  8. Gliptins are DPP IV inhibitors Prolong endogenous GLP 1 action GLP 1 therapies Resistant to endogenous DPP IV action

  9. Dual therapy 2nd line instead of SU 2nd line instead of MF 3rd line would be insulin Triple therapy SoT guidelines 3rd line after MF+SU instead of insulin 4th line would be insulin Pioglitazone and Gliptins

  10. Pioglitazone or Gliptins? • Pioglitazone preferable to gliptins if – • Marked insulin insensitivity is suspected • Gliptin is contraindicated • Poor response or intolerance to gliptin in the past • Continue only if ≥0.5% drop in HbA1c at end of 6/12 • Do not use if C/I

  11. Pros Insulin sensitiser Stabilise β-cell function Minimal risk of hypos Cons Weight gain and fluid retention Delayed onset of action OR of 1.45 for fractures Use FRAX CV risk: ↓ for pioglitazone Juurlink et.al. (BMJ 2009) Retrospective Cohort Death and HF less with pioglitazone Where do we stand with Pioglitazone?

  12. Pioglitazone or Gliptins? Gliptins preferable to glitazones if – Further weight gain would cause significant problems Glitazone is C/I Poor response to or did not tolerate glitazone in the past Not for initial monotherapy Continue only if ≥0.5% fall in HbA1c at 6 months 12

  13. Sitagliptin studies

  14. Which Gliptin?

  15. Cautions and S/E: Gliptins • C/I: allergy, moderate to severe renal impairment, pregnancy • S/E: nausea, nasopharyngitis, SJ syndrome, hypos with SU • For Vildagliptin: • Monitor LFTs • Caution in CCF and in the elderly • 

  16. Pros Well tolerated Low risk of hypos Weight neutral Oral agent Promotion of β-cell mass Licensed for second or third line Rx Sitagliptin can be used with insulin Cons May alter immune system ↑ risk of some infections Caution in renal impairment Effect on long term mortality/morbidity unclear Where do we stand with gliptins?

  17. 69 ♂ T2 DM since 1995 Alcohol excess (15 U/W) 74 Kg [BMI=32] Ex-smoker, BP=122/80 HbA1c=8.8%, TC=6.0 GGT=113 Rx Bezalip MR 400mg OD Gliclazide 160mg BD MF MR 500 mg BD Amitriptyline 10mg OD Refuses Insulin Cannot tolerate statins Back to our case…………….

  18. GLYCAEMIC CONTROL Third line oral agent GLIPTIN GLITAZONE ACARBOSE [GLP 1 analogues] LIPID PROFILE Have we achieved all we can? Further lifestyle measures? Improved HbA1c=better CV risk Back to our case………………

  19. GLP 1 mimetics/analogues Add to metformin and SU where insulin would be considered as the next option if - BMI≥35 with problems associated with high weight Inadequate glucose control BMI<35 and insulin unacceptable or weight loss would benefit other co-morbidities Continue only if ≥1% HbA1c fall and ≥3% loss in weight at 6 months Currently not licensed for use with insulin Liraglutide licensed for use with pioglitazone 19

  20. Liraglutide versus Exenatide (1) • Liraglutide effect and action in diabetes [LEAD] trial 6 • Open label, MN, parallel group trial • 26 weeks • 464 patients with T2DM on MF and/or SU with HbA1c 7-11% and BMI≤45 • Randomised to receive liraglutide 1.8mg OD or exenatide 10 mcg BD

  21. Liraglutide versus Exenatide (2)

  22. ABCD Exenatide Audit[Presented at DUK, Dr Ryder] • 6717 patients, 3054 data complete • Data collected over 1 year • HbA1c drop: 9.41 → 8.65 (1.00%) • Weight loss: 114 → 109 (5-10 kgs) • S/E • 28% had GI S/E • 7.2% stopped Rx • 7 cases of pancreatitis (0.18%)

  23. TRIPLE THERAPY Indications as before DUAL THERAPY With MF or SU Additional SU/MF not tolerated/CI AND Additional glitazone/gliptin not tolerated/CI 1.8 mg not recommended Liraglutide NICE TA-2010

  24. Statins in T2 DM JBS2 [SIGN, NICE] • All >40 yrs [grade A] • 18-39 yrs with associated problems Evidence • CARDS, ASCOT, HPS • Strong evidence in T2DM • 1 mmol/l ↓ = 21% RR Simvastatin 40 mg Simvastatin 80 mg Atorvastatin 80 mg OR Simvastatin 80 mg + Ezetimibe 10 mg

  25. Statins in T1 DM JBS2 [SIGN, NICE] • All >40 yrs [grade B] • 18-39 yrs with associated problems Evidence • CARDS, ASCOT, HPS • Less strong evidence • 1 mmol/l ↓ = same ↓ in events [ns] CONCLUSION In younger patients with type 1 DM absolute risk is low but risk is higher compared to age matched people without DM

  26. Aspirin as Primary Prevention in DM • Over the age of 50: • On anti-HT with BP<145/90 OR • Strong family h/o premature IHD OR • CV risk score ≥ 20% over 10 years using UKPDS risk engine

  27. 71 ♂ T2 DM since 2008 IHD 1989 HT 1988 BMI=28 Macroproteinuria eGFR=68 TC=2.7 Rx: Lisinopril 40mg OD Irbesartan 300 mg OD Atenolol 50mg OD BDZ 2.5mg OD Adalat retard 90mg OD Simvastatin 10mg OD What other info do you want? What are the priorities in management? Case 2

  28. Diabetic NephropathyBurden of Illness • Incidence • Diabetic nephropathy develops in around 25% of patients with type 2 diabetes • People with diabetes account for 25% of those entering renal replacement therapy • Mortality • Microalbuminuria indicates a substantially increased mortality risk in patients with type 2 diabetes • Patients with type 2 diabetes and high levels of albumin have a mortality rate 148% higher than control. British Diabetic Association Report, April 1997. Jarrett RJ, et al. Diabetic Med 1984; (1): 17-19.

  29. A: U-Prot <150 mg/L B: U-Prot 150–300 mg/L C: U-Prot >300 mg/L CVD Mortality by Urinary Protein Excretion in Type 2 Diabetes 1.0 0.9 Survival curves for CVD mortality A 0.8 B 0.7 0.6 C Overall: p<0.001 0.5 0 0 10 20 30 40 50 60 70 80 90 Months U-Prot = urinary protein concentration Miettinen H et al. Stroke. 1996; 27: 2033–2039.

  30. Microalbuminuria (31-299 mg/day) ACR >2.5 in men ACR>3.5 in women Macroalbuminuria >300 mg/24 hour Exercise Pregnancy Poor sugar control CCF Hypertension UTI Micro and macroalbuminuria

  31. Albuminuria Marker for CV disease and nephropathy

  32. Natural History of Type 2 Diabetic Nephropathy Clinical type 2 diabetes Functional changes* Structural changes† Rising blood pressure Microalbuminuria Proteinuria Rising serum creatinine levels End-stage renal disease Cardiovascular death Onset of diabetes 2 5 10 20 30 Years * Renal haemodynamics altered, glomerular hyperfiltration † Glomerular basement membrane thickening , mesangial expansion , microvascular changes +/-

  33. Strategies to prevent progression of diabetic nephropathy • Extremely good BP control → also ↓ UAER <130/75 in type 1 <140/80 in type 2 Individualise target • Good glycaemic control • ACEI/ARB but be prepared to use multiple agents • CV risk reduction to reduce mortality

  34. Mean arterial pressure (mm Hg) 98 100 102 104 106 108 110 0 r = 0.66; p < 0.05 -2 GFR decline(ml/min/year) -4 -6 -8 -10 Slower Decline in Renal Function with Lower Blood Pressure Goals Results of studies ³ 3 years in patients with type 2 diabetic nephropathy Bakris GL. Diabetes Res 1998; 39(suppl): S35-S42.

  35. What about primary prevention? • Good glycaemic control • DCCT [2.2% vs 3.4% per year developed µalb] • UKPDS [23% vs 34% had µalb at 12 yrs] • But does not abolish it • Use of RAS inhibitors • Losartan, candesartan, enalapril • Unable to reduce µalb over 5 yrs

  36. Back to our case……………...... • Consider other causes of proteinuria • Refer to renal team if: • e-GFR<30 OR • If e-GFR falls by > 4 ml/min/year • CV risk reduction • Aspirin, Simvastatin to 40 mg • Individualise BP target • Achieve target HbA1c • Ensure digital retinal screening is up to date

  37. 65 ♀ T2 DM 2001 HT BMI=30.4, Xsmoker HbA1c=10.5% TC=4.6 ACR Normal Rx: Glimiperide 4 mg OD Glucophage SR 2 g OD What next? Not keen on insulin Case 3

  38. 87 ♀ very active T2 DM 1992 HT Macroproteinuria Impaired vision BMI=26.4, BP=182/80 HbA1c=6.9% Rx: MF 3 gm/day Gliclazide 320 mg/day Perindopril 8mg OD Irbesartan 300mg OD Case 4

  39. 06/2007: eGFR 36 so MF stopped 08/07: HbA1c 9.8% so pio started 06/08: HbA1c 7.9% but BMI ↑ 29.1 and BP↑ 176/100 10/2010: pio stopped and MF re-started as eGFR 40 Now HbA1c 8%, 146/56, eGFR 43 Rx: Gliclazide 320, MF 500 Perindopril, irbesartan Frusemide 40, amlodipine 5 Bisoprolol 5 What could have been done different? What now? Case 4 continued

  40. 65 ♀ T2 DM 2004 HT NAFLD BMI=33, BP 140/80 HbA1c=11.1% Rx: MF 3 gm Gliclazide 320 mg Ramipril 5 mg Simvastatin 40 mg What are the options? Case 5

  41. 61 ♀ T2 DM 2000 HT, OA Smoker BMI=47.2, BP=140/90 HbA1c=7.9%, TC=5.9 Rx: Aspirin, perindopril Atenolol, frusemide Orlistat trial X Novomix 30 – 52 BD MF 2 gm/day Can we do anything to help her lose weight? Case 6

  42. Case 6 continued • Role of insulin sensitisers • Pioglitazone added in Feb 2010

  43. DIABETES DRUG COSTS ACROSS SOUTH OF TYNE £6.9 million [7.2%]

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