Dr Tahseen A. Chowdhury Royal London Hospital. New Guidelines in Diabetes: NICE or Nasty?

Transcription

1 Dr Tahseen A. Chowdhury Royal London Hospital New Guidelines in Diabetes: NICE or Nasty?

2 I have no conflicts of interest I do not undertake talks / advisory bodies / research for any pharma company Consultant in diabetes 1 session per week in primary care

3 Reminder of why diabetes is important Tight glycaemic control how low should we go? Newer agents when to consider them?

4 Diabetes in the UK: Type 2 diabetes

5 Physical inactivity Overweight and obesity Age High-fat and low-fibre diet Urbanisation Family history Ethnicity Low birth weight

6 Why is diabetes important? Retinopathy Commonest cause of blindness in people of working age Cirrhosis Third commonest cause of cirrhosis world wide Stroke 3x increased risk Heart Disease 75% of patients with diabetes die of CVD Nephropathy Commonest cause of ESRF Cancer X2 increased risk of colon cancer Foot Problems Commonest cause of amputation

7 Treat it as a cardiovascular disease ¾ of patients with diabetes die from CV disease Reduction in life expectancy by 3-10 years Certain groups are at high risk South Asian / Afro-Caribbean Previous GDM, obese, FH, known IFG/ IGT Presence of microvascular complications increases risk of CVD Diabetes costs ~9% of NHS budget Huge societal costs (disability etc.) Major cost is treatment of complications

8 A 42 year old South Asian man attends your surgery with tiredness and nocturia. BMI is 26.5 kg/m 2 and there is a strong family history. HbA1c is 50 mmol/mol You diagnose diabetes How do you reduce his risk of complications?

9 1. Lifestyle and Education 2. Blood pressure 5. Glucose Control 3. Cholesterol 4. Screening

10 Steno-2 study - 12 years of intensive treatment: SBP 130 mm Hg v 145 mm Hg T chol 3.5 mmol/l v 5 mmol/l Almost all patients on ACEI / ARBs Almost all patients on statins Gave the following benefits: 56% decr. CV mortality 46% decr. in total mortality 50% decr. in laser treatment 83% decr. in ESRF 50% decr. in amputation 50% decr. in CABG 85% decr. in stroke Number of CV events reduced per 1000 people treated for 5 years: Lower HbA1c by 0.9% (10 mmol/mol) = 8 Lower T Chol by 1 mmol/l = 23 Lower BP by 10/5 mmhg = 29

11 To prevent To prevent To prevent

12 He is now 46 years old BMI is 27kg/m 2 trying with diet, sedentary job (taxi driver) HbA1c is 68 mmol/mol Maximal dose metformin and SU BP is 135/80 mmhg on Ramipril 10mg od Cholesterol is 4.2 mmol/l on Simvastatin 40mg od Retinal screen minimal background DR Urine ACR 1.8 mg.mmol/l (<2.5)

13 1. 42 mmol/mol (6.0%) mmol/mol (6.5%) mmol/mol (7.0%) mmol/mol (7.5%) mmol/mol (8.0%)

14 % risk reduction UKPDS results of tight glycaemic control P= P= P=0.046 P= P=0.029 P=0.052 extraction

15 UKPDS at 10 year FU Overall Risk reductions for myocardial infarction (15%, P=0.01) Death from any cause (13%, P=0.007) Metformin group Risk reductions for myocardial infarction (33%, P=0.005) Death from any cause (27%, P=0.002)

16 VADT 1791 pts, 5.6 year FU HbA1c 8.4% vs 6.9% Overall No significant difference in macrovascular nor microvascular complications

17 Is lower better? Perhaps not: ACCORD Tight (A1c<6.0%) vs less tight (A1c %) 257 deaths in tight control vs 203 death in less tight (relative risk increased by 22%) Deaths appeared to be more CVD events? Induced by hypoglycaemia (dead in bed syndrome)

18 Why might such studies not show an advantage of tight glucose control? Intensive GC started too late? UKPDS randomised from diagnosis ACCORD/Advance/VADT mean 10 years duration Duration of intensive treatment too short UKPDS 15 years ACCORD/Advance/VADT 3-5 years Ceiling effect - < 7.0%, 53 mmol/mol - no increase in benefit Therapies might cause side effects (CVD, weight gain, hypoglycaemia) which dilutes effect of tight glucose control

19 What do NICE 2015 guidelines say? NICE 2015 PATIENT CENTRED CARE When caring for older adults with Type 2 diabetes, particular attention should be given to their broader health and social care needs. more likely to have co-existing medical conditions and be on greater number of medicines. benefit from risk reduction may be reduced Much of the evidence for this guideline has been generated in younger adults (age yrs)

20 NICE 2015 glycaemic targets Diet only HbA1c > 48mmol/mol Aim for < 53 mmol/mol First intensification HbA1c > 58 mmol/mol Aim for < 53 mmol/mol Second intensification HbA1c > 58 mmol/mol Aim for < 53 mmol/mol

21 What do the NICE 2015 guidelines say? INDIVIDUALISED CARE Adopt an individualised approach. taking into account personal preferences, co-morbidities, risks from polypharmacy, and ability to benefit from long term interventions because of reduced life expectancy NICE 2015 TARGETS Consider relaxing the target HbA1c on a case by case basis, with particular consideration for people who are older or frail.. who are unlikely to achieve longer term risk reduction benefits for whom intensive management would not be appropriate, for example, people with significant co-morbidities

22 IDF Managing Older People with Type 2 diabetes 2014 Functionally Independent Usual target mmol/mol Functionally Dependent Usual target mmol/mol Frail up to 70 mmol/mol may be appropriate Dementia up to 70 mmol/mol may be appropriate End of Life Avoid symptomatic hyperglycaemia

23 EASD and ADA Consensus guidelines 2012 General target of mmol/mol Older adults >65 years: HbA1c of % (58-64 mmol/mol) may be appropriate

24 What factors should you consider when deciding on glycaemic target? Age / Life expectancy / Co-morbidity Duration of DM Motivation, capacity for self care, social support Perhaps aim for tighter control in: Younger (<65 years) Shorter duration of diabetes (< 10 years) Few co-morbidities (esp. renal / CVD) Higher motivation / knowledge

25 He is now 46 years old BMI is 27kg/m 2 trying with diet, sedentary job (taxi driver) HbA1c is 68 mmol/mol Maximal dose metformin BP is 135/80 mmhg on Ramipril 10mg od Cholesterol is 4.2 mmol/l on Simvastatin 40mg od Retinal screen mild background DR Urine ACR 1.8 mg.mmol/l (<2.5)

26 1. Pioglitazone 2. Sulfonylurea 3. Repaglinide 4. Insulin 5. Gliptin 6. GLP1 agonist 7. SGLT2 antagonist

27 Mortality benefit in obese type 2 diabetes Start slow and titrate after meals If not tolerated, metformin MR is an option Stop at egfr of 30 (consider reducing at 40) Beneficial in heart failure Continue when commencing insulin Continue in women who get pregnant Can be used in GDM

28 Advantages Oral Once daily Generally well tolerated HbA1c reduction mmol/mol (takes 4-6 months) Little hypoglycaemia Disadvantages Heart failure / oedema LFT monitoring (but may be of benefit in NASH) Risk of fractures in post menopausal women Weight gain 3-5kg? Bladder Cancer

29 Advantages Good glycaemic control Generally well tolerated HbA1c reduction mmol/mol Disadvantages Injection (needs considerable nursing input) Blood glucose monitoring Hypoglycaemia Weight gain 3-5kg

30 Any benefit of analogue over intermediate? No convincing evidence? Levemir associated with less weight gain Good evidence that use of Human insulins first line will save considerable resources Cost per prevention of severe hypoglycaemic episode is ~ 400,000 NICE suggests change to levemir or lantus if hypos on NPH, carer needs to give insulin (need for less injections) Better results when started early (HbA1c ~58 mmol/mol) Continue metformin less weight gain and less insulin requirement

31 IR-insulin (mu/l) The INCRETIN EFFECT Incretin effect * * * * * * * Time (min) Key observations A hormone produced from the L cells of the small intestine Produced when you eat Stimulates insulin release from the pancreas Helps increase size and number of beta cells Reduces appetite Is reduced in diabetes

32 Exenatide + Exenatide LAR Liraglutide Lixisenatide Dulaglutide

33 NICE BMI > 35 kg/m 2, psychological or medical problems assoc. with obesity + HbA1c > 58 mmol/mol BMI < 35 kg/m 2 consider if insulin therapy would have significant occupational implications, or weight loss would benefit other obesity related co-morbidities Adverse effects predominantly GI?? Pancreatitis risk / pancreatic cancer no convincing evidence Use for six months, but should lose 3% of body weight and drop HbA1c by 11 mmol/mol Use with insulin should be with specialist care and ongoing support from a Consultant led MDT

34 DPP-IV inhibitors This is the enzyme that breaks down GLP-1 Inhibition leads to increased levels of GLP-1 Sitagliptin / Linagliptin (renal disease)

35 Regulatory studies 52 week administration appears to result in 0.8% reduction in HbA1c No weight change b-cell function improves Well tolerated no major side effects recent BMJ meta-analysis increased risk of pancreatitis from 15/ to 16/ No increase in CVD, but so far no sign of CVD protection

36 Tubular lumen Proximal renal tubular cell Interstitium SGLT-2 Inhibitor Na + Glucose X SGLT-2 Na + Na/K ATPase K + GLUT2

37 Phase III study: 546 metformin treated patients 6 months: 2.5mg HbA1c -0.67% 5mg HbA1c -0.7% 10mg HbA1c -0.8% Weight loss kg Side effects UTIs and Thrush 8-13% Dehydration with diuretics DKA some reports of Euglycaemic DKA

38 HR 0.62 (95% CI 0.49, 0.77) p< Cumulative incidence function. HR, hazard ratio 38

39 Population studied A high CV risk population with modest hyperglycaemia on standard glucose-lowering and CV therapy Empagliflozin reduced hospitalisation for heart failure by 35% Empagliflozin reduced CV death by 38% Empagliflozin improved survival by reducing all-cause mortality by 32% 39

40 Simvastatin 1 for 5.4 years Ramipril 2 for 5 years Empagliflozin for 3 years High CV risk 5% diabetes, 26% hypertension Pre-statin era High CV risk 38% diabetes, 46% hypertension Pre-ACEi/ARB era <29% statin T2DM with high CV risk 92% hypertension >80% ACEi/ARB >75% statin S investigator. Lancet 1994; 344: , 2. HOPE investigator N Engl J Med 2000;342:145-53, HOPE.htm 40

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42 NICE 2015 THERAPEUTIC PATHWAY FOR GLYCAEMIC MANAGEMENT OF TYPE 2 DIABETES NICE 2015 glucose therapy pathway Diet and lifestyle alone HbA1c > 48 mmol/mol Targets: Consider relaxing the target HbA1c on a case by case basis in: People who are older or frail People with significant comorbidities such as cardiovascular disease or renal impairment Metformin (MR if SR not tolerated) Aim for < 53 mmol/mol HbA1c > 58 mmol/mol 1 st intensification: Metformin + DPP-4i or Metformin + Pioglitazone or Metformin + Sulfonylurea or Metformin + SGLT-2i Aim for < 53 mmol/mol If metformin intolerant: First line DPP-4i, pioglitazone or SU Repaglinide can be considered, but outside of current licence 1 st intensification with DPP-4i + pio Or DPP-4i + SU Or Pio + SU 2 nd intensification with insulin based treatment HbA1c > 58 mmol/mol 2 nd intensification: Metformin + DPP-4i + SU or Metformin + Pioglitazone + SU or Metformin + Pioglitazone + SGLT-2i or Metformin + SU + SGLT-2i or Insulin based treatment Aim for < 53 mmol/mol HbA1c > 58 mmol/mol If BMI > 35 kg/m 2 (33 in Asians), or BMI < 35 for whom insulin would have occupational implications, or weight loss would benefit obesity related co-morbidities, choose Metformin + SU + GLP-1 If BMI < 35 kg/m 2 (33 in Asians), choose Metformin + NPH Insulin

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44 Reinforce diet, lifestyle Ensure education + screening Get BP and cholesterol controlled Reinforce adherence to therapy Agree an individualised target Measure HbA1c 3-6 monthly Choice of drugs based on safety, tolerability and individual clinical circumstances SMBG only with insulin and hypoglycaemic drugs with driving/machinery

45 Overall a pragmatic guideline based on best evidence and cost effectiveness Recognition that lifestyle BP and cholesterol are the most effective interventions Targets for individuals need to be negotiated on a case by case basis

46 THANK YOU FOR YOUR ATTENTION