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Drug Treatments in Type 2 Diabetes Dr Richard Brice MB BCh MA MRCGP GPSI in Diabetes Chairman, Whitstable Medical Practice UK Trends for Diabetes National diabetes prevalence Forecast Diabetes UK Report “Diabetes in the UK” (2009) Equivalent to 3.9% of the population Prevalence ( % of population) 2005. American College of Physicians. All Rights Reserved. 2005. American College of Physicians. All Rights Reserved. Diabetes: An NHS priority UK/LR/0809/0366 Date of preparation: August 2009 The Cost of Diabetes to the NHS Budget Costs are increasing as a result of the obesity epidemic, sedentary lifestyles and an ageing population 10% = 1m per hour Diabetes UK Report “Diabetes in the UK” (2009) The Burden for People with T2D 60-70% will die of cardiovascular disease1 Almost 1 in 3 will develop overt kidney disease2 Commonest cause of blindness in the working population3 Up to 50% will develop neuropathy4 Commonest cause of lower limb amputation5 Depression twice as common compared with the general population6 Sexual dysfunction is a problem7,8 (prevalence not known) 1 Duckworth et al NEJM, 2009;360:129-39;2 DoH (2006); 3Hamilton et al. Management of diabetic retinopathy, London 1996: BMJ Publishing; 4Boulton, Clin Diabetes 2005; 23: 915; 5National Diabetes Support Team (2006). Diabetic foot guide; 6Katon et al Diabetes Care 2004;27: 914920. 7Al-Hunayan et al. Br J Urol Int 2007;99 (1): 130134; 8Diabetes in the UK 2009:Key Statistics in Diabetes. Diabetes UK Life Expectancy and Diabetes Life expectancy is decreased by 510 yrs in type 2 diabetes Goodkin, J Occup Med 1975; 17: 716721; Donnelly et al. BMJ 2000; 320:10621066 T2D: the Challenge Targets Amenable to Pharmacotherapy HbA1c 5 yrs T1DM 5 years insulin n = 75 Type 1 DM 15 years n = 54 Frequency of severe hypoglycaemia increases over time Error bars = 95% confidence intervals T1DM 15 yrs 45 Morbidity of hypoglycaemia in diabetes Musculoskeletal Falls, accidents (driving) Fractures, dislocations Brain Blackouts, seizures, coma Cognitive dysfunction Psychological effects Cardiovascular Myocardial ischaemia (angina and infarction) Cardiac arrhythmia 46 Driving and diabetes nThe DVLA issue Medical Rules on a number of conditions, including diabetes nFor up-to-date guidance please visit the DVLA or .uk websites: Information for drivers with insulin diabetes .uk/en/Motoring/DriverLicensing/MedicalRulesForDriv ers/MedicalA-Z/DG_185427 Information for drivers of cars or motorcycles with diabetes treated by tablets, diet, or both .uk/prod_consum_dg/groups/dg_digitalassets/dg/ en/motor/documents/digitalasset/dg_067957.pdf nPhysicians should ensure that patients with diabetes are aware of the DVLA regulations and guidance in relation to hypoglycaemia and driving 1. .uk/en/Motoring/DriverLicensing/MedicalRulesForDrivers/MedicalA-Z/DG_187349 47 Increasing HCP awareness around hypoglycaemia in type 2 diabetes nGPs, practice nurses and pharmacists need to: nBe aware of the prevalence of hypoglycaemia in patients with type 2 diabetes nRecognise the causes and risk factors for hypoglycaemia in type 2 diabetes nInform patients of the risks nBe aware that patients may use different language I feel a bit hungry late mornings especially if Ive been out shopping or I have dizzy dos 48 Glycaemic Levels During the DCCT/EDICGlycaemic Levels During the DCCT/EDIC DCCT/EDIC Study Research Group.N Engl J Med. 2005;353:2643-53. DCCT/EDIC: Intensive glucose control DCCT/EDIC: Intensive glucose control associated with reduced long-term CV riskassociated with reduced long-term CV risk DCCT/EDIC Study Research Group. N Engl J Med. 2005;353:2643-53. Any initial CV event* Time (years) N = 1441 with type 1 diabetes, mean baseline age 27 42% Risk (9%63%) P = 0.02 57% Risk (12%79%) P = 0.02 CV death, nonfatal MI, stroke* 52 events 31 events 25 events 11 events 0 0.12 0.08 0.10 0.06 0.04 0.02 05101520 0 0.12 0.08 0.10 0.06 0.04 0.02 05101520 DCCT ends DCCT endsA1C 7.4% vs 9.1% *Cumulative incidence ConventionalIntensive HbA1c cross-sectional, median values UKPDS 33 Lancet 1998; 352: 837-853 Post-Trial Changes in HbA1c UKPDS results presented Mean (95%CI) 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Eng J Med 2008; 359 Microvascular Disease Hazard Ratio Intensive (SU/Ins) vs. Conventional glucose control (photocoagulation, vitreous haemorrhage, renal failure) HR (95%CI) 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Eng J Med 2008; 359 Myocardial Infarction Hazard Ratio (fatal or non-fatal myocardial infarction or sudden death) Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI) 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Eng J Med 2008; 359 All-cause Mortality Hazard Ratio Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI) 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Eng J Med 2008; 359 Blood-glucose lowering therapy Therapeutic Choices NPH Insulin As per CG66 Other Insulin 1.Long-acting analogue as an alternative to starting NPH 2.Premix insulin as per CG66 TZD 1.Added to Met + SU 2.Added to Met + SU if poor response to DPP-4 inhib or not tolerated. Sitagliptin 1.Added to Met + SU 2.Added to Met + SU if poor response to TZD or not tolerated. Exenatide 1. Added to Met + SU Acarbose As per CG66 SU As per CG66 TZD 1. Add to Met 2. Add to SU DPP-4 inhibitor 1. Add to Met 2. Add to SU NPH Insulin As per CG66 Other Insulin 1.Long-acting analogue as an alternative to starting NPH 2.Premix insulin as per CG66 Metformin As per CG66 SU As per CG66 Consider First Consider Second Consider Third Consider Fourth Standard approach Alternative approach HbA1c 6.5% Monitor for deterioration HbA1c 7.5% Monitor for deterioration HbA1c 6.5% Monitor for deterioration Blood-glucose lowering therapy Therapeutic Choices NPH Insulin As per CG66 Other Insulin 1.Long-acting analogue as an alternative to starting NPH 2.Premix insulin as per CG66 TZD 1.Added to Met + SU 2.Added to Met + SU if poor response to DPP-4 inhib or not tolerated. DPP-4 inhibitor 1.Added to Met + SU 2.Added to Met + SU if poor response to TZD or not tolerated. Exenatide 1. Added to Met + SU Acarbose As per CG66 SU As per CG66 TZD 1. Add to Met 2. Add to SU DPP-4 inhibitor 1. Add to Met 2. Add to SU NPH Insulin As per CG66 Other Insulin 1.Long-acting analogue as an alternative to starting NPH 2.Premix insulin as per CG66 Metformin As per CG66 SU As per CG66 Consider First Consider Second Consider Third Consider Fourth Standard approach Alternative approach Consider sulfonylurea here if: patient is not overweight (tailor the assessment of body-weight-associated risk according to ethnic group), or metformin is not tolerated or is contraindicated, or a rapid therapeutic response is required because of hyperglycaemic symptoms Blood-glucose lowering therapy Therapeutic Choices NPH Insulin As per CG66 Other Insulin 1.Long-acting analogue as an alternative to starting NPH 2.Premix insulin as per CG66 TZD 1.Added to Met + SU 2.Added to Met + SU if poor response to DPP-4 inhib or not tolerated. DPP-4 inhibitor 1.Added to Met + SU 2.Added to Met + SU if poor response to TZD or not tolerated. Exenatide 1. Added to Met + SU Acarbose As per CG66 SU As per CG66 TZD 1. Add to Met 2. Add to SU DPP-4 inhibitor 1. Add to Met 2. Add to SU NPH Insulin As per CG66 Other Insulin 1.Long-acting analogue as an alternative to starting NPH 2.Premix insulin as per CG66 Metformin As per CG66 SU As per CG66 Consider First Consider Second Consider Third Consider Fourth Standard approach Alternative approach Consider substituting a DPP4- inhibitor or a TZD for an SU if there is significant risk of hypos or an SU is not tolerated or is contraindicated HbA1c 6.5% Monitor for deterioration Blood-glucose lowering therapy Therapeutic Choices NPH Insulin As per CG66 Other Insulin 1.Long-acting analogue as an alternative to starting NPH 2.Premix insulin as per CG66 TZD 1.Added to Met + SU 2.Added to Met + SU if poor response to DPP-4 inhib or not tolerated. Sitagliptin 1.Added to Met + SU 2.Added to Met + SU if poor response to TZD or not tolerated. Exenatide 1. Added to Met + SU Acarbose As per CG66 SU As per CG66 TZD 1. Add to Met 2. Add to SU DPP-4 inhibitor 1. Add to Met 2. Add to SU NPH Insulin As per CG66 Other Insulin 1.Long-acting analogue as an alternative to starting NPH 2.Premix insulin as per CG66 Metformin As per CG66 SU As per CG66 Consider First Consider Second Consider Third Consider Fourth Standard approach Alternative approach Consider adding exenatide to metformin and SU if: BMI 35 in patients of European descent, or BMI 35 and insulin is unacceptable or weight-loss would benefit other comorbidities HbA1c 7.5% Monitor for deterioration Slide No 60 Liraglutide STA recommendation (triple therapy)2 “Liraglutide 1.2 mg daily in triple therapy regimens is recommended as an option for the treatment of people with T2DMwhen: control of blood glucose remains or becomes inadequate (HbA1c 7.5%, or other higher level agreed with the individual), and the person has : a body mass index (BMI) 35 kg/m2 in those of European descent (with appropriate adjustment for other ethnic groups) and specific psychological or medical problems associated with high body weight, or a BMI 35 kg/m2, and therapy with insulin would have significant occupational implications or weight loss would benefit other significant obesity-related co morbidities.” 2. National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. 10 September 2010. Section 1 Guidance. Section 1.1. Liraglutide STA recommendation (dual therapy)2 “Liraglutide 1.2 mg daily in dual therapy regimens (in combination with metformin or a sulphonylurea) is recommended as an option for the treatment of people with T2DM, only if: the person is intolerant of either metformin or a sulphonylurea, or treatment with metformin or a sulphonylurea is contraindicated; and the person is intolerant of thiazolidinediones and dipeptidyl peptidase-4 (DPP-4) inhibitors, or treatment with thiazolidinediones and DPP-4 inhibitors is contraindicated.” 2. National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. 10 September 2010. Section 1 Guidance. Section 1.3. Slide No 62 Liraglutide FAD recommendation (stopping rules)2 Treatment with liraglutide 1.2mg daily should only be continuedif a beneficial metabolic response has been shown. In triple therapy regimens, “beneficial metabolic response” is defined as: a reduction of at least 1 percentage point in HbA1c; and a weight loss of at least 3% of initial body weight at 6 months In dual therapy regimens, “beneficial metabolic response is defined as: a reduction of at least 1 percentage point in HbA1c only People with T2DM currently receiving liraglutide 1.2mg who do not meet the criteria specified, or who are receiving liraglutide 1.8 mg, have the option to continue their current treatment until they and their clinicians consider it appropriate to stop. 2. National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. .uk/nicemedia/live/11895/50663/50663.pdf Last accessed 17 September 2010. Section 1 Guidance. Section 1.2 and 1.4 Slide No 63 Liraglutide FAD recommendations (1.8mg dose)2 Liraglutide 1.8 mg daily is not recommended for the treatment of people with type 2 diabetes. 2. National Institute for Health and Clinical Excellence. Final Appraisal Determination. Liraglutide for the treatment of Type 2 diabetes mellitus. 10 September 2010. Section 1 Guidance. Section 1.5 A clinical composite endpoint: Reaching HbA1c7.0% combined with weight loss1 Rosiglitazone 4 mg LEAD 1, Marre Diab Med. 2009 Glimepiride 4 mg LEAD 2, Nauck Diabetes Care 2008 Exenatide 10 g BID LEAD 6, Buse Lancet 2009 Liraglutide 1.8 mg LEAD 6, Buse Lancet 2009 Glargine 24 IU LEAD 5, Russell-Jones Diabetologia 2009 25% 78% 72% Liraglutide 1.2 mg LEAD 2, Nauck Diabetes Care 2008 32% 15% 56% Sitagliptin 100mg LIRA-DPP4 Study, Pratley Lancet 2010 Indirect comparison of intention- to-treat data from 5 phase III trials with liraglutide and active comparators1 72% HbA1c Weight 1. Data on file: Composite endpoint UKPDS 2x2 Glucose 353:61722 Steno-2: N Engl J Med 2003;348:38393 Steno-2: relative risk reduction with Steno-2: relative risk reduction with intensive treatmentintensive treatment Relative risk reduction for intensive vs conventional treatment (%) CVD Nephropathy Retinopathy Autonomic neuropathy * p 0.05 * p 0.01 * * * * Adapted from: N Engl J Med 2003;348:38393 Intensive Multiple Risk Factor Management in Patients Intensive Multiple Risk Factor Management in Patients with Type 2 Diabetes: with Type 2 Diabetes: STENO-2STENO-2 Primary Composite Endpoint* (%) Months of Follow-up N=160; follow-up = 7.8 years Primary composite endpoint: conventional therapy (44%) and intensive therapy (24%). *Death from CV causes, nonfatal MI, CABG, PCI, nonfatal stroke, amputation, or surgery for peripheral atherosclerotic artery disease. Behavior modification and pharmacologic therapy. Adapted from Gaede P et al. N Eng J Med 2003;348:383393. 01224364872966084 Aggressive treatment of: Microalbuminuria with ACEIs, ARBs, or combination Hypertension Hyperglycemia Dyslipidemia Secondary