Presentation is loading. Please wait.

Presentation is loading. Please wait.

Drug Treatments in Type 2 Diabetes Dr Richard Brice MB BCh MA MRCGP GPSI in Diabetes Chairman, Whitstable Medical Practice.

Similar presentations


Presentation on theme: "Drug Treatments in Type 2 Diabetes Dr Richard Brice MB BCh MA MRCGP GPSI in Diabetes Chairman, Whitstable Medical Practice."— Presentation transcript:

1 Drug Treatments in Type 2 Diabetes Dr Richard Brice MB BCh MA MRCGP GPSI in Diabetes Chairman, Whitstable Medical Practice

2 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)

3

4 ©2005. American College of Physicians. All Rights Reserved.

5

6 Diabetes: An NHS priority UK/LR/0809/0366 Date of preparation: August 2009

7 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)

8 The Burden for People with T2D 60-70% will die of cardiovascular disease 1 Almost 1 in 3 will develop overt kidney disease 2 Commonest cause of blindness in the working population 3 Up to 50% will develop neuropathy 4 Commonest cause of lower limb amputation 5 Depression twice as common compared with the general population 6 Sexual dysfunction is a problem 7,8 – (prevalence not known) 1 Duckworth et al NEJM, 2009;360:129-39; 2 DoH (2006); 3 Hamilton et al. Management of diabetic retinopathy, London 1996: BMJ Publishing; 4 Boulton, Clin Diabetes 2005; 23: 9–15; 5 National Diabetes Support Team (2006). Diabetic foot guide; 6 Katon et al Diabetes Care 2004;27: 914– Al-Hunayan et al. Br J Urol Int 2007;99 (1): 130–134; 8 Diabetes in the UK 2009:Key Statistics in Diabetes. Diabetes UK

9 Life Expectancy and Diabetes Life expectancy is decreased by 5–10 yrs in type 2 diabetes Goodkin, J Occup Med 1975; 17: 716–721; Donnelly et al. BMJ 2000; 320:1062–1066

10 T2D: the Challenge Diabetes & Vascular Disease ObesityHypertensionThrombosisHyperglycaemia Dyslipidaemia Atherosclerosis

11 Targets Amenable to Pharmacotherapy HbA1c < 7.0% (53 mmol/ml) BP <130/80 Total cholesterol <4.0, LDL <2.0

12 12 NICE BP Algorithm 2008 NICE Clinical Guideline 66 Type 2 Diabetes (update) 2008

13 Lipid Management Get them on a statin, usually simvastatin 40mg Aim for total cholesterol <4.0 and LDL <2.0 In statin intolerance, encourage several different statins Even a low dose of a statin is better than any other lipid lowering Rx Plant sterols etc should be an adjunct to statin treatment, not a substitute

14 Relation between the proportional reduction in MAJOR VASCULAR EVENTS and mean absolute LDL reduction in 14 statin trials Cholesterol Treatment Trialists Collaboration (Lancet 2008: 371: )

15 15 Alsheikh-Ali et al J Am Coll Cardiol 2007;50:409-18

16 16 STELLAR - Efficacy Change in LDL-C at 6 weeks Change in LDL-C from baseline (%) 0–10 –20 –30–40–50–60 10mg* –5–15–25–35–45–55 20mg† 40mg‡ 10mg 20mg mg mg 10 mg 20 mg 40 mg 80 mg 10mg 20mg 40mg Rosuvastatin 10 mg (–46%) 40mg *p<0.002 vs ATV 10mg; SIM 10, 20, 40mg; PRA 10, 20, 40mg †p<0.002 vs ATV 20, 40mg; SIM 20, 40, 80mg; PRA 20, 40mg ‡p<0.002 vs ATV 40mg; SIM 40, 80mg; PRA 40mg Jones PH et al. Am J Cardiol 2003; 92: 152–160 Rosuvastatin Atorvastatin Simvastatin Pravastatin

17 Normal Islet Function: Glucose Regulation

18 UK/LR/0411/0135Date of preparation: May 2011 Type 2 diabetes Years from diagnosis Pre-diabetes Onset Diagnosis Insulin secretion Insulin resistance Postprandial glucose Macrovascular complications Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26: ; Nathan DM. N Engl J Med. 2002;347: Fasting glucose Microvascular complications Natural History of Type 2 Diabetes

19 Major Metabolic Defects in T2D Insulin resistance  -cell dysfunction Hyperglycaemia (and dyslipidaemia)  glucose uptake ( ↑ lipolysis )  glucose output  VLDL production  glucose uptake and metabolism Bailey CJ. Insulin resistance and antidiabetic drugs. Biochem Pharmacol. 1999;58:

20 Postprandial Glucagon Is Inappropriately Elevated in Type 2 Diabetes Insulin ‡ (µU/mL) Time (min) Glucagon (µg/mL) Meal Hyperglycaemia Deficient Insulin Release Glucagon Not Suppressed (Postprandially) Defects in Diabetes Glucose (mg/%) Mean ± SEM;*N = 14; † N = 12; ‡ mean insulin values N = 5. Adapted from Muller WA, et al. N Engl J Med. 1970;283: Muller WA, et al Copyright © 1970 Massachusetts Medical Society. All rights reserved. Translated with permission 2005.Massachusetts Medical Society Nondiabetic Subjects † Type 2 Diabetes*

21 The Incretin Effect Demonstrates the Response to Oral vs IV Glucose Mean ± SE; N = 6; *P .05; = glucose infusion time. Nauck MA, et alNauck MA, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63: Copyright The Endocrine Society.The Endocrine Society Venous Plasma Glucose (mmol/L) Time (min) C-peptide (nmol/L) Time (min) Incretin Effect Oral Glucose IV Glucose * * * * * * *

22 GLP-1 Effects in Humans Promotes satiety and reduces appetite Beta cells: Enhances glucose-dependent insulin secretion Adapted from Flint A, et al. J Clin Invest. 1998;101: ; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: ; Adapted from Nauck MA, et al. Diabetologia. 1996;39: ; Adapted from Drucker DJ. Diabetes.1998;47: Flint A, et alLarsson H, et al Nauck MA, et alDrucker DJ Liver: ↓ Glucagon reduces hepatic glucose output Alpha cells: ↓ Postprandial glucagon secretion Stomach: Helps regulate gastric emptying

23 The Incretin Effect Is Reduced in Patients With Type 2 Diabetes Insulin (mU/L) Time (min) * * * * * * * Time (min) * * * *P ≤.05 compared with respective value after oral load. Nauck MA, et alNauck MA, et al. Diabetologia. 1986;29: Reprinted with permission from Springer-Verlag © 1986.Springer-Verlag © 1986 Patients With Type 2 Diabetes Control Subjects Intravenous Glucose Oral Glucose

24 * * * * * * * Postprandial GLP-1 Levels Are Decreased in Patients With Type 2 Diabetes Time (min) Meal GLP-1 (pmol/L) Mean ± SE; N = 102; *P <.05 between T2DM and NGT groups. Toft-Nielsen M, et alToft-Nielsen M, et al. Determinants of the impaired secretion of glucagon-like peptide 1 in type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86: Copyright The Endocrine Society.The Endocrine Society Normal Glucose Tolerance Impaired Glucose Tolerance Type 2 Diabetes

25 GLP-1 Effects in Humans Promotes satiety and reduces appetite Beta cells: Enhances glucose-dependent insulin secretion Adapted from Flint A, et al. J Clin Invest. 1998;101: ; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160: ; Adapted from Nauck MA, et al. Diabetologia. 1996;39: ; Adapted from Drucker DJ. Diabetes.1998;47: Flint A, et alLarsson H, et al Nauck MA, et alDrucker DJ Liver: ↓ Glucagon reduces hepatic glucose output Alpha cells: ↓ Postprandial glucagon secretion Stomach: Helps regulate gastric emptying

26 Back to contents

27 DPP-4 Inhibitors: Rationale DPP-IV=dipeptidyl peptidase IV Adapted from Drucker DJ Expert Opin Invest Drugs 2003;12(1):87–100; Ahrén B Curr Diab Rep 2003;3:365–372. Intestinal GLP-1 release GLP-1 (9-36) inactive Mixed Meal GLP-1 (7-36) active DPP-4 inhibitor DPP-4

28 Treating T2D – the Challenge To address core defects as well as their sequelae Address insulin resistance Preserve  - cell function Prevent/delay vascular complications Durable glycaemic control Management of hypertension Management of dyslipidaemia Therapy limitations Concordance with multiple therapies

29 UKPDS: a 1% Reduction in HbA1c Significantly Reduced the Risk of Diabetes-related Complications UKPDS = United Kingdom Prospective Diabetes Study; PVD = peripheral vascular disease Stratton et al. BMJ 2000;321:405–412 Microvascular complications Any diabetes- related endpoint † Myocardial infarction Amputation or death from PVD Stroke * -37% * -21% * -14% * -43% ** -12% Median follow up = 10 years, n = 3642 for relative risk analysis † Primary endpoint; *p<0.0001; **p=0.035 Reduction in risk (%) Diabetes- related deaths * -21%

30 Currently Available Treatments for Glycaemic Control in T2D DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=Type 2 diabetes mellitus Adapted from Cheng AY, Fantus IG. CMAJ 2005; 172: 213–226. GLP-1 agonists Improve glucose-dependent insulin secretion, suppresses glucagon secretion, slow gastric emptying GLP-1 agonists Improve glucose-dependent insulin secretion, suppresses glucagon secretion, slow gastric emptying  -glucosidase inhibitors Delay intestinal carbohydrate digestion and absorption  -glucosidase inhibitors Delay intestinal carbohydrate digestion and absorption Glitazones Increase insulin sensitivity and glucose uptake in skeletal muscle. Decrease lipolysis in adipose tissue and decrease hepatic glucose output. Glitazones Increase insulin sensitivity and glucose uptake in skeletal muscle. Decrease lipolysis in adipose tissue and decrease hepatic glucose output. Sulphonylureas and Meglitinides Increase insulin secretion from pancreatic  -cells Sulphonylureas and Meglitinides Increase insulin secretion from pancreatic  -cells Biguanides (metformin) Decrease hepatic glucose production and increase glucose uptake Biguanides (metformin) Decrease hepatic glucose production and increase glucose uptake Insulins Increase glucose uptake in skeletal muscle and reduce hepatic glucose production Insulins Increase glucose uptake in skeletal muscle and reduce hepatic glucose production DPP-4 inhibitors Prolong GLP-1 action, stimulate insulin secretion, suppress glucagon release DPP-4 inhibitors Prolong GLP-1 action, stimulate insulin secretion, suppress glucagon release

31 HbA 1c cross-sectional, median values UKPDS 33 Lancet 1998; 352:

32 Aggregate Clinical Endpoints UKPDS 33 Lancet 1998; 352:

33 HbA 1c cohort, median values overweight patients UKPDS Group. Lancet 1998;352:854-65

34 Change in Weight cohort, mean values overweight patients UKPDS Group. Lancet 1998;352:854-65

35 Hypoglycaemic episodes per annum Actual Therapy analysis overweight patients UKPDS Group. Lancet 1998;352: ConventionalMetforminChlorpropramideGlibenclamideInsulin

36 Myocardial Infarction M v I p=0.12 overweight patients M v C p=0.010 UKPDS Group. Lancet 1998;352:854-65

37 UKPDS: benefit of metformin in overweight Type 2 diabetes patients* Diabetes-related endpoints Diabetes-related deaths All-cause mortality Myocardial infarction Risk reduction (%) p = p = p = p = 0.01 United Kingdom Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 854–865. *Compared to conventional treatment group

38 What is hypoglycaemia? Hypoglycaemia (or a ‘hypo’) occurs when the level of glucose in the blood falls too low Clinical definition of hypoglycaemia 1 : Mild – when a person can self-treat the episode Severe – an episode that requires external medical assistance or assistance from another person to recover 1. Barnett et al. Int J Clin Pract

39 Causes of hypoglycaemia Anti-diabetes treatment (for example insulin and sulphonylureas) 1 Irregular eating habits or delayed eating 2 Exercise, either when an individual is more physically active than usual or regular exercise without sufficient food intake 2 Alcohol consumption, particularly in those on anti-diabetes treatments or where there is also insufficient food intake 2 1. Zammit and Frier, Diabetes Care, Vol 28, No 12, Barnett et al. Int J Clin Pract

40 Specific risk factors for severe hypoglycaemia in type 2 diabetes Diabetes medication, particularly insulin and sulphonylureas 1 Intensive glycaemic control 2,3 Extremes of age- older people due to of cognitive decline, younger people because of impaired awareness and ability to self-treat 1,4,5 Long duration of diabetes 1 History of previous severe hypoglycaemia 5 Impaired awareness of hypoglycaemia 6,7 Sleep (via impaired awareness/autonomic response to hypoglycaemia) 8 Renal impairment 1 Periods of fasting e.g. Ramadan, clinical investigations 1. Amiel SA et al. Diabet Med. 2008;25(3):245– Wright et al. J Diabetes Complications. 2006;20:395–40 3. California Healthcare Foundation. J Am Ger Soc. 2003;51(5, suppl):S265–S280, 4. Matyka K et al. Diabetes Care. 1997;20(2):135–141, 5. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2008;32(suppl 1):S62–S64, 6. Chico A et al. Diabetes Care. 2003;26(4):1153– Henderson JN et al. Diabet Med. 2003;20:1016–1021, 8. Cryer, P. E. Diabetes ,

41 Risk factor: Age Hypoglycaemia in the elderly Advanced age is a risk factor for hypoglycaemia and many individuals will have had diabetes for several years 1 Symptoms of hypoglycaemia in elderly patients can include neuroglycopenic symptoms, such as weakness, drowsiness, poor concentration, dizziness and confusion and neurological symptoms such as blurred vision, lack of co-ordination and slurred speech 2 Many of the prominent symptoms of hypoglycaemia in elderly people may be misinterpreted as other neurological conditions such as transient cerebral ischaemia, vertebrobasilar insufficiency or vasovagal attacks 2 Elderly people may, in general, have reduced awareness of hypoglycaemia symptoms 3 1. Amiel SA et al. Diabet Med. 2008;25(3):245– McAulay et al. Diabetic Medicine. 2001; 18: Matyka K et al. Diabetes Care. 1997; vol 20;2:

42 What are the Symptoms of Hypoglycaemia? Autonomic symptoms (these act as a warning signal): palpitations, pallor, sweating, nausea, tremor, anxiety, dilated pupils. Generally occur at glucose levels <4 Neuroglycopaenic symptoms (where glucose levels are too low for the brain to function optimally: confusion, slurred speech, personality change, double vision, seizures, coma Generally occur at glucose levels <3 Hunger may occur at a wide variety level of blood glucose levels, and is a very non-specific symptom

43 Arterialised venous blood glucose concentration (mmol/l) Inhibition of endogenous insulin secretion 4.6 mmol/L Counterregulatory hormone release Glucagon Adrenaline 3.8 mmol/L Onset of symptoms mmol/L Neurophysiological dysfunction Evoked responses mmol/L Onset of EEG changes 3.0 mmol/L Cognitive dysfunction Inability to perform complex tasks 2.8 mmol/L Severe neuroglycopenia Reduced conscious level Convulsions Coma <1.5 mmol/L Adapted from: Hypoglycaemia and Clinical Diabetes”, 2nd edition, Eds. Frier BM and Fisher M, 2007, John Wiley and Sons, Chichester Endocrine, symptomatic and neurological responses to acute hypoglycaemia in non- diabetic subjects 43

44 The glycaemic threshold for hypoglycaemia symptom response alters with age Hypoglycaemia and Clinical Diabetes”, 2nd edition, Eds. Frier BM and Fisher M, 2007, John Wiley and Sons, Chichester (Adapted from: Matyka et al (1997) Diabetes Care 20: 135) 44 In young adult males awareness of symptoms occurred when blood glucose was 3.6 mmol/L, but impairment in cognitive function occurred at 2.6 mmol/L In older males these thresholds are much closer together - awareness of symptoms occurred almost simultaneously with cognitive decline Blood glucose (mmol/L) symptoms reaction time (defined as 4-choice reaction time test) younger men n=7 (22-26 years) older men n=7 (60-70 years) younger men Glycaemic thresholds for subjective symptomatic awareness of hypoglycaemia and for the onset of cognitive dysfunction in young and elderly non-diabetic males symptoms reaction time

45 Annual prevalence of severe hypoglycaemia (%) Severe: requiring external assistance T2DM SU T2DM < 2 yrs T2DM > 5 yrs T1DM < 5 yrs Adapted from: UK Hypoglycaemia Study Group (2007) Diabetologia 50: 1140 Type 2 DM sulphonylureas n =103 Type 2 DM <2 years insulin n = 85 Type 2 DM >5 years insulin n = 75 Type 1 DM <5 years n = 46 Type 1 DM >15 years n = 54 Frequency of severe hypoglycaemia increases over time Error bars = 95% confidence intervals T1DM > 15 yrs 45

46 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

47 Driving and diabetes The DVLA issue ‘Medical Rules’ on a number of conditions, including diabetes For up-to-date guidance please visit the DVLA or direct.gov.uk websites: ‘Information for drivers with insulin diabetes’ ers/MedicalA-Z/DG_ ‘Information for drivers of cars or motorcycles with diabetes treated by tablets, diet, or both’ Physicians should ensure that patients with diabetes are aware of the DVLA regulations and guidance in relation to hypoglycaemia and driving

48 Increasing HCP awareness around hypoglycaemia in type 2 diabetes GPs, practice nurses and pharmacists need to: Be aware of the prevalence of hypoglycaemia in patients with type 2 diabetes Recognise the causes and risk factors for hypoglycaemia in type 2 diabetes Inform patients of the risks Be aware that patients may use different language ‘I feel a bit hungry late mornings especially if I’ve been out shopping’ or ‘I have dizzy dos’ 48

49 Glycaemic Levels During the DCCT/EDIC DCCT/EDIC Study Research Group.N Engl J Med. 2005;353:

50 DCCT/EDIC: Intensive glucose control associated with reduced long-term CV risk DCCT/EDIC Study Research Group. N Engl J Med. 2005;353: 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 DCCT ends A1C 7.4% vs 9.1% *Cumulative incidence ConventionalIntensive

51 HbA 1c cross-sectional, median values UKPDS 33 Lancet 1998; 352:

52 Post-Trial Changes in HbA 1c UKPDS results presented Mean (95%CI) 10-Year Follow-up of Intensive Glucose Control in Type 2 Diabetes. N Eng J Med 2008; 359

53 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

54 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

55 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

56 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

57 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

58 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

59 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

60 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 T2DM…when: – 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 Section 1 Guidance. Section 1.1.

61 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 Section 1 Guidance. Section 1.3.

62 Slide No 62 Liraglutide FAD recommendation (stopping rules) 2 Treatment with liraglutide 1.2mg daily should only be continued…if 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. Last accessed 17 September Section 1 Guidance. Section 1.2 and 1.4http://www.nice.org.uk/nicemedia/live/11895/50663/50663.pdf

63 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 Section 1 Guidance. Section 1.5

64 A clinical composite endpoint: Reaching HbA1c<7.0% combined with weight loss 1 Rosiglitazone 4 mg LEAD 1, Marre Diab Med Glimepiride 4 mg LEAD 2, Nauck Diabetes Care 2008 Exenatide 10 μg BID LEAD 6, Buse Lancet 2009 Liraglutide 1.8 mg LEAD 6, Buse Lancet 2009 Glargine 24 IU LEAD 5, Russell-Jones Diabetologia % 78% 72% Liraglutide 1.2 mg LEAD 2, Nauck Diabetes Care % 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 comparators 1 72% HbA 1c Weight 1. Data on file: Composite endpoint

65 UKPDS 2x2 Glucose & Blood Pressure Outcome UKPDS 75. Diabetologia 2006: 49: p for trend = ITT rate per 1,000 patient years n=887

66 Steno-2: treatment conditions Intensive group Aim: to modify CV risk factors to strict targets: – Systolic BP < 130 – Diastolic BP < 80 – HbA 1c < 6.5% – Fasting serum total cholesterol 4.8 – Fasting serum triglycerides 1.7 – Aspirin for those with known ischaemia or peripheral vascular disease – Automatic treatment with ACE inhibitor Conventional group Aim: to modify CV risk factors to conventional targets: – Systolic BP < 160 – Diastolic BP < 95 – HbA 1c < 7.5% – Fasting serum total cholesterol: 6.4 – Fasting serum triglycerides: 2.2 – Aspirin for those with known ischaemia Steno-2: Lancet 1999;353:617–22 Steno-2: N Engl J Med 2003;348:383–93

67 Steno-2: relative risk reduction with intensive 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;348:383–93

68 Intensive Multiple Risk Factor Management in Patients with Type 2 Diabetes: STENO-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;348:383– Aggressive treatment of † : – Microalbuminuria with ACEIs, ARBs, or combination – Hypertension – Hyperglycemia – Dyslipidemia – Secondary prevention of CVD Conventional Therapy Intensive Therapy † 20% Absolute Risk Reduction

69 Slide Source Lipids Online Slide Library Percent of Total Calculated Risk Reduction in Cardiovascular Disease-Related Events Lipids STENO-2: Lipid-Lowering Therapy Accounted for More Than 70% of Cardiovascular Risk Reduction Analysis of STENO-2 data based on the risk engine from the United Kingdom Prospective Diabetes Study (UKPDS) Hemoglobin A 1c Systolic Blood Pressure Reprinted with permission from Gaede P, Pederson O. Diabetes. 2004; 53(Suppl 3):S39−S47. Copyright © 2004 American Diabetes Association.

70 Steno-2 Study Results  Intensive therapy resulted in an absolute risk reduction of:  20% for all cause mortality  29% for cardiovascular events  13% for CV mortality  Relative risk reduction in microvascular disease of 50%

71 Summary The goal is to achieve good glucose, blood pressure and lipid control with minimal side effects In practice, this means achieving the lowest possible glucose levels, without paying the price of hypoglycaemia, weight gain and other side effects HbA1c <7.0% (lower for newly diagnosed, higher for the elderly and those with CVD) BP <130/80 Cholesterol <4.0, LDL<2.0


Download ppt "Drug Treatments in Type 2 Diabetes Dr Richard Brice MB BCh MA MRCGP GPSI in Diabetes Chairman, Whitstable Medical Practice."

Similar presentations


Ads by Google