1、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),20
2、05. 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 li
3、festyles and an ageing population,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 Commo
4、nest 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; 4Bou
5、lton, 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 expecta
6、ncy 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,Diabetes & Vascular Disease,Obesity,Hypertension,Thrombosis,Hyperglycaemia,Dyslipidaemia,Atherosclerosis,Insulin Resistance,Hyperinsulinaemia,Targets Amenab
7、le to Pharmacotherapy,HbA1c 7.0% (53 mmol/ml) BP 130/80 Total cholesterol 4.0, LDL 2.0,12,NICE BP Algorithm 2008,NICE Clinical Guideline 66 Type 2 Diabetes (update) 2008,Lipid Management,Get them on a statin, usually simvastatin 40mg Aim for total cholesterol 4.0 and LDL 2.0 In statin intolerance, e
8、ncourage 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,Relation between the proportional reduction in MAJOR VASCULAR EVENTS and mean absolute LDL reduction in 14 statin tri
9、als,Cholesterol Treatment Trialists Collaboration (Lancet 2008: 371:117-125),15,Alsheikh-Ali et al J Am Coll Cardiol 2007;50:409-18,16,STELLAR - Efficacy Change in LDL-C at 6 weeks,Change in LDL-C from baseline (%),0,10,20,30,40,50,60,10 mg *,5,15,25,35,45,55,20 mg ,40 mg ,10 mg,20 mg,80mg,10 mg,20
10、mg,40 mg,80 mg,10 mg,20 mg,40 mg,40 mg,*p0.002 vs ATV 10mg; SIM 10, 20, 40mg; PRA 10, 20, 40mg p0.002 vs ATV 20, 40mg; SIM 20, 40, 80mg; PRA 20, 40mg p0.002 vs ATV 40mg; SIM 40, 80mg; PRA 40mg,Jones PH et al. Am J Cardiol 2003; 92: 152160,Rosuvastatin Atorvastatin Simvastatin Pravastatin,Normal Isle
11、t Function: Glucose Regulation,Type 2 diabetes,Years from diagnosis,0,5,-10,-5,10,15,Pre-diabetes,Onset,Diagnosis,Adapted from Ramlo-Halsted BA, Edelman SV. Prim Care. 1999;26:771-789; Nathan DM. N Engl J Med. 2002;347:1342-1349,Natural History of Type 2 Diabetes,Major Metabolic Defects in T2D,Insul
12、in resistance,-cell dysfunction,Hyperglycaemia (and dyslipidaemia),glucose uptake (lipolysis ),glucose outputVLDL production, glucose uptake and metabolism,Bailey CJ. Insulin resistance and antidiabetic drugs. Biochem Pharmacol. 1999;58:1511-1520,Postprandial Glucagon Is Inappropriately Elevated in
13、Type 2 Diabetes,120,60,0,Insulin (U/mL),100,120,140,-60,0,60,120,180,240,Time (min),Glucagon (g/mL),Meal,360,300,240,110,80,Glucose (mg/%),Mean SEM;*N = 14; N = 12; mean insulin values N = 5. Adapted from Muller WA, et al. N Engl J Med. 1970;283:109-115. Copyright 1970 Massachusetts Medical Society.
14、 All rights reserved. Translated with permission 2005.,Nondiabetic Subjects,Type 2 Diabetes*,The Incretin Effect Demonstrates the Response to Oral vs IV Glucose,Mean SE; N = 6; *P .05; 01-02 = glucose infusion time. Nauck MA, et al. Incretin effects of increasing glucose loads in man calculated from
15、 venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63:492-498. Copyright 1986. The Endocrine Society.,Venous Plasma Glucose (mmol/L),Time (min),C-peptide (nmol/L),11,5.5,0,01,60,120,180,01,60,120,180,0.0,0.5,1.0,1.5,2.0,Time (min),02,02,Incretin Effect,Oral Glucose IV Glucose,GLP
16、-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;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39
17、:1546-1553.; Adapted from Drucker DJ. Diabetes.1998;47:159-169.,Liver: Glucagon reduces hepatic glucose output,Alpha cells: Postprandial glucagon secretion,Stomach: Helps regulate gastric emptying,The Incretin Effect Is Reduced in Patients With Type 2 Diabetes,0,20,40,60,80,Insulin (mU/L),0,30,60,90
18、,120,150,180,Time (min),0,20,40,60,80,0,30,60,90,120,150,180,Time (min),*P .05 compared with respective value after oral load. Nauck MA, et al. Diabetologia. 1986;29:46-52. Reprinted with permission from Springer-Verlag 1986.,Patients With Type 2 Diabetes,Control Subjects,Intravenous Glucose,Oral Gl
19、ucose,*,*,*,*,*,*,*,Postprandial GLP-1 Levels Are Decreased in Patients With Type 2 Diabetes,20,15,10,5,0,0,60,120,180,240,Time (min),Meal,GLP-1 (pmol/L),Mean SE; N = 102; *P .05 between T2DM and NGT groups. Toft-Nielsen M, et al. Determinants of the impaired secretion of glucagon-like peptide 1 in
20、type 2 diabetic patients. J Clin Endocrinol Metab. 2001;86:3717-3723. Copyright 2001. The Endocrine Society.,Normal Glucose Tolerance Impaired Glucose Tolerance Type 2 Diabetes,GLP-1 Effects in Humans,Promotes satiety and reduces appetite,Beta cells: Enhances glucose-dependent insulin secretion,Adap
21、ted from Flint A, et al. J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al. Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al. Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ. Diabetes.1998;47:159-169.,Liver: Glucagon reduces hepatic glucose output,Alpha cel
22、ls: Postprandial glucagon secretion,Stomach: Helps regulate gastric emptying,Back to contents,DPP-4 Inhibitors: Rationale,DPP-IV=dipeptidyl peptidase IV Adapted from Drucker DJ Expert Opin Invest Drugs 2003;12(1):87100; Ahrn B Curr Diab Rep 2003;3:365372.,Intestinal GLP-1 release,GLP-1 (9-36) inacti
23、ve,Mixed Meal,GLP-1 (7-36) active,DPP-4 inhibitor,DPP-4,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 dyslipidaemi
24、a,Therapy limitations,Concordance with multiple therapies,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;321:405412,Microvascular complicatio
25、ns,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; *p0.0001; *p=0.035,Reduction in risk (%),Diabetes- related deaths,* -21%,Currently Availabl
26、e 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: 213226.,HbA1c,cross-sectional, median values,UKPDS 33 Lancet 1998; 352: 837-853,Aggregate Clinical Endpoints,UKPDS 33
27、 Lancet 1998; 352: 837-853,HbA1c,cohort, median values,overweight patients,UKPDS Group. Lancet 1998;352:854-65,Change in Weight,cohort, mean values,overweight patients,UKPDS Group. Lancet 1998;352:854-65,Hypoglycaemic episodes per annum,Actual Therapy analysis,overweight patients,UKPDS Group. Lancet
28、 1998;352:854-65,Conventiona l Metformin Chlorpropramide Glibenclamide Insulin,Myocardial Infarction,M v I p=0.12,overweight patients,M v C p=0.010,UKPDS Group. Lancet 1998;352:854-65,UKPDS: benefit of metformin in overweight Type 2 diabetes patients*,0,5,10,15,20,25,30,35,40,45,Diabetes-related end
29、points,Diabetes-related deaths,All-cause mortality,Myocardial infarction,Risk reduction (%),p = 0.0023,p = 0.017,p = 0.011,p = 0.01,United Kingdom Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352: 854865.,*Compared to conventional treatment group,What is hypoglycaemia?,Hypoglycaemia (or a
30、hypo) occurs when the level of glucose in the blood falls too lowClinical definition of hypoglycaemia1: 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. 2010,38,C
31、auses of hypoglycaemia,Anti-diabetes treatment (for example insulin and sulphonylureas)1 Irregular eating habits or delayed eating2 Exercise, either when an individual is more physically active than usual or regular exercise without sufficient food intake2 Alcohol consumption, particularly in those
32、on anti-diabetes treatments or where there is also insufficient food intake2,1. Zammit and Frier, Diabetes Care, Vol 28, No 12, 2005 2. Barnett et al. Int J Clin Pract. 2010,39,Specific risk factors for severe hypoglycaemia in type 2 diabetes,Diabetes medication, particularly insulin and sulphonylur
33、eas 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 impa
34、ired 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):245254 2. Wright et al. J Diabetes Complications. 2006;20:39540 3. California Healthcare Foundation. J Am Ger Soc. 2003;51(5, sup
35、pl):S265S280, 4. Matyka K et al. Diabetes Care. 1997;20(2):135141, 5. Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Can J Diabetes. 2008;32(suppl 1):S62S64, 6. Chico A et al. Diabetes Care. 2003;26(4):11531157 7. Henderson JN et al. Diabet Med. 2003;20:10161021, 8. Cry
36、er, P. E. Diabetes. 2008. 57, 1369-1376,40,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 weaknes
37、s, 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
38、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):245254 2. McAulay et al. Diabetic Medicine. 2001; 18:690-705 3. Matyka K et al. Diabetes Care. 1997; vol 20;2:1
39、35-141,41,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 opti
40、mally: confusion, slurred speech, personality change, double vision, seizures, comaGenerally occur at glucose levels 3 Hunger may occur at a wide variety level of blood glucose levels, and is a very non-specific symptom,5.04.03.02.01.00,Arterialised venous blood glucose concentration (mmol/l),Inhibi
41、tion of endogenous insulin secretion,4.6 mmol/L,Counterregulatory hormone releaseGlucagonAdrenaline,3.8 mmol/L,Onset of symptoms,3.2-2.8 mmol/L,Neurophysiological dysfunctionEvoked responses,3.0-2.4 mmol/L,Onset of EEG changes,3.0 mmol/L,Cognitive dysfunctionInability to perform complex tasks,2.8 mm
42、ol/L,Severe neuroglycopeniaReduced conscious levelConvulsionsComa,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 su
43、bjects,43,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 sym
44、ptoms 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,50 40 30 20 100,Annual prevalence of severe hypoglycaem
45、ia (%) 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 5 years insulin n = 75 Type 1 DM 15 years n = 54,Frequency of severe hypoglycaemia increases over ti
46、me,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) Ca
47、rdiac arrhythmia,46,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 http:/www.direct.gov.uk/en/Motoring/DriverLicensing/MedicalRulesF
48、orDrivers/MedicalA-Z/DG_185427 Information for drivers of cars or motorcycles with diabetes treated by tablets, diet, or both http:/www.direct.gov.uk/prod_consum_dg/groups/dg_digitalassets/dg/en/motor/documents/digitalasset/dg_067957.pdf Physicians should ensure that patients with diabetes are aware of the DVLA regulations and guidance in relation to hypoglycaemia and driving,1. http:/www.direct.gov.uk/en/Motoring/DriverLicensing/MedicalRulesForDrivers/MedicalA-Z/DG_187349,47,Increasing HCP awareness around hypoglycaemia in type 2 diabetes,
