MANAGEMENT OF TYPE 2 DIABETES AND NEW NICE GUIDELINES Dr SUNIL ZACHARIAH CONSULTANT ENDOCRINOLOGIST
INTRODUCTION <ul><li>The epidemic of type 2 diabetes and the recognition that achieving specific glycaemic goals can subst...
GLYCEMIC GOALS OF THERAPY <ul><li>DCCT (Diabetes Control and Complications Trial), UKPDS (UK Prospective Diabetes Study) a...
<ul><li>Results of ACCORD study, which had the primary objective of decreasing CVD with interventions aimed at achieving H...
HbA1c <ul><li>Check 2-6 monthly (according to individual needs) until stable on unchanging therapy </li></ul><ul><li>6 mon...
Lifestyle interventions <ul><li>Weight loss as little as 1 kg will ameliorate hyperglycemia </li></ul><ul><li>? Anti-obesi...
‘ Diabesity epidemic’ <ul><li>Increase in prevalence of diabetes is closely linked to marked increase in obesity </li></ul...
TRENDS IN INACTIVITY
Physical inactivity as 4 th  primary risk factor for all-cause mortality
Impact of bariatric surgery on type 2 diabetes <ul><li>60 Obese patients (BMI>40), with recently diagnosed T2DM [Australia...
<ul><li>Impact of bariatric surgery on diabetes does not appear to be purely as a result of weight loss </li></ul><ul><li>...
PATIENT EDUCATION <ul><li>Structured education is an integral part of diabetes care </li></ul><ul><li>Ideally offer it pre...
DIETARY ADVICE <ul><li>Integrate with diabetes management plan </li></ul><ul><li>Sensitive to person’s needs, culture and ...
SELF-MONITORING <ul><li>Self-monitoring of plasma glucose should be available </li></ul><ul><li>To those on insulin treatm...
METFORMIN <ul><li>Major effect is to decrease hepatic glucose output and lower fasting glycemia </li></ul><ul><li>Typicall...
<ul><li>Weight stability or modest weight loss </li></ul><ul><li>UKPDS demonstrated a beneficial effect of metformin on CV...
SULFONYLUREAS <ul><li>Lower glycaemia by enhancing insulin secretion </li></ul><ul><li>Efficacy is similar to metformin  <...
THIAZOLIDINEDIONES <ul><li>Glitazones are peroxisome proliferator-activated receptor gamma modulators </li></ul><ul><li>In...
<ul><li>Weight gain, fluid retention, with peripheral edema </li></ul><ul><li>2 fold increased risk of CCF </li></ul><ul><...
NICE guidelines on Glitazones <ul><li>Do not start or continue TZDs if the person has heart failure or is at higher risk o...
GLINIDES <ul><li>2 glinides currently available </li></ul><ul><li>Repaglinide and Nateglinide </li></ul><ul><li>As monothe...
The action of repaglinide on    -cells ATP-sensitive K +   channel Voltage-dependent Ca 2+  channel  Membrane potential C...
<ul><li>The risk of weight gain is similar to sulfonylureas, but hypoglycemia may be less frequent </li></ul><ul><li>Mainl...
ACARBOSE <ul><li>NICE: Consider Acarbose for a person unable to use other oral glucose-lowering medications </li></ul><ul>...
INCRETIN-BASED THERAPIES IR-insulin (mU/l) 80 60 40 20 – 10 – 5 60 120 180 0 * * * * * * * Time (min) Incretin effect Insu...
INCRETIN-EFFECT <ul><li>The augmented insulin response to oral glucose (the incretin response), is reported to be reduced ...
The incretin effect is reduced in patients with type 2 diabetes 0 20 40 60 80 Insulin (mU/L) 0 30 60 90 120 150 180 Time (...
Incretins and glycaemic control Adapted from 7. Drucker DJ.  Cell Metab . 2006;3:153–165. 8.  Miller S, St Onge EL.  Ann P...
SITAGLIPTIN <ul><li>Licensed for use in T2DM at a dose of 100 mg once a day </li></ul><ul><li>Can be added to metformin, a...
24-week Add-on Therapy to Metformin Study Mean change in HbA 1c  over time 9 *Dose of metformin was ≥1,500 mg/day in both ...
VILDAGLIPTIN <ul><li>Licensed at a dose of 50 mg once or twice daily </li></ul><ul><li>In T2DM as dual oral therapy </li><...
Vildagliptin produced an additional 1.1% reduction in HbA1c when added to metformin Vildagliptin 50mg bd + metformin Place...
NICE: DPP-4 inhibitors <ul><li>Continue DPP-4 inhibitor therapy only if there is a reduction of >0.5% HbA1c in 6 months </...
Incretins and glycaemic control Adapted from 7. Drucker DJ.  Cell Metab . 2006;3:153–165. 8.  Miller S, St Onge EL.  Ann P...
GLP-1 Analogues <ul><li>Exenatide </li></ul><ul><ul><li>Synthetic form of Exendin-4, derived from the salivary secretions ...
Structure of native GLP-1 and two GLP-1  analogues 97% homology to native GLP-1 53% homology to native GLP-1
Pivotal phase III clinical studies – combined (ITT) exenatide lowered HbA 1c 0.1 0.2 30-wk data; Mean (SE)  1 DeFronzo RA,...
Change in body weight over time, ITT population Exenatide with metformin -0.3 ± 0.3 kg -2.8 ± 0.5 kg -1.6 ± 0.4 kg Time (w...
Open-label extension study – combined 82-week  completers data. Exenatide continued to reduce weight 82-wk completers; Mea...
<ul><li>5 mcg or 10 mcg twice daily </li></ul><ul><li>Main side effects are nausea and vomiting, developing antibodies to ...
NICE: EXENATIDE <ul><li>Continue exenatide only if a person has a reduction in HbA1c>1% and >3% of initial body weight in ...
LIRAGLUTIDE <ul><li>97% homologous with native human GLP-1 </li></ul><ul><li>Half life of 11-15 hours </li></ul><ul><li>Pe...
Starting Insulin therapy <ul><li>If other measures do not keep HbA1c to <7.5% (or other agreed target), discuss benefits a...
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  • Repaglinide stimulates insulin secretion from beta-cells only when glucose is also present. This is in contrast with sulphonylureas, which induce insulin secretion even in the absence of glucose. In patients with Type 2 diabetes, stimulation of insulin secretion in the absence of glucose may increase the risk of hypoglycaemia. Repaglinide is the first prandial glucose regulator and has the properties which define the class. Both repaglinide and sulphonylureas act to stimulate insulin secretion by closing ATP-sensitive potassium ion channels in the beta-cell membrane. However, studies have shown that the PGRs and SUs have different patterns of binding to sites on the cell membrane with repaglinide acting on a distinct site for its primary activity being different to that of SUs, and also having different effects on beta-cell activity: Unlike SU’s; Repaglinide does not inhibit the biosynthesis of insulin or other proteins Repaglinide does not directly promote exocytosis of insulin Repaglinide does not stimulate insulin secretion in the absence of glucose Repaglinide is effective in metabolically stressed cells Repaglinide has a fast onset and offset of action, minimising beta-cell stimulation The mechanism of action of repaglinide (and PGRs) is therefore fundamentally different from that of the sulphonylureas.
  • The incretin effect The effect of incretins on insulin secretion is clearly indicated in this study. Healthy volunteers (n=8) fasted overnight before received an oral glucose load of 50 g/400 ml or an isoglycaemic intravenous glucose infusion for 180 minutes. As can be seen in the left figure, venus plasma was similar with both glucose interventions. However, insulin response was greater following oral glucose ingestion than following intravenous glucose infusion, demonstrating the contribution of incretins on insulin secretion. References Nauck et al. Diabetologia 1986;29:46–52
  • DISCUSSION The β -cell secretory response to glucose ingestion, as measured by increases in plasma insulin, was reduced in patients with type 2 diabetes. Patients with diabetes exhibited a greater β -cell secretory response than control subjects, as indicated by higher insulin secretion levels, during the 180-minute course of intravenous glucose infusion. BACKGROUND Differences in insulin response to oral and intravenous glucose administration, which are attributed to factors other than glucose itself, describe the incretin effect; the incretin effect appears to be reduced in patients with type 2 diabetes. Measured insulin and C-peptide responses to a 50 g oral glucose load and an isoglycaemic intravenous infusion. Additionally, an attempt was made to correlate incretin effects to GIP responses. Insulin measurements are shown here. Plasma insulin responses were studied for 14 patients with type 2 diabetes in this study and 8 metabolically healthy control subjects. Nauck MA, et al. Diabetologia 1986;29:46–52
  • Drucker DJ. The biology of incretin hormones. Cell Metabolism 2006;3:153-165. Miller S, St Onge EL. Sitagliptin: A dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Ann Pharmacother 2006;40:1336-1343.
  • Charbonnel B, Karasik A, Liu J et al for the Sitagliptin Study 020 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006;29:2638-2643.
  • Drucker DJ. The biology of incretin hormones. Cell Metabolism 2006;3:153-165. Miller S, St Onge EL. Sitagliptin: A dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes. Ann Pharmacother 2006;40:1336-1343.
  • DISCUSSION Significant HbA 1c reductions were seen with the exenatide 5 µg and 10 µg treatment arms in all three studies ( P &lt; 0.002 vs placebo). The baseline HbA 1c was 8.5% for the placebo group, 8.4% for the exenatide 5 µg BD treatment arm, and 8.5% for the exenatide 10 µg BD treatment arm. Exenatide is associated with reduction in HbA 1c , regardless of oral therapy (MET and/or SU), and disease duration. The SU + MET study patients had longer disease duration than those in the other arms.
  • DISCUSSION Progressive, dose-dependent reduction in weight was seen in exenatide-treated patients At Week 30, weight changes from baseline were -2.8 ± 0.5 kg (10 µg), -1.6 ± 0.4 kg (5 µg) for exenatide treated patients (P &lt; 0.001 vs placebo 10 μ g and P &lt; 0.001 vs placebo 5 μ g) No special weight loss programmes, exercise programmes, or standardised diets were used in the study STUDY BACKGROUND A 30-week triple-blind, phase III study; patients with type 2 diabetes randomised to placebo, exenatide 5 or 10 µg BD with metformin, ITT N = 336
  • DISCUSSION Shown here are data for 393 patients at Week 82, which includes 30 weeks of the placebo-controlled, double-blind studies and 52 weeks of open-label extension (OLE) 1 . Upon receiving exenatide, patients in the placebo cohort showed a similar decrease in body weight similar to that observed with exenatide treatment in the first 30 weeks. Mean body weight reductions mediated by exenatide during the first 30 weeks (5 μ g: -1.9 ± 0.3 kg; 10 μ g: -2.7 ± 0.4 kg) were sustained and appeared to be progressive through 82 weeks (10 μ g : -4.5 ± 0.5 kg) 1. BACKGROUND (Blonde L, et al. 2006) Mean weight change when viewed by quartiles ranged from a reduction of 11.9 kg in quartile 1 to a weight gain of 1.7 kg in quartile 4 2 A 4.4 kg mean reduction in weight from baseline was observed in patients receiving 10 μ g BD 2 1 Blonde L, et al. Poster presented at the American Diabetes Association Meeting 2005 (Abstract 477P) 2 Blonde L, et al. Diabetes Obes Metab 2006;8:436–47
  • Consultant presentations

    1. 1. MANAGEMENT OF TYPE 2 DIABETES AND NEW NICE GUIDELINES Dr SUNIL ZACHARIAH CONSULTANT ENDOCRINOLOGIST
    2. 2. INTRODUCTION <ul><li>The epidemic of type 2 diabetes and the recognition that achieving specific glycaemic goals can substantially reduce morbidity have made the effective treatment of hyperglycemia a top priority </li></ul><ul><li>Intensive glycaemic control has been demonstrated to have a powerful beneficial effect on diabetes-specific microvascular complications, including retinopathy, nephropathy and neuropathy </li></ul><ul><li>Development of new classes of blood glucose-lowering medications to supplement the older therapies has increased the number of treatment options </li></ul>
    3. 3. GLYCEMIC GOALS OF THERAPY <ul><li>DCCT (Diabetes Control and Complications Trial), UKPDS (UK Prospective Diabetes Study) and Stockholm Diabetes Study in Type 1 diabetes have helped to establish the glycaemic goals of therapy that result in improved long term outcomes </li></ul><ul><li>Most recent glycemic goal recommended by the American Diabetes Association is HbA1c<7%, whereas International Diabetes Federation recommends HbA1c<6.5% </li></ul>
    4. 4. <ul><li>Results of ACCORD study, which had the primary objective of decreasing CVD with interventions aimed at achieving HbA1c<6% vs. interventions aimed at achieving hbA1c<7.9%, showed excess CVD mortality in the intensive treatment group. </li></ul><ul><li>ADVANCE study did not demonstrate any excess CVD mortality with HbA1c<6.5% </li></ul><ul><li>Individualize target </li></ul><ul><li>Take into consideration factors such as life expectancy, risk of hypoglycemia, presence of CVD </li></ul>
    5. 5. HbA1c <ul><li>Check 2-6 monthly (according to individual needs) until stable on unchanging therapy </li></ul><ul><li>6 monthly once blood glucose level and blood glucose-lowering therapy are stable </li></ul>
    6. 6. Lifestyle interventions <ul><li>Weight loss as little as 1 kg will ameliorate hyperglycemia </li></ul><ul><li>? Anti-obesity medications </li></ul><ul><li>NICE guidelines regarding bariatric surgery </li></ul>
    7. 7. ‘ Diabesity epidemic’ <ul><li>Increase in prevalence of diabetes is closely linked to marked increase in obesity </li></ul><ul><li>Obesity lies in the causative pathway to glucose intolerance and is a major factor in progression from IGT to type 2 diabetes </li></ul><ul><li>Every 1 kg increase in weight is associated with a 9% relative increase in diabetes prevalence </li></ul>
    8. 8. TRENDS IN INACTIVITY
    9. 9. Physical inactivity as 4 th primary risk factor for all-cause mortality
    10. 10. Impact of bariatric surgery on type 2 diabetes <ul><li>60 Obese patients (BMI>40), with recently diagnosed T2DM [Australia] </li></ul><ul><li>Between 2002-2006 </li></ul><ul><li>30 received lifestyle interventions, 30 had gastric banding, along with usual diabetes care </li></ul><ul><li>Remission of T2DM (HbA1c<6.2%) while taking no medications occurred in 73% of surgical group but only 13% of conventional group. </li></ul><ul><li>At 2 year follow-up surgical group lost 20.7% weight while conventional group lost 1.7% </li></ul>
    11. 11. <ul><li>Impact of bariatric surgery on diabetes does not appear to be purely as a result of weight loss </li></ul><ul><li>Significant improvements in insulin resistance are observed in the first week after surgery before any appreciable weight loss has occurred </li></ul><ul><li>?effects on gut hormones </li></ul>
    12. 12. PATIENT EDUCATION <ul><li>Structured education is an integral part of diabetes care </li></ul><ul><li>Ideally offer it preferably through a group education programme, to every person and/or their carer at and around the time of diagnosis, with annual reinforcement and review </li></ul><ul><li>Programme should meet the quality criteria laid down by DOH and Diabetes UK Patient Education Working Group </li></ul><ul><li>Meet the local cultural, linguistic, cognitive and literacy needs </li></ul>
    13. 13. DIETARY ADVICE <ul><li>Integrate with diabetes management plan </li></ul><ul><li>Sensitive to person’s needs, culture and beliefs </li></ul><ul><li>Include high-fibre, low-glycemic index sources of carbohydrate </li></ul><ul><li>Include low-fat dairy products and oily fish </li></ul><ul><li>Control intake of foods containing saturated fats and trans fatty acids </li></ul>
    14. 14. SELF-MONITORING <ul><li>Self-monitoring of plasma glucose should be available </li></ul><ul><li>To those on insulin treatment </li></ul><ul><li>To those on oral glucose-lowering medications to provide information on hypoglycemia </li></ul><ul><li>To assess changes in glucose control resulting from medications and lifestyle changes </li></ul><ul><li>To monitor changes during intercurrent illness </li></ul><ul><li>To ensure safety during activities, including driving </li></ul>
    15. 15. METFORMIN <ul><li>Major effect is to decrease hepatic glucose output and lower fasting glycemia </li></ul><ul><li>Typically metformin monotherapy will lower HbA1c by 0.8-1.5% </li></ul><ul><li>Step up metformin over several weeks to minimize risk of gastrointestinal side effects </li></ul><ul><li>Consider trial of Metformin SR if GI tolerability prevents the person continuing with metformin </li></ul><ul><li>Interferes with B12 absorption, but is very rarely associated with anemia </li></ul>
    16. 16. <ul><li>Weight stability or modest weight loss </li></ul><ul><li>UKPDS demonstrated a beneficial effect of metformin on CVD outcome </li></ul><ul><li>Renal dysfunction with metformin use may increase the risk of lactic acidosis (less than 1 case per 100000 treated patients) </li></ul><ul><li>If eGFR <45 or creatinine >130, half the dose </li></ul><ul><li>If eGFR <30 or creatinine >150, stop metformin </li></ul>
    17. 17. SULFONYLUREAS <ul><li>Lower glycaemia by enhancing insulin secretion </li></ul><ul><li>Efficacy is similar to metformin </li></ul><ul><li>Major adverse effects are hypoglycemia and weight gain (2 kg) </li></ul><ul><li>NICE guidelines </li></ul><ul><li>Prescribe a sulfonylurea with a low acquisition cost (not glibenclamide) when an insulin secretagogue is indicated </li></ul><ul><li>Educate the patient about the risk of hypoglycemia, particularly if he or she has renal impairment </li></ul>
    18. 18. THIAZOLIDINEDIONES <ul><li>Glitazones are peroxisome proliferator-activated receptor gamma modulators </li></ul><ul><li>Increase the sensitivity of muscle, fat and liver to endogenous and exogenous insulin (“Insulin sensitizers”) </li></ul><ul><li>As monotherapy reduces HbA1c by 0.5-1.4% </li></ul><ul><li>More durable effect on glycemic control, particularly compared with sulfonylyureas </li></ul>
    19. 19. <ul><li>Weight gain, fluid retention, with peripheral edema </li></ul><ul><li>2 fold increased risk of CCF </li></ul><ul><li>Increase in adiposity, largely subcutaneous, with some reduction in visceral fat shown in some studies </li></ul><ul><li>TZDs either have a beneficial (pioglitazone) or neutral (rosiglitazone) effect on atherogenic lipid profiles </li></ul><ul><li>Recent meta-analysis on Rosiglitazone </li></ul>
    20. 20. NICE guidelines on Glitazones <ul><li>Do not start or continue TZDs if the person has heart failure or is at higher risk of fracture </li></ul><ul><li>Continue TZD therapy only if there is a HbA1c reduction of >0.5% in 6 months </li></ul><ul><li>TZD might be preferable to DPP4 inhibitor if the person has marked insulin insensitivity </li></ul>
    21. 21. GLINIDES <ul><li>2 glinides currently available </li></ul><ul><li>Repaglinide and Nateglinide </li></ul><ul><li>As monotherapy reduces HbA1c by 1-1.5% </li></ul><ul><li>Like the sulfonylureas, the glinides stimulate insulin secretion, although they bind to a different site within the sulfonylurea receptor </li></ul>
    22. 22. The action of repaglinide on  -cells ATP-sensitive K + channel Voltage-dependent Ca 2+ channel Membrane potential Ca 2+ ATP Insulin Glucose Ca 2+ -dependent K + channel Metabolism Protein synthesis Insulin granules Na + channel Cl - channel NUCLEUS PRANDIN SmPC Aug 2007 Repaglinide
    23. 23. <ul><li>The risk of weight gain is similar to sulfonylureas, but hypoglycemia may be less frequent </li></ul><ul><li>Mainly to control post-prandial surge </li></ul><ul><li>[As patients get closer to HbA1c target, post prandial glucose becomes the most significant contributing factor] </li></ul>
    24. 24. ACARBOSE <ul><li>NICE: Consider Acarbose for a person unable to use other oral glucose-lowering medications </li></ul><ul><li>Alpha-Glucosidase inhibitor, which reduces the rate of digestion of polysaccharides in the proximal small intestine, primarily lowering post prandial glucose levels without causing hypoglycemia </li></ul><ul><li>Increased delivery of carbohydrate to the colon results in increased gas production and GI side effects (25-45% stoppage) </li></ul>
    25. 25. INCRETIN-BASED THERAPIES IR-insulin (mU/l) 80 60 40 20 – 10 – 5 60 120 180 0 * * * * * * * Time (min) Incretin effect Insulin response Plasma glucose (mmol/l) – 10 – 5 60 120 180 10 Time (min) 5 0 15 Plasma glucose Oral glucose load (50 g/400 ml) Isoglycaemic glucose infusion <ul><ul><li>Insulin response is greater following oral glucose than i.v glucose, despite similar plasma glucose concentration </li></ul></ul>90 0 180 270 Plasma glucose (mg/dl)
    26. 26. INCRETIN-EFFECT <ul><li>The augmented insulin response to oral glucose (the incretin response), is reported to be reduced or abolished in patients with T2DM </li></ul><ul><li>Restoration of the incretin response could improve glycemic control in such patients </li></ul>
    27. 27. The incretin effect is reduced in patients with type 2 diabetes 0 20 40 60 80 Insulin (mU/L) 0 30 60 90 120 150 180 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. Patients with type 2 diabetes Control subjects Intravenous Glucose Oral Glucose Insulin (mU/L) * * * * * * * * * *
    28. 28. Incretins and glycaemic control Adapted from 7. Drucker DJ. Cell Metab . 2006;3:153–165. 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343. Blood glucose control DPP-4 enzyme rapidly degrades incretins Active GLP-1 and GIP Release of incretin gut hormones Pancreas GI tract <ul><li>Glucagon </li></ul><ul><li>from alpha cells (GLP-1) Glucose dependent </li></ul>Alpha cells Increased insulin and decreased glucagon reduce hepatic glucose output <ul><li>Glucose dependent </li></ul><ul><li>Insulin </li></ul><ul><li>from beta cells (GLP-1 and GIP) </li></ul>Beta cells Insulin increases peripheral glucose uptake Ingestion of food
    29. 29. SITAGLIPTIN <ul><li>Licensed for use in T2DM at a dose of 100 mg once a day </li></ul><ul><li>Can be added to metformin, a glitazone, a sulfonylurea or a sulfonylurea+metformin, when current regime does not achieve glycemic control </li></ul><ul><li>HbA1c reduction of 0.5-1% </li></ul><ul><li>Weight neutral and low risk of hypoglycemia </li></ul><ul><li>Post prandial glucose also reduced (p<0.05) compared to placebo </li></ul><ul><li>Slightly higher rates of constipation, nasopharyngitis and dizziness </li></ul>
    30. 30. 24-week Add-on Therapy to Metformin Study Mean change in HbA 1c over time 9 *Dose of metformin was ≥1,500 mg/day in both arms. All-patients-as-treated population Diabetes Care , Vol. 29,2006; 2638–2643 n=453 n=224 Weeks 0 6 12 18 24 % HbA 1c 7.0 7.2 7.4 7.6 7.8 8.0 8.2 Reduction in HbA 1c of 0.65% p< 0.001 versus placebo Placebo + metformin * Sitagliptin 100 mg o.d. + metformin* 0
    31. 31. VILDAGLIPTIN <ul><li>Licensed at a dose of 50 mg once or twice daily </li></ul><ul><li>In T2DM as dual oral therapy </li></ul><ul><li>Reduces HbA1c by 0.6-1.1% </li></ul><ul><li>Reduces postprandial glucose </li></ul><ul><li>Weight neutral and low risk of hypoglycemia </li></ul><ul><li>Main side effects are headache, nosopharyngitis, dizziness </li></ul>
    32. 32. Vildagliptin produced an additional 1.1% reduction in HbA1c when added to metformin Vildagliptin 50mg bd + metformin Placebo + metformin Mean change from baseline HbA1C (%) Time (weeks of treatment) -1.2 -1.0 -0.8 -0.4 -0.2 0.0 0.2 0.4 4 8 12 16 20 24 0 -1.1% vildagliptin vs placebo (p<0.001) n= n= 143 137 130 126 143 143 143 143 143 143 from Bosi et al. Diabetes Care, 2007;30:890–895 Mean baseline HbA1c: 8.3-8.4% -0.6
    33. 33. NICE: DPP-4 inhibitors <ul><li>Continue DPP-4 inhibitor therapy only if there is a reduction of >0.5% HbA1c in 6 months </li></ul><ul><li>DPP-4 inhibitor is preferable to a Glitazone if </li></ul><ul><li>Further weight gain would cause significant problems </li></ul><ul><li>TZDs are contraindicated </li></ul><ul><li>Person has a poor response or did not tolerate TZDs in the past </li></ul>
    34. 34. Incretins and glycaemic control Adapted from 7. Drucker DJ. Cell Metab . 2006;3:153–165. 8. Miller S, St Onge EL. Ann Pharmacother 2006;40:1336-1343. Blood glucose control DPP-4 enzyme rapidly degrades incretins Active GLP-1 and GIP Release of incretin gut hormones Pancreas GI tract <ul><li>Glucagon </li></ul><ul><li>from alpha cells (GLP-1) Glucose dependent </li></ul>Alpha cells Increased insulin and decreased glucagon reduce hepatic glucose output <ul><li>Glucose dependent </li></ul><ul><li>Insulin </li></ul><ul><li>from beta cells (GLP-1 and GIP) </li></ul>Beta cells Insulin increases peripheral glucose uptake Ingestion of food
    35. 35. GLP-1 Analogues <ul><li>Exenatide </li></ul><ul><ul><li>Synthetic form of Exendin-4, derived from the salivary secretions of the Gila monster lizard ( Heloderma suspectum ) </li></ul></ul><ul><li>Liraglutide </li></ul><ul><ul><li>Novel long-acting analog obtained by acylation of GLP-1 with fatty acid chain </li></ul></ul>
    36. 36. Structure of native GLP-1 and two GLP-1 analogues 97% homology to native GLP-1 53% homology to native GLP-1
    37. 37. Pivotal phase III clinical studies – combined (ITT) exenatide lowered HbA 1c 0.1 0.2 30-wk data; Mean (SE) 1 DeFronzo RA, et al. Diabetes Care 2005;28:1092–1100; 2 Buse JB, et al. Diabetes Care 2004;27:2628–2635 ; 3 Kendall DM, et al. Diabetes Care 2005;28:1083–1091. -0.6 -0.8 247 245 241 8.5 8.5 8.5 -0.5 - 0.9 123 125 129 8.7 8.5 8.6 -0.4 - 0.8 -1 -0.5 0 0.5 Baseline N 113 110 113 8.2 8.3 8.2 <ul><li>HbA 1c (%) </li></ul>* P < 0.002 vs placebo * P < 0.001 vs placebo * * * * * * * P < 0.0001 vs placebo SU 2 MET 1 MET + SU 3 Placebo BD 0.1 Exenatide 5 µg BD Exenatide 10 µg BD
    38. 38. Change in body weight over time, ITT population Exenatide with metformin -0.3 ± 0.3 kg -2.8 ± 0.5 kg -1.6 ± 0.4 kg Time (week) ITT population, N = 336 (Placebo, N = 113; exenatide 5 µg, N = 110; exenatide 10 µg, N = 113) *P ≤ 0.05 ** P ≤ 0.001 compared to placebo DeFronzo RA, et al. Diabetes Care 2005;28:1092–1100. Placebo Exenatide 5 µg Exenatide 10 µg Mean (±SE) change in body weight from baseline (kg) 5 10 15 20 25 30 0 -4 -3 -2 -1 0 1 * ** * ** ** ** ** *
    39. 39. Open-label extension study – combined 82-week completers data. Exenatide continued to reduce weight 82-wk completers; Mean (SE); Weight was a secondary endpoint Adapted from Blonde L, et al. Poster presented at the American Diabetes Association Meeting 2005 (Abstract 477P) Baseline body weight 98 kg 100 kg 100 kg 0 10 20 30 40 50 60 70 80 90 -5 -4 -3 -2 -1 0 Mean ∆ body weight (kg) Placebo BD (N = 128) Exenatide 5 µg BD (N = 128) Exenatide 10 µg BD (N = 137 ) Open-label extension (all patients exenatide 10 µg BD) Placebo-controlled Trials Time (week) 1
    40. 40. <ul><li>5 mcg or 10 mcg twice daily </li></ul><ul><li>Main side effects are nausea and vomiting, developing antibodies to exenatide </li></ul>
    41. 41. NICE: EXENATIDE <ul><li>Continue exenatide only if a person has a reduction in HbA1c>1% and >3% of initial body weight in 6 months </li></ul><ul><li>Discuss the benefits of exenatide to allow the person to make an informed decision </li></ul>
    42. 42. LIRAGLUTIDE <ul><li>97% homologous with native human GLP-1 </li></ul><ul><li>Half life of 11-15 hours </li></ul><ul><li>Permitting once daily injection </li></ul><ul><li>1.2 and 1.8 mg/day </li></ul><ul><li>Added to metformin plus rosiglitazone, it reduces HbA1c by 1.5% (p<0.01) </li></ul><ul><li>Main side effects are nausea and vomiting </li></ul>
    43. 43. Starting Insulin therapy <ul><li>If other measures do not keep HbA1c to <7.5% (or other agreed target), discuss benefits and risk of insulin treatment </li></ul><ul><li>Initiate with structured programme </li></ul>

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