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Role of Combination Therapy in Type II Diabetes

Role of Combination Therapy in Type II Diabetes. Dr Cleo Cheng Midwest Health Beverley 22.11.2011. Objectives :. Refresh pathophysiology of DM ↑awareness of at risk groups to screen Competence in conducting brilliant GPMP–DM ↑Awareness of latest combination therapies (Gliptins).

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Role of Combination Therapy in Type II Diabetes

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  1. Role of Combination Therapy in Type II Diabetes Dr Cleo Cheng Midwest Health Beverley 22.11.2011

  2. Objectives : • Refresh pathophysiology of DM • ↑awareness of at risk groups to screen • Competence in conducting brilliant GPMP–DM • ↑Awareness of latest combination therapies (Gliptins)

  3. Presentation Plan: • Diabetes overview – 10 min • Screening at risk groups – 10min • GPMP – 30min • DM foot assessment– 10min • Medications – 20min • Q & A – 10min

  4. Diabetes in Australia – BIG problem & getting bigger Around 275 Australians develop DM/day For every person diagnosed, there is another not yet diagnosed = 1.7 million DM Total no of Australians with DM & and pre-DM = around 3.2 million Means: 4.0% - Diagnosed (4% missed) 8.0% - DM 15% - Pre DM & DM ↟300% in past 20 years –Obesogenic environment Diabetes Atlas, third edition, International Diabetes Federation, 2007Diabetes and Cardiovascular Disease: Time to Act, International Diabetes Federation, 2001AusDiab Report, 2006The Economic Costs of Obesity, 2006World Health Organisation Diabetes Uni

  5. What is Diabetes?

  6. Diabetes TOO MUCH SUGAR IN THE BLOOD!!... but starving in the face of plenty!! • Insulin :  let glucose into cells • - insufficient • - inefficient • Glucagon :  let glucose out of liver cells • - lost of negative feedback  too much β-cellsof Islet of Langerhans in pancreas  insulin α-cells of Islet of Langerhans in pancreas  glucagon

  7. – + Insulin# (plasma concentration) Glucagon* (plasma concentration) – + Roles of Glucagon and Insulin in Normal Glucose Homeostasis Glucose (plasma concentration) #Insulin secretion is also stimulated by other nutrients, such as amino acids and free fatty acids, and neural input *Glucagon secretion is also influenced by other nutrients, hormones, and neural input.

  8. Type 2 Diabetes Pathophysiology Impaired insulin secretion -Cells produce excess glucagon -Cells produce less insulin Hyperglycaemia Increased HGP Decreased glucose uptake DeFronzo RA. Diabetes 2009; 58:773–95.

  9. Islet-Cell Dysfunction Glucagon (α cell) Pancreas Insulin (β cell) Insulin resistance Glucose uptake Hepatic glucose output Hyperglycaemia Liver Muscle Adipose tissue Physiology in Type 2 Diabetes Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.

  10. Diabetes But there are other forces at work to BSL • Glucocorticoid • Catecholamine • Thyroid hormones • Growth Hormones • Adipose/Fat cells EXERCISE -  BSL

  11. Normal IGT Type 2 diabetes Insulin Resistance and -cell Dysfunction in T2DM Insulin resistance Increased insulinresistance Insulin secretion Hyperinsulinemia, then -cell failure Post-prandial glucose Abnormal glucose tolerance Fasting glucose Hyperglycemia Adapted from Type 2 Diabetes BASICS. International Diabetes Center, Minneapolis, 2000.

  12. Types of Diabetes

  13. Types of Diabetes • Type I – Autoimmune mediated/IDDM • Childhood onset - preschool • Adolescent – puberty • LADA – young adults • Type II – Insulin resistance and relative insufficiency/NIDDM • Adult onset • Most common 85-90% • Gestational – Insulin resistance due to placental hormones • Transient but  NIDDM risk later on • Others–rare <5% • Congenital/CF related/Cushing/Hyperthyroidism/ • Pancreatitis/haemochromatosis/pancreatectomy

  14. Who is susceptible?

  15. At Risk groups - NIDDM • Family history • Obesity/Overweight - BMI >25 (85%) • Over 40+ • Ethnicity: • Aboriginal/TSI/Maori (>18) • Indian (>30) • Chinese (>30) • Vietnamese/Cambodian/Laos/Thai (>30)

  16. How to screen?

  17. AUSDRISK • 10 questions to assess risk of developing NIDDM over next 5 years • Completed by patient +/- help of a doctor/nurse or practice staff • 40–49 +“high score”  eligible: NIDDM risk evaluation (MBS 713)/GP • Tool available in 3formats: • Interactive diabetes risk assessment tool - online risk level calculator • Non-interactive diabetes risk assessment tool • Australian type 2 diabetes risk assessment tool (AUSDRISK) http://www.diabetesaustralia.com.au/en/For-Health-Professionals/Resources/

  18. http://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/di17-diabetes-detection-diagnosis.pdfhttp://www.nhmrc.gov.au/_files_nhmrc/publications/attachments/di17-diabetes-detection-diagnosis.pdf

  19. Diagnosing NIDDM • Fasting BSL • >5.4  ?- do GTT • >7.0   - NIDDM  • Random BSL • >11.1   -NIDDM  ____________________________________________ • HbA1c • >6.4%   -NIDDM 

  20. GPMP -Diabetes

  21. GPMP/TCA : NIDDM • 1. Disease Specific Care • HbA1c/BSL/BP/Lipids/Aspirin • 2. Complications • – Foot care/Eye/Kidney/Sexual Dysfunction • 3. Lifestyle Changes • –Weight/SNAP/Immunisation/Mental Health/Sleep • 4. Medication Review • – Compliance/understanding/ability/?HMR • 5. IDDM • – Driving/Medic alert bracelet/Glucagon Kit

  22. 1. Disease Specific Care • 1. HbA1c % - <6.4/<7.0 / elderly • 2. BSL - Fast 4-6/Post -8 (+2 = Fair ; +4 = Poor) • 3. BP -130/80 (avoid thiazide diuretics/ B – blockers) -Annual ECG • 4. Lipids • TC <4.0; TG<1.5; HDL>1.0; LDL<2.5 (1.8) • 5. Aspirin - CVS risk calculator >15%  (75-100mg/day)

  23. 2. Complications • 1. Nerve Damage/Foot care • Neuropathy • ABCS Foot Assessment** • 2. Eye Damage -Biannual retinal assessment -ophthalmologist/ optometrist • 3. Kidney Damage -Microalbuminuria (<20nmol/L- spot) -Urine Albumin/creatinine ratio (<3.5 –W; <2.5 –M) • 4. Sexual Dysfunction • ED – earliest indicator for microvascular complication

  24. 3. Lifestyle • 1. Weight Management • <90cm –M; <84cm- W • BMI :20-25 • 2. Smoking – Quit/CXR/Spirometry • 3. Nutrition - Understanding of GI/GL- ? Dietician input • 4. Alcohol - M <2 SD; W<1 SD • 5. Physical Activity 30 min/d ; 5/7 - ? Exercise physio • 6. Immunisation - Influenza/pneumococcal/Tetanus • 7. Mental Health - Sleep/depression–DASS/K10- ?psychologist

  25. 4. Medication Review • 1. Compliance – metformin/ exenetide • 2. Understanding of how medication works • 3. Does medication needs changing? - Correlating this with BSL readings/HbA1c% - Time for insulin? • 4. Patient’s ability to manage medication • ? HMR • 5. Adverse reaction/Side effects? - infections? Osteoporosis? Hypo? acidosis? renal /liver function?

  26. 5. IDDM • Driving • Check BSL prior to driving & 1-2 hourly on long trips. • If BGL < 5 do not drive. • Always carry jelly beans & graze on low GI food on long trips • All IDDM needs to notify Registrar of Motor Vehicles of their insulin use • Medic Alert Bracelet • Glucagon Kit • Know how to use as well as educate a close friend or family member

  27. DM Foot Assessment

  28. ABCS Diabetes Foot Assessment A - Anaesthesia B – Blood supply C - Care S - Structure 5 A’s: Ask - Symptoms Assess - Signs Advise - Foot care; foot wear; action plans Assist - Involving other carers Arrange - Regular reviews +/- referrals Traffic Lights: - General foot care advice - Regular podiatry care and assessment - Refer promptly to a podiatrist

  29. NIDDM Medication

  30. Insulin Lifestyle Changes Oral + Insulin + + Oral Combination + Oral Monotherapy Diet and Exercise Standard Approach to Management of T2DM: Treatment Intensification Adapted from Riddle MC. EndocrinolMetabClin North Am. 2005;34:77-98.

  31. Current Drugs Used in T2DM GLP-1 analogues glucagon secretion; insulin secretion; gastric emptying; improve satiety Thiazolidinediones ↓lipolysisin adipose tis, ↑glucose uptake in skeletal mm &↓glucose production in liver Sulfonylureas/Glinides ↑insulin secretion from pancreatic -cells -glucosidase inhibitors Delay intestinal carbohydrate absorption DPP-4 inhibitors Prolong GLP-1 action leading to improved pancreatic islet glucose sensing, ↑glucose uptake Biguanides ↑ glucose uptake; ↓hepatic glucose production

  32. Agents : Lower hypoglycaemic risks • Metformin1  • Alpha-glucosidase inhibitors2  • Thiazolidinediones1,3  • GLP-1 agonists4  • DPP-4 inhibitors5–7  • Insulin  • Sulfonylurea  • Glinides 1. Kahn SE, et al. N Engl J Med. 2006;355:2427–2443;2. Cefalu WT. Nature. 2007;81:636–649;3. Bolen S, et al. Ann Intern Med. 2007;147:386–399;4. DeFronzo RA, et al. Diabetes Care. 2005;28:1092–1100;5. Stonehouse A. Curr Diabetes Rev. 2008;4:101–109; 6. Aschner P, et al. Diabetes Care. 2006;29:2632–2637;7. Rosenstock J, et al. Diabetes Obes Metab 2008;10:376–386

  33. Weight Gain - Common SE of NIDDM Treatments OAD Agents Weight Change (kg) -3.8–0.5 Metformin1–3 -0.4–1.7 SUs1–4 0.9–4.6 TZDs4–6 0.3–3.0 Meglitinides4,7,8 -0.3–1.9 Metformin + SU1–3 0.8–2.1 Metformin + TZD5,6,9 −5 −4 −3 −2 −1 0 1 2 3 4 5 Weight Loss (kg) Weight Neutral Weight gain (kg) OAD=oral antidiabetic agent; SU=sulfonylurea; TZD=thiazolidinedione. 1Glucophage [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004. 2Glucovance [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004. 3Metaglip [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2002. 4Malone M. Ann Pharmacother. 2005; 39: 2046–2055. 5Actos [package insert]. Indianapolis, Ind: Eli Lilly and Company, 2004. 6Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005. 7Starlix [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2004. 8Prandin [package insert]. Princeton, NJ: Novo Nordisk, Inc, 2004. 9Avandamet [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005.

  34. Agents :neutral to positive weight loss • Metformin  • GLP-1 agonists  • DPP-4 inhibitors  • Insulin  • Sulfonylurea  • Glinides • Thiazolidinediones 

  35. Exenetide DPP4-I

  36. 200 150 100 50 0 -30 0 30 60 90 120 150 180 210 Time (min) Oral IV Proof of a GI ‘Incretin Effect’: ΔResponses to Oral vs IV Glucose OGTT and Matched IV Infusion 400 300 Insulin (pmol/L) Glucose (mg/dL) 200 100 0 -30 0 30 60 90 120 150 180 210 Time (min) Adapted from Nauck MA, et al. J ClinEndocrinolMetab. 1986;63:492-8.

  37. Ingestion of food Glucose-dependent Insulin from β cells (GLP-1 and GIP) Glucose uptake by muscles Release of gut hormones — incretins* Pancreas Blood glucose in fasting and postprandial states β cells α cells Active GLP-1 & GIP Glucose production by liver GI tract Glucose-dependent  Glucagon fromα cells (GLP-1) DPP-4 enzyme InactiveGLP-1 InactiveGIP *IncretinGLP-1 & GIP are released by the intestine throughout the day; their levels ↑in response to a meal. Incretins modulate Insulin & Glucagon to ↓BSL during Hyperglycaemia

  38. Inhibition of DPP-4 Increases Active GLP-1 Meal Intestinal GLP-1 release GLP-1 t½=1–2 min ActiveGLP-1 DPP-4 GLP-1 inactive (>80% of pool) DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR.Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126–1131. DPP-4inhibitor 44

  39. Exenatide (Byetta) Exenatide (Exendin-4) • Synthetic version of salivary protein found in the Gila monster • Approximately 50% identity with human GLP-1 • Binds to known human GLP-1 receptors on  cells in vitro • Resistant to DPP-4 inactivation • Injectable S/C – like insulin • BD before meals (10-30min prior) • Cold storage

  40. Exenatide – Authority PBS • In combination (double therapy) with Met or SU where A1c>7% • In combination with Met and SU and A1c>7% (triple therapy) where both Met and SU doses have reached maximum

  41. DPP-4 inhibitors • Sitagliptin – Januvia • Vildagliptin – Galvus • Saxagliptin – Onglyza Combination Therapy: • Galvumet– 50/500; 50/850; 50/1000 • Janumet - 50/500; 50/850; 50/1000

  42. Mechanisms of Action of Currently Available Treatments Pancreatic Islet Dysfunction Insulin Resistance (Impaired insulin action) Inadequate glucagonsuppression (-cell dysfunction) Insufficient Insulin secretion (β-celldysfunction) Progressive decline of β-cell function Metformin TZDs Sulfonylureas Glinides DPP-4 Weight of red arrows reflects the degree to which DPP-4 inhibitors influence the disease mechanisms. DPP-4=dipeptidyl peptidase-4; TZD=thiazolidinedione; T2DM=type 2 diabetes mellitus. Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3(suppl 1): S24–S40.

  43. Gliptins: DPP4-I • Safety & efficacy have not been compared to Insulin • Weight neutral or small loss • Risk of hypos vs SU significantly less • Weight gain and hypos can still occur with SU, may need to reduce SU dose • Long term risk:benefit not known • Not in pregnancy or breast feeding • Not for T1DM

  44. PBS listing information for Gliptins PBS listed Authority Required (STREAMLINED) item (code: 3540) PBS-subsidised treatment is for dual oral combination therapy with Met or SU The listing also allows switching from another Gliptin, GLP-1 or Glitazone Gliptins are not PBS-subsided for monotherapy, triple therapy or in combination with a Glitazone

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