1. Dr Cleo Cheng Midwest Health Beverley 22.11.2011

2. 1. Refresh pathophysiology of DM 2. ↑awareness of at risk groups to screen 3. Competence in conducting brilliant GPMP–DM 4. ↑Awareness of latest combination therapies (Gliptins)

3.  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, 2007 Diabetes and Cardiovascular Disease: Time to Act, International Diabetes Federation, 2001 AusDiab Report, 2006 The Economic Costs of Obesity, 2006 World Health Organisation Diabetes Uni

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

7. # 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. + Glucagon* (plasma concentration) – – Insulin # (plasma concentration) + Glucose (plasma concentration)

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

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

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

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

13.  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

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

18. 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) /GPNIDDM risk evaluation (MBS 713) Tool available in 3formats: Interactive diabetes risk assessment toolInteractive 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/

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

21.  Fasting BSL ◦ >5.4  ? - do GTT ◦ >7.0   - NIDDM   Random BSL o >11.1   - NIDDM  ____________________________________________  HbA1c o >6.4%   - NIDDM 

23.  1. Disease Specific Care  Hb A1c/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

26.  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 1.0; LDL<2.5 (1.8)  5. Aspirin - CVS risk calculator >15%   (75-100mg/day)

27.  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

28.  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

29.  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?

30.  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

32. Traffic Lights: - General foot care advice - Regular podiatry care and assessment - Refer promptly to a podiatrist 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

34. Lifestyle Changes Adapted from Riddle MC. Endocrinol Metab Clin North Am. 2005;34:77-98. Diet and Exercise Oral Monotherapy Oral Combination + Oral + Insulin ++ Insulin

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

36. Metformin 1  Alpha-glucosidase inhibitors 2  Thiazolidinediones 1,3  GLP-1 agonists 4  DPP-4 inhibitors 5–7  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

37. TZDs 4–6 Metformin + TZD 5,6,9 Metformin + SU 1–3 Meglitinides 4,7,8 SUs 1–4 Metformin 1–3 Weight Change (kg)OAD Agents OAD=oral antidiabetic agent; SU=sulfonylurea; TZD=thiazolidinedione. 1 Glucophage [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004. 2 Glucovance [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2004. 3 Metaglip [package insert]. Princeton, NJ: Bristol-Meyers Squibb Company, 2002. 4 Malone M. Ann Pharmacother. 2005; 39: 2046–2055. 5 Actos [package insert]. Indianapolis, Ind: Eli Lilly and Company, 2004. 6 Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005. 7 Starlix [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2004. 8 Prandin [package insert]. Princeton, NJ: Novo Nordisk, Inc, 2004. 9 Avandamet [package insert]. Research Triangle Park, NC: GlaxoSmithKline, 2005. Weight Gain - Common SE of NIDDM Treatments −5−4−3−2−1012345 -3.8–0.5 -0.4–1.7 0.9–4.6 0.3–3.0 -0.3–1.9 0.8–2.1 Weight Neutral Weight Loss (kg) Weight gain (kg)

38. Metformin  GLP-1 agonists  DPP-4 inhibitors  Insulin  Sulfonylurea  Glinides  Thiazolidinediones 

40. Exenetide DPP4-I

42. Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63:492-8. OGTT and Matched IV Infusion Glucose (mg/dL) 0 50 100 150 200 -300306090120150180210 Time (min) Insulin (pmol/L) 0 100 200 300 400 -300306090120150180210 Time (min) OralIV

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

44. Inhibition of DPP-4 Increases Active GLP-1 GLP-1 inactive (>80% of pool) Active GLP-1 Meal DPP-4 Intestinal GLP-1 release GLP-1 t ½ =1–2 min DPP-4 inhibitor 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. 44

45. 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

46.  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

47. 1. Sitagliptin – Januvia 2. Vildagliptin – Galvus 3. Saxagliptin – Onglyza Combination Therapy: ◦ Galvumet – 50/500; 50/850; 50/1000 ◦ Janumet - 50/500; 50/850; 50/1000

48. Mechanisms of Action of Currently Available Treatments 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. Sulfonylureas Glinides TZDsMetformin DPP-4 Pancreatic Islet Dysfunction Inadequate glucagon suppression (  -cell dysfunction) Progressive decline of β- cell function Insufficient Insulin secretion (β-cell dysfunction) Insulin Resistance (Impaired insulin action)

49.  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

50. 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

51.  Usual dose 100mg daily; BD in combination with Metformin  Reduce dose in moderate-severe CRF ◦ CrCl 30-50 = 50mg daily ◦ CrCl <30 = 25mg daily  URTI, Nasopharyngitis  Rare anaphylaxis, angioedema, rash, urticaria, exfoliative skin conditions, pancreatitis

52.  50mg bd with Metformin, 50mg daily with SU  Single pill combination to improve compliance  Use only if GFR>60  Not for patients with hepatic impairment, ALT/AST >2x  Incidence of skin reactions and pancreatitis rare  No Cyp450 interactions

53.  Dose 5mg daily  Not in renal failure, has to have CrCl>50  No combination with Metformin available yet

54. Dosing HbA1c (%) Difference from placebo + metformin adjusted mean CV safety data Januvia 1 (sitagliptin) 100 mg once daily -0.65 * Mean baseline 7.96% - Galvus 2 (vildagliptin) 50 mg once or twice daily - 0.7** (once daily dosing) -1.1** (twice daily dosing) Mean baseline 8.4% - Onglyza 3 (saxagliptin) 5 mg once daily -0.8*** Mean baseline 8.1% Not associated with an increased risk of CV events in a pooled retrospective analysis of the Phase 2b/3 clinical program 4 *p < 0.001 vs placebo + metformin **p < 0.05 vs placebo + metformin ***p < 0.0001 vs placebo + metformin 1. Januvia Approved Product Information. 2. Galvus Approved Product Information. 3. Onglyza Approved Product Information 4. Frederich R et al. Postgrad Med. 2010122:16–27.

55.  Januvia (Sitagliptin) ◦ URTI** ◦ Nasopharyngitis** ◦ Headache (uncommon)  Galvus (Vildagliptin) ◦ Dizziness (uncommon) ◦ Tremor (uncommon) ◦ Headache (uncommon)

56.  DPP-4 and GLP-1 based therapies offer a novel new way to manage T2DM  Actions are beneficial physiologically  S/E are relatively minor  They are effective, but long term safety and benefits not yet available  Used early in T2DM most useful  Single pill combo with Metformin useful

58. Ok, you can go home now!!!....