Presentation on theme: "Dr Cleo Cheng Midwest Health Beverley 22.11.2011."— Presentation transcript:
Dr Cleo Cheng Midwest Health Beverley 22.11.2011
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)
Diabetes overview – 10 min Screening at risk groups – 10min GPMP – 30min DM foot assessment – 10min Medications – 20min Q & A – 10min
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
◦ 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!!
# 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)
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
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
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?
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
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
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
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
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
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
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
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)
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
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
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
Dose 5mg daily Not in renal failure, has to have CrCl>50 No combination with Metformin available yet
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.
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
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