Drug Therapy for Diabetes Mellitus. Adj A/Prof Daniel Chew Dept of Endocrinology 8 th July 2017

Transcription

1 Drug Therapy for Diabetes Mellitus Adj A/Prof Daniel Chew Dept of Endocrinology 8 th July 2017

2 Diabetes Subtypes Optimal Treatment

3 Ominous Octet DeFronzo. DIABETES, VOL. 58, APRIL 2009

4 Schematic Overview of Pathogenesis of Diabetic Complications Physiol Rev 93: , 2013

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6 Cumulative Mortality median of 7.9 years of gain of life Diabetologia online 16 th August 2016

7 Cumulative Incidence of the composite CV or Death Endpoint median of 8.1 years of CV free Diabetologia online 16 th August 2016

8 Summary of studies examining the effect of sulfonylurea (SU) treatment DeFronzo. DIABETES, VOL. 58, APRIL 2009

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10 Elements of Decision Making

11 ADA Guidelines: Antiglycemic Treatment in T2DM American Diabetes Association. Diabetes Care 2017

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14 Other Considerations when deciding on Diabetes Medications Care Setting Outpatient long - term considerations Inpatient acute illness - sepsis, AoCKD, NBM Peri-operative DM in pregnancy

15 Insulin Hexamer ZINC Monomer Monomer

16 Types of Insulin Basal Supplements Premeal Bolus rdna Human insulin NPH Humulin N or Insulatard OR Insulin Analogs Glargine + (Lantus) Determir * (Levemir) + Shifted Isoelectric point rdna Human insulin Regular Humulin R or Actrapid OR Insulin Analogs Lispro (Humalog) Aspart (Novorapid) Glulisine (Apidra) * Binding to Albumin Non-Hexameric insulin analogs

17 Serum Insulin levels To Replicate Physiological Insulin Secretion Hormonal Nadir Dawn Phenomenon 6u 6u 6u Basal Secretion (Approx 1 unit/hr = 24 units/day) BF Lunch Dinner 10pm 4am * 70kg with minimal insulin resistance

18 Treating fasting hyperglycaemia lowers the entire 24-hour plasma glucose profile Plasma glucose (mg/dl) Meal Meal Meal Time of day (hours) Nocte NPH or LA Basal Analogue T2DM Hyperglycaemia due to an increase in fasting glucose Normal Plasma glucose (mmol/l) Comparison of 24-hour glucose levels in control subjects vs patients with diabetes (p<0.001). Adapted from Hirsch I, et al. Clin Diabetes 2005;23:78 86.

19 Insulin Requiring Diabetes Marked hyperglycemia Rapid onset of severe symptoms Significant weight loss Ketoacidosis Type 1 or Type 2 with severe concurrent illness or glucotoxicity < 30 years of age at presentation Lean (No metabolic syndrome/acanthosis nigricans) To exclude Type 1 Diabetes Mellitus Immune markers Eg Anti-GAD, Islet cell Ab Low C-peptide reserves 19

20 Metformin Important insulin sensitiser Recommended doses mg/day Renal Clearance Unmetabolised Contraindicated Renal ( Creat 150umol/L, <30ml/min* ) Hepatic, Cardiac failure, Alcohol abuse Sepsis and hypoperfusion Cautious use in elderly, anorexic GI Intolerance Interferes with Vitamin B12 absorption *Diabet Med 24: , 2007

21 Biologic Effect of Primary Drug Hepatic Metabolism? Or Renal Excretion? Active Metabolites?

22 Incretins GLP-1 Receptor Agonists S/C Exenatide BD S/C Liraglutide OM (97%homology+FA) Dipeptidyl peptidase IV (DPP-IV) Inhibitors Sitagliptin Vildagliptin Saxagliptin Linagliptin, etc

23 Benefits of Incretins Effectively reduces HbA1c Reduced food intake and weight loss (With incretin analogues) Glucose-dependent insulinotropic effect Glucose-dependent inhibition of elevated plasma glucagon levels

24 PANCREATIC BETA CELL GLP-1R GIPR ATP/ADP Modified, Diabetes 51 (Suppl. 1):S19 S24, 2002

25 Basal insulin added to GLP-1 receptor agonist: LIRA-DETEMIR study design Open-label randomisation (1:1) Continue MET + liraglutide 1.8 mg (Control group) Main study n=161; extension n=122 Addition of insulin detemir to MET + liraglutide Main study n=162; extension n=140 Patients with suboptimal control on MET SU Addition of liraglutide 1.8 mg to MET HbA 1c 7% 39% Main study 26 weeks Extension 26 weeks 12-week run-in phase HbA 1c <7% 61% Continue MET + liraglutide 1.8 mg (Observational group) Main study n=498; extension n=461 MET, metformin; SU, sulphonylurea DeVries JH et al. Diabetes Care 2012;35:

26 HbA 1c (%) Addition of insulin detemir to liraglutide: Change in HbA 1c (%) Run-in phase Randomised phase (Weeks 0 to 52) 8.5 Time (weeks) p< Liraglutide 1.8 mg Liraglutide 1.8 mg + IDet Observational liraglutide 1.8 mg Mean (2SE); data are LOCF Last observation before intensification is included as LOCF in the initial treatment group; ANCOVA on FAS LOCF for difference in randomised phase ANCOVA, analysis of covariance; FAS, full analysis set; HbA 1c, glycosylated haemoglobin; IDet, insulin detemir; LOCF, last observation carried forward; SE, standard error Rosenstock J et al. J Diabetes Complications 2013;27:

27 What is the Relation? Phlorizin Apple Tree Proximal Tubule Epithelial Cell

28 Comparing SGLT2 - Inhibitors

29 SGLT2 Inhibitors: gliflozin Works independently of insulin Inhibiting the SGLT2 glucose transporter found in proximal tubule of nephron, responsible for glucose reabsorption Dose-dependant renal glycosuria, lowering both plasma glucose levels and insulinemia Reductions in HbA1c 0.7% Reductions in Total Body Weight 2 to3 %

30 SGLT2 Inhibitors: gliflozin Reduced CVD events and mortality Greater risk of amputation: toe or metatarsal (Canagliflozin)* Risk volume depletion and hypotension: Caution with severe hyperglycemia, concurrent diuretics, acute illness Normoglycemic DKA: Concurrent illness, stress/counter regulatory hormones *DOI: /NEJMoa

31 Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors Keep high index of suspicion: Check ph, Serum Bicarbonate and serum BHB Ogawa and Sakaguchi Doi: /jdi.12401

32 Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes N Engl J Med 2016;375:323-34

33 Case Study 1 Mr T 75 year old Chinese Male Strong family history of T2DM T2DM since 50years old Hypertension Ex-smoker PO Glipizide 15mg BD PO Metformin 850mg BD HbA1c 7.5%, Creatinine 80 umol/l Urine microalbumin +ve, Early DM retinopathy

34 HbA1c above target range * Check for: A. Episodes of hypoglycaemia B. Compliance to anti-diabetic medications (including extent of non compliance) C. Compliance to medical nutrition therapy (including extent of non compliance) D. Weight trend - Weight gain due to hypoglycaemia and hunger. Reductions in the dose of SU and insulin may in fact paradoxically improve the glucose control. - Weight loss (>5-10% of body weight) and a high HbA1c (>9%) are likely insulinopenic and should be started on insulin E. Presence of other medications or medical conditions that can change blood glucose control (e.g. glucocorticoids, inter-current infection, cancer). F. Intensify or alter non-pharmacological therapy (i.e. nutrition therapy, exercise, pharmacotherapy) based on cause(s) identified. G. Start and/or optimize dose of pharmacological therapy *When interpreting the HbA1c, the following should be taken into account: (A) Conditions that may falsely elevate or lower HbA1c (e.g. blood loss, recent blood transfusion or haemoglobinopathies). (B) The HbA1c may not fully reflect blood glucose levels for changes that have taken place less than 3 months before the HbA1c.

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36 Case Study 1 Decreased PO Glipizide 5mg BD Maintained PO Metformin 850mg BD Regular meal times + Light Supper HbA1c 6.7% - 6.8% No hypoglycemia symptoms or documented KIV switch the sulphonylurea to a DPP4 inhibitor

37 HbA1c at or below target range 1 Check for: (A) Episodes of hypoglycaemia (B) Compliance to anti-diabetic medications (including extent of non compliance) (C) Weight trend 2 - Weight gain due to hypoglycaemia and hunger. Reductions in the dose of SU and insulin may in fact paradoxically improve the glucose control. Consider deescalating insulin or SU (or other OHGAs) if any of the following are present: 1. Episodes of hypoglycaemia 2. HbA1c is at target despite significant non-compliance to medications 3. HbA1c is below target range *When interpreting the HbA1c, the following should be taken into account: (A) Conditions that may falsely elevate or lower HbA1c (e.g. blood loss, recent blood transfusion or haemoglobinopathies). (B) The HbA1c may not fully reflect blood glucose levels for changes that have taken place less than 3 months before the HbA1c.

38 Case Study2 : 54 year old Male T2DM for 10 years Strong family history of DM & IHD, BMI 30.1 kg/m2 Fasting Glucose 9.8 mmol/l, HbA1c % PO Glipizide 5mg BD PO Sitagliptin/Metformin 50mg/1000mg BD PO Acarbose 50mg TDS egfr > 60, Urine ACR +ve, No macrovascular Cx. Diet and Exercise as best as can be No hypoglycemia 1. Add an SGLT2 Inhibitor 2. Initiate Basal Insulin Stop Acarbose 3. Initiate Basal Insulin KIV add SGLT2 Inhibitor or GLP-1 agonist 4. Initiate Basal Bolus 38

39 Summary Establish Glycaemic Targets Individualise Treatment Use Metformin as the cornerstone of diabetes treatment in T2DM Consider degree of hyperglycemia, risk of hypoglycemia, renal function and other comorbidities in the selection of Rx Timely Insulinisation

40 Summary SGLT2 Inhibitors for patients at risk of hypoglycemia, cardiovascular and renal benefits but increased risk of genitourinary infections and normoglycemic DKA - synergise well with insulin treatment New formulations of long acting basal analogue insulin eg Glargine 300 Units/ml, Insulin Degludec GLP1 Agonists and Long Acting Basal Insulin combinations

41 Ideal Diabetic Medication Effective in lowering glucose No or Low risk of hypoglycemia Positive extraglycemic effects Weight Lipid profile Blood Pressure Safe, Tolerable, Ease of use Low Cost / Expense Ability to maintain glucose levels close to non-diabetic range Surrogate Markers HbA1c Lipids Reduce long term microvascular and macrovascular complications - Endpoints

42 Useful References AACE/ACE Comprehensive Diabetes Manangement Algorithm 2015: ENDOCRINE PRACTICE Vol 21 No. 4 April 2015 ADA/EASD Standards of Care Oral Glucose-lowering Agents in Type 2 Diabetes Mellitus An update Appropriate Care Guide: MOH & ACE Published 3 rd July 2017

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