Pharmacotherapy of Type 2 Diabetes

Transcription

1 Pharmacotherapy of Type 2 Diabetes

2 Disclosures I am a member of a Biodel, Lilly, Metavention, NovoNordisk, and VTech Pharma Advisory Boards and have served as a consultant for Merck and Takeda

3 20 Glucose mmol/l 10 U/mL Insulin Nondiabetic Early type-2 Late type Glucagon pg/ml Butler P: Diabetes, Minutes CP

4 Effects of Type 2 Diabetes on Glucose Metabolism Gut Liver Glycogenolysis Brain Glycogen Glycogen Gluconeogenesis FFA FFA Muscle Lactate CO 2 Glycerol Lactate Alanine Glutamine Fat Kidney CP

5 The Ideal Therapy Glucocentric: Normalize preprandial, postprandial, and intraprandial glucose concentrations Holistic: Normalize everything In a manner that is convenient, comfortable, and affordable

6 Premise for Intensive Management of Type 2 Diabetes Appropriate use of agents whose mechanism(s) of action are complimentary and suitable for a given individual is required to achieve optimal glycemic control in people with type 2 diabetes

7 Lifestyle Modification Not only may improve survival, but also Improves insulin secretion and action Lowers glucose concentrations Lowers blood pressure Lowers lipids Improves sleep quality And it makes you feel better

8 Metformin Epidemiologic studies suggest that it decreases both micro- and macrovascular complications One randomized controlled trial (UKPDS) indicates it reduces both microvascular and macrovascular complications in obese people with short duration of diabetes However, in that study, addition of metformin to a sulfonylurea resulted in an increase in mortality in obese individuals

9 How Does Metformin Lower Glucose Concentrations? Effect on HbA1c: -1.0 to -1.5% In rodents, Improves insulin action increases AMPK Antagonizes glucagon Inhibits mitochondrial glycerophoshate dehyrogenease In humans, Lowers fasting insulin Lowers glucose production Decreases gluconeogenesis Increases GLP-1

10 Effects Metformin on Glucose Tolerance Glucose mg/dl Pre-Metformin Post-Metformin Insulin U/mL Time (min) DeFronzo R, JCEM MFMER

11 Sulfonylureas Many retrospective epidemiologic studies suggest use associated with increased CVD and/or mortality Nurses Health Study noted use increased risk of cardiovascular heart disease compared to non-users (mostly metformin alone) However, reduced overall mortality over the long term in the follow up of the UKPDS Implications of selectivity for pancreatic and extrapancreatic channels unclear Long-term effects on beta cell mass and function not known

12 How do Sulfonylureas Lower Glucose Concentrations? Effect on HbA1c: -1.0 to -1.5% Stimulate insulin secretion in a nonglucose dependent manner Increase overall insulin availability but do not restore early postprandial insulin secretion Do not directly alter insulin action Do not directly suppress glucagon

13 Effects of Tolazamide Glucose Tolerance and Insulin Secretin mg/dl Oral glucose Post Tolazamide Pre-Treatment Insulin U/mL Glucose Minutes Firth R et al: Diabetes, MFMER

14 GLP-1 Agonists No long term outcome studies showing reduced micro- or macrovascular events Consistently results in modest weight loss Short term studies indicate GLP-1 agonist may have a favorable effect on endothelial function but no effect on heart failure May increase the risk of pancreatitis. If so, effect appears to be small. Long term effect on cancer (e.g. pancreas, thyroid, colon, and breast) uncertain

15 How do GLP-1 Agonists Lower Glucose Concentrations? Effect on HbA1c: -1.0 to -1.5% Stimulate insulin secretion in a glucose dependent manner Suppresses glucagon Increases satiety May improve hepatic insulin action either directly or via CNS

16 Effects of GLP-1 On Insulin and Glucagon Secretion in Type 2 Diabetes 17.5 Glucose 350 Insulin 25 Glucagon (mmol/l) pmol/l GLP-1 Placebo pmol/l Minutes Minutes Minutes Nauck M, Diabetologia MFMER

17 Question Does inhibition of glucagon reduce postprandial glucose concentrations control?

18 200 Insulin Non-Diabetic Insulin Profile pmol/l 100 Suppressed glucagon Non-suppressed glucagon Diabetic Insulin Profile pmol/l Shah P: AJP, 1999 Minutes

19 Glucagon 200 Non-Diabetic Insulin Profile ng/l Suppressed glucagon Non-suppressed glucagon 200 Diabetic Insulin Profile ng/l 100 Shah P: AJP, Minutes

20 12 Glucose Non-Diabetic Insulin Profile mmol/l mmol/l Diabetic Insulin Profile Suppressed glucagon Non-suppressed glucagon Shah P: AJP, Minutes

21 DPP-4 Inhibitors No long term outcome studies showing reduced micro- or macrovascular events Do not alter weight Do not have an effect on endothelial function May increase the risk of heart failure and pancreatitis May modulate immune function and inflammation

22 How do DPP-4 Inhibitors Lower Glucose Concentrations? Effect on HbA1c: -0.7 to -0.9% Stimulate insulin secretion in a glucose dependent manner Minimal suppression of glucagon Do not alter satiety

23 Effects DPIV Inhibitors on Glucagon Secretion in Type 2 Diabetes mmol/l 18 9 Glucose Insulin Insulin Placebo Vildagliptin pmol/l Glucagon ng/l 55 0 Vella A, Diabetes, Minutes

24 Thiazolindiones May decrease cardiovascular events Increases body fat Increases risk of congested heart failure Decreases bone density and increases risk of fractures May increase risk of bladder cancer

25 How Do Thiazolindiones Lower Glucose Concentrations? Effect on HbA1c: -0.7 to -0.9% Improves hepatic insulin action primarily by increasing insulin induced suppression of gluconeogenesis Effects on extra-hepatic insulin action (at physiologic insulin concentrations) is less clear Increases insulin secretion Does not alter glucagon secretion

26 Effects Three Months of Treatment With Either Pioglitazone or Glipizide on Insulin Secretion Pioglitazone Insulin pmol/min Pre treatment Post treatment Nondiabetic pmol/min Insulin Glipizide Time (min) Basu, A, (unpublished) 2013 MFMER

27 SGLT 2 Inhibitors People with SGLT 2 mutations live normal lives despite extensive glycosuria SGLT 2 present in the kidney and perhaps in alpha cells; SGLT 1 present in many tissues (e.g. intestine, brain) SGLT 2 inhibitors decrease both weight (glycosuria) and blood pressure (volume) May increase risk of falls and CV events particularly in the elderly and/or in the presence of volume depletion May increase glucagon and glucose production

28 How Do SGLT 2 Inhibitors Lower Glucose Concentrations? Effect on HbA1c: -1.0 to -1.2% Lowers glucose by increasing glucose disappearance via a non-insulin dependent process (i.e. glycosuria) Effectiveness decreases as renal function decreases Glucose level achieved and risk of hypoglycemia likely will depend on K m Increases risk of urinary and genital infections Lowers overall mortality in high risk subjects

29 How Do SGLT 2 Inhibitors Lower Glucose Concentrations? Urinary glucose (g/hr) Empagliflozin Baseline Mean plasma glucose Ferrannini E: JCI, MFMER

30 Glycated Hemoglobin Levels Placebo Empagliflozin 10 mg Empagliflozin 25 mg % Week Zinman et al: NEJM, MFMER

31 Pts with event (%) Cardiovascular Outcomes and Death from Any Cause Primary Outcome P=0.04 Placebo Empagliflozin Death from CV Causes P<0.001 Pts with event (%) Death from Any Cause P<0.001 Hospitalization for HF P=0.002 Placebo Empagliflozin Month Month Zinman et al: NEJM, MFMER

32 mm Hg Systolic Blood Pressure Placebo Empagliflozin 10 mg Empagliflozin 25 mg Heart Rate bpm Week 2015 MFMER

33 Do SGLT 2 Inhibitors Alter Insulin or Glucagon Secretion? pmol/l Glucose Baseline Acute dosing Chronic dosing Insulin pmol/l Glucagon pmol/l Time (min) Ferrannini E: JCI, MFMER

34 Insulin Epidemiologic studies suggest use associated with increased mortality Reduced overall mortality over the long term in the follow up of the UKPDS Results in systemic hyperinsulinemia Increases the risk of hypoglycemia

35 Goals for Exogenous Insulin Prandial Increase rate of absorption Decrease intra-individual variability Make relatively hepatic specific Basal Prolong duration of action Decrease intra-individual variability Make relatively hepatic specific

36 New Basal Insulins U-300 glargine Degludec

37 U-100 Glargine 2015 MFMER

38 Insulin Glargine A-Chain Asn Gly Substitution B-Chain Extension Arg Arg CP

39 Concentrations ( IU/mL) Intra-subject Variability With Glargine Subject 2 Subject 14 Subject Hours Subject 3 Subject 18 Subject Hours Scholtz et al: Diabetes 48(suppl 1):A97, 1999 Subject 7 Subject 19 Subject Hours Subject 9 Subject 22 Subject Hours

40 U-300 Glargine (Toujeo)

41 Reduction of Depot Surface Lantus U300 Steinstraesser et al. Diabetes Obes Metab. 2014;16: MFMER slide-40

42 U-300 Insulin Glargine Pharmacodynamic Profile Glucose Infusion Rates mg/kg/min Gla-100 U Gla-300 U Hours T1/2 = hours vs. 13 hours glargine Within subject variability: 34% Becker et al: Diabetes Care 38:637, 2015

43 Outcomes U-300 Glargine Type 1 Diabetes (Edition 4) Comparable HbA1c vs. Glargine U-100 Decreased nocturnal hypoglycemia first 8 weeks; no difference in confirmed, severe, or nocturnal hypoglycemia thereafter Type 2 Diabetes (Edition 1, 2 and 3) Comparable HbA1c vs. Glargine U-100 No difference in confirmed or severe but lower or same nocturnal hypoglycemia

44 Insulin Degludec (Tresiba)

45 Insulin degludec Identical to human insulin except for removal of threonine at B30 S S G I V E Q C C T S I C S L Y Q L E N Y C N A chain S S S S F V N Q H L C G S H L V E A L Y L V C G B chain desb30 Insulin E R G F F Y T P K T Multi-hexamer chains self-assemble to from subcutaneous depot HO Hexadecandioyl Fatty diacid side chain O N H O O N H OH L- -Glu Glutamic acid spacer Hexamers disassemble, releasing monomers which absorbs to the circulation Jonassen et al. Pharm Res 2012;29: MFMER slide-44

46 Insulin Degludec Pharmacodynamic Profile Glucose Infusion Rates mg/kg/min T1/2 = 25 hours Within subject CV: 20% degludec vs 82 % glargine 0.8 U/kg 0.6 U/kg 0.4 U/kg Hours Heise T et aldiabetes, Obesity, Metabolism 14:944, 2012

47 Outcomes Insulin Degludec Type 1 Diabetes (Begin Basal Bolus, Begin Flex) Comparable HbA1c vs. Glargine U-100 Lower or same overall, nocturnal, or severe hypoglycemia Type 2 Diabetes (Begin Long, Asia, Basal Bolus, Flex) Comparable HbA1c vs. Glargine U-100 Lower or same overall, nocturnal, or severe hypoglycemia Variability (Nakamura, Diabetologia 58: ,2015 Lower mean and SD of fasting glucose but no difference in CV

48 The Ideal Prandial Insulin Absorbed sufficiently rapidly to mimic the postprandial pattern of change in insulin concentrations that occur in non-diabetic humans Safe Reproducible Appropriate balance (both biologic and temporal) of effects on the liver and extra-hepatic tissues 2015 MFMER

49 New Prandial Insulins Afrezza (Technosphere Insulin) Faster Aspart 2015 MFMER

50 20 Glucose mmol/l 10 U/mL Insulin Nondiabetic Early type-2 Late type Minutes CP MFMER

51 Afrezza

52 Structure of a Technosphere Particle HO 2 C O H N HN O O NH N H O CO 2 H Potocka et al: J Diabetes Sci Technol 4:1164, MFMER

53 Afrezza Forms microparticles under acidic conditions that can be dried to powder. Dissolves in the presence of neutral or basic conditions Absorbed after inhalation Intravenous dose: 97% cleared by the kidney PO dose: 95% excreted in feces Clearance decreased with renal or liver disease

54 Insulin Concentrations Following Inhalation of Afrezza Compared to Injection of Lispro Insulin 20 units Technosphere 8 units Lispro ulu/ml Minutes FOA: Briefing Document, MFMER

55 Outcomes Afrezza Type 1 and Type 2 Diabetes Inferior or same reduction of HbA1c vs. aspart Lower severe hypoglycemia Lost weight or less weight gain More DKA Two fold higher drop out rate Cough and reversible decrease in FEV 1 FDA Briefing Document; Pittas, A. et al: Lancet Diabetes-Endocrinology 3:886, 2015, Bode, B; Diabetes Care 38:2266,2015

56 Fast Aspart Insulin aspart formulated with nicotinamide (vitamin B3), arginine and zinc Nicotinamide increases the rate of absorption by enhancing rate of disassociation to monomers Arginine improves stability Zinc stabilizes insulin hexamer

57 Insulin Concentrations After Injection of Faster Aspart Versus Aspart Insulin Insulin pmol/l Faster aspart Aspart Minutes Minutes Heise: Diabetes, Obesity and Metabolism 17:682, MFMER

58 Effects of Faster Aspart Versus Aspart on Postprandial Glucose Concentrations Meal Fast aspart Insulin aspart mmol/l Minutes Bode: Diabetes Suppl 1:A253, MFMER

59 Faster Aspart Press release from NovoNordisk announced that compared to insulin aspart, faster aspart resulted in: A significantly greater reduction in HbA1c with no difference in hypoglycemia in people with type 1 diabetes Comparable reduction in HbA1c and comparable rates of hypoglycemia in patients with type 2 diabetes.

60 Faster Aspart Is it fast enough to make a difference in clinical use? Can it be used in insulin pumps and if so, does it lower HbA1c and reduce hypoglycemia Is it safe with repeated injections or long term infusion?

61 How to Successfully Implement Intensive Management of Type 2 Diabetes In order to achieve optimal glycemic control in people with type 2 diabetes: Use agents whose mechanism(s) of action are complimentary That are given at the appropriate time and in an appropriate doses Whose benefits outweigh risks in the individual in whom they are being used

62 Questions & Discussion 2015 MFMER