Recent advances in the management of Diabetes Mellitus

diabetes mellitus in detail

1. RECENT ADVANCES IN MANAGEMENT OF DIABETES MELLITUS Dr.Shaila Banu Final year Post Graduate Dpt of Pharmacology GMC , ATP

2. Learning Objectives Define Diabetes mellitus Enumerate Goals Outline Therapy available for Type 1 & Type 2 Compare & contrast conventional insulins & newer analogues Classify Oral antidiabetic drugs

3. DIABETES M ELLITUS Syndrome : metabolic, vascular and neuropathic components – interrelated Metabolic disorder: hyperglycemia (fasting plasma glucose >126 mg/dl and/or >200 mg/dl 2 hours after 75 g of oral glucose) due to defects in insulin secretion , insulin action or both Coronary artery disease = diabetes Metabolic syndrome: Type 2 Diabetes Mellitus, Central obesity, Hypertension, Hyperlipidemia [hypertriglyceridemia , reduced HDL]

4. Histo r y Diabetes : syphon (to pass through) Appolonius of Memphis. “Pissing evil”(17 th century) Mellitus: Honeyed Thomas wills

5. TY P ES TYPE I : Absolute insulin deficiency / Autoimmune disease TYPE 2 : Insulin resistance , inadequate insulin secretory response TYPE 3 : β cell, insulin action , exocrine pancreas, drugs, infection GE S T A T IONAL DIAB ETE S

6. Therapy of diabetes : Comprehensive Diabetic care the symptoms related to hyperglycemia (fatigue, polyuria, weight loss) To prevent or reduce the acute metabolic decompensation and chronic end-organ complications. Com ponents of Comprehensive Diabetic Care Management of diabetes Gl y cemic control Diet /life style exercise /drugs Treat associated conditions Dyslipidemia Hypertension Obesity Screen for / mana g e com plications Retinopathy Neuropathy N e ph r opathy CVS Disease Others

7. Treatment Goals INDEX GOAL 1. Hb A1C < 7.0 % 2. Pre-prandial plasma glucose 90–130 mg/dL 3. Peak post prandial plasma glucose <180 mg/dL 4. Blood pressure <130/80 mm of hg 5. LDL-C <100 mg/dL 6. HDL-C >40 mg/dL 7. Triglycerides <150 mg/dL ● ● ● To maintain normoglycemia to normalize Hb A1c To prevent complications To improve QOL

8. Modalities of treatment

9. Insulin No single event in the history of medicine has changed the lives of so many people ,so suddenly – Stephen Hume

10. Insulin Evolution of insulin : Exogenous insulin available for more than 90 yrs Top medical breakthroughs Most powerful diabetic agent Limited only by hypoglycemia

11. Clinical use Meal time insulin: rapid & short acting Basal insulin : IA& LA Based on s p ecies of ori g in Human Por ci ne Bovine Classify ??

12. TIME COURSE OF ACTION ONSET PEAK DOA REGULAR 30-45 m 2 -4 h 5-8 h LISPRO 15 m 1-1.5 h 2-5 h ASPART 15 m 1 h 3-5 h GLULISINE 15 m 1-1.5 h 1-2 h NPH 1- 2 h 6-12 h 18-24 h ULTRALENTE 4 -6 h 16-18 h 20-36 h GLARGINE 2 -5 h FLAT 18- 24 DETEMIR 1- 2 h FLAT 6-24

13. Traditional Insulin preparations Short Acting : Insulin Regular Intermediate Acting : Isophane Insulin Suspension ( NPH) , Insulin Zinc Suspension ( Lente) Slow Acting : Extended Insulin Zinc Suspension ( Ultralente)

14. Ideal insulin Should match the physiological insulin secretion 50% in basal conditions Remainder in response to meals Secretion : Pulsatile Biphasic Acute insulin res ponse : rapid 1st phase 5-10 mins / suppress HGO /

15. Traditional insulins Traditional insulins : Solutions of regular insulin, dissolved in a buffer at neutral pH Forms a hexamer when stored in the presence of Zn ions ( self aggregation ) S/C Injection : dissociate into dimers & then into monomers / time : 30 - 45 mins

16. Limitations of re g ular insulins Regular insulin : Delayed onset [1/2 hr -1 hr ] POST PRANDIAL HYPERGLYCEMIA Peak : 2-3 hrs Duaration of action : 5-8 hrs HYPOGLYCEMIA LATE POST PRANDIAL has to be administered 30-45 mins before meals : dose cannot be adjusted according to size of meals Absorption varies with injection site and exercise

17. I nsulin analogs Rapid acting Lispro Aspart Glulisine Long acting Glargine Detemir Ultra long acting Degludec Inhaled insulin Afrezza Insulin combinations Mixture : short acting (25%–50%) and long acting (50%–75%)

18. Designer insulins Modified recombinant insulins Regular insulin : altered through an amino acid / substitution / addition / deletion Rearrangement impart a particular physicochemical /PK property Proline and lysine at b 28 and b 29

19. Rapid acting analogues Rapid onset : 5 - 15 mins – better postprandial control PEAK : 1-2 hrs, DURATION : 4-5 hrs - decreased risk of late postprandial hypoglycemia Mimics physiology : less propensity to cause hexamers , Dissociate rapidly / associate with less cohesive force - Physical & chemical stability - faster absorption .

20. MODIFIED LONG ACTING ANALOGUES Substitution of Glycine for Asparagine at A 21 / Provides Stability + 2 Arginines at B Chain Addition of Fatty Acid to the Amino Group Of Lys B 29 / Myristoylated Insulin

21. DETE M IR New long-acting insulin analogue threonine in B30 replaced by Myrsitic acid Addition of C-14 fatty acid chain to the amino group of LYS B 29 / Myristoylated insulin Increase self aggregation in SC tissue & reversible binding to albumin Detemir : has the Most reproducible effect of the IA & LA insulins

22. GLARGINE pH 4.0 SC Tissue pH 7.4 MICRO-PRECIPITATION MAY CAUSE VARIABILITY IN ABSORPTION, HENCE, IN ACTION DETEMIR PH 7.4 SC Tissue pH 7.4 Binding to Albumin No Precipitation MORE PREDICTABLE IN ABSORPTION, HENCE IN ACTIO N MECHANISM

23. Insulin D e g l ud e c Newe st U L TRA long a c t i ng basal insulin, Modified insulin with one amino acid deleted (threonine at position B30 ) and is conjugated to hexadecanedioic acid via γ-l-glutamyl spacer at the amino acid lysine at position B29. Active at a physiologic pH, forms multihexamers complexes that slow absorption on subcutaneous injection ; Also binds well to albumin These two characteristics contribute to the prolonged effect of degludec (>24 h at steady state). T 1 ⁄ 2- (25-40 hr) /100U & 200U/ML [PEN] Unlike Glargine it is effective at physiological pH less severe hypoglycemia than glargine. Unlike Glargine & Detemir, it can be mixed with other insulins

24. Glargine, Degludec, and Detemir have minimal peak activity at steady- state A major concern about all newer insulin analogues is their altered mitogenic properties and resultant risk of carcinogenicity on long term use.

25. Inhaled insulin Recently introduced Afrezza Meal time insulin FDA approval in both type 1 and type 2 diabetes [ Add on therapy for uncontrolled type 2]. Monomeric formulation Decreases the risk of hypoglycemia and weight gain Kinetics similar to ultra short acting insulins / Alternative to ultra SA insulins [ More rapid onset and shorter duration than injected insulin analogues ] / Used in combination with a long-acting insulin in type 1 DM. It is not widely used / Expensive Adverse events include cough and throat irritation . Not to be used in individuals who smoke rs , Asthma ,COPD .

26. INHALED INSULINS

27. New for Type 1 DM Faster acting aspart [Fiasp] has added

28. Or al i nsu li n [ Orame d ’ s] i s c urr e n tl y i n a p i vo ta l cli n ica l s t udy go i ng through FDA regulatory channels and is considered a game-changer . An orally ingestible insulin capsule ( ORMD-0801 ). [Protein oral delivery technology (POD) ].

29. New for Type 1 DM Otelixizumab Teplizumab Intravenous humanised

30. Nasal spray Patches Artificial pancreas Transplant beta cells Personalised medicine [grouping of diseases, targeted therapy , developments in genetics and big data ]

31. INSULIN PATCH

32. TRANSPLAT BETA CELLS

33. Mixtures : 70 % NPH 50% NPH , , 30% REG 50% REG Lispro 75% Lispro Protamine , 25%

34. Non-Insulin Antidiabetic Drugs

35. ORAL : 1. Insulin secretagogues :

36. K ATP Channel Modulators: Sulfonylureas 1. Tolbutamide, Tolazamide, And Chlorpropamide : Rarely Used Now 2.Glipenclamide,Glipizide,Gliclazide,Glimepiride are used now

37. KATP Channel Modulators: Nonsulfonylureas Repaglinide. Oral insulin secretagogue of the Meglitinide class, stimulates insulin release by closing KATP channels Metabolized by the liver (CYP3A4) to inactive derivatives, ~10% is metabolized by the kidney Hypoglycemia , weight gain Nateglinide : orally effective insulin secretagogue, block KATP channels Rapid but less-sustained secretion of insulin Effective in reducing postprandial glycemic elevations in patients with type 2 diabetes. It is metabolized primarily by hepatic CYPs ( 2C9, 70%; 3A4, 30% ) and should be used cautiously in patients with hepatic insufficiency. Hypoglycaemia , weight gain

38. Thiazolidinediones Ligands for the PPAR γ receptor : Rosiglitazone And Pioglitazone MOA : Activate PPAR γ receptors- adipocyte differentiation, increased tissue sensitivity to insulin [ liver, adipose tissue, and skeletal muscle] Pioglitazone reduces plasma triglycerides by 10%–15%, raises HDL cholesterol levels , and increases LDL cholesterol. ADR: Weight gain and Edema Increased incidence of heart failure of up to 2-fold [plasma volume expansion] Rosiglitazone increased the risk of cardiovascular events (myocardial infarction, stroke). FDA has lifted the previous ban Increased risk of bone fracture in women Affect transaminases , liver function monitored

39. GL P -1–Bas e d Agents Incretins [ GI hormones released after meals and stimulate insulin secretion

40. Liraglutide The liraglutide peptide is a long-acting, DPP-4-resistant form of GLP- 1, but with a Lys34Arg substitution and addition of an α-glutamic acid spacer coupled to a C16 fatty acyl group at Lys26. . The pharmacodynamic profile of liraglutide mimics GLP-1 and exenatide. Improvement in glycemic control and weight loss Adjunctive therapy in patients not achieving glycemic control with

41. Albiglutid e : Fusion prot ein , two sequential GLP-1 moieties linked to human albumin ; The GLP-1 sequences are modified to prevent DPP-4 cleavage. Dulaglutide : Fusion protein consisting of two linked molecules that have a modified version of GLP-1 linked to the fc portion of a human immunoglobulin ; Lixisenatide : A slightly longer form of exenatide GLP-1RA s : Pharmacodynamics are comparable to each other & can be used with other oral antidiabetic agents and basal insulin. While all of the GLP-1RAS have demonstrated efficacy as monotherapy, none is considered as a first- line agent . The differences in efficacy are small relative to the overall effect of the drugs, and definitive differences await more comprehensive studies.

42. Adverse Effects : Nausea and vomiting [neural activation of specific CNS neurons]. GI side effects. Hypoglycemia associated with GLP-1 agonist treatment is rare, but the combination of GLP-1 agonist with sulfonylurea drugs causes an increased rate of hypoglycemia compared to sulfonylurea treatment alone. Because of the reliance on renal clearance , exenatide, and probably lixisenatide, should not be given to persons with moderate-to-severe renal failure (creatinine clearance < 30 mL/min). possible association of exenatide treatment with pancreatitis; The GLP-1 receptor is expressed by thyroid C cells. Although there is not an established clinical association with medullary carcinoma of the thyroid, GLP-1 agonists should not be given to these patients.

43. DPP-4 Inh i b i to r s Dipeptidyl peptidase IV : serine protease . inactivation of GLP-1 and GIP. Sitagliptin, Saxagliptin, Linagliptin, alogliptin & Vildagliptin

44. Mechanism of Action: Alogliptin, linagliptin, and sitagliptin are competitive inhibitors of DPP-4; vildagliptin and saxagliptin bind the enzyme covalently. 2-fold elevation of active GIP and GLP-1 and is associated with increased insulin secretion , reduced glucagon levels, and improvements in both fasting and postprandial hyperglycemia. No d i r ec t e ff ec ts on i nsu li n s e ns i t i v i ty , g a s t r i c m o tilit y , or s atiety& No effect body weight. DPP-4 inhibitors, used as monotherapy in type 2 diabetic patients, reduce

45. SGLT2 is a Na+-glucose cotransporter : proximal portion of the renal tubule. SGLT 2 is a high-affinity, low- capacity transporter that moves glucose against a concentration gradient from the tubular lumen using energy generated from Na+ flux through the epithelial cells. Renal retention of glucose is nearly complete in nondiabetic persons, Na+Glucose Transporter 2 Inhibitors

46. Pramlintide A Synthetic form of amylin with several amino acid modifications to improve bioavailability acts through the amylin receptor in specific regions of the hindbrain. Activation of the amylin receptor reduces glucagon secretion, delays gastric emptying, and fosters a feeling of satiety. Subcutaneous injection prior to meals. Adverse Effects: nausea and hypoglycemia. Prandial insulin doses be reduced 30%–50% at the time of pramlintide initiation and then retitrated. Contraindicated in patients with gastroparesis or other disorders of motility. Pramlintide is a pregnancy category C drug. Therapeutic Uses: Pramlintide is approved for treatment of Type 1 and 2 diabetes as an adjunct in patients who take insulin with meals.

47. Bile Acid–Binding Resins Colesevelam : Approved for the treatment of type 2 diabetes . Mechanism of Action. Bile acid metabolism is abnormal in patients with type 2 diabetes . Reduce intestinal glucose absorption, also act as signaling molecules through nuclear receptors, some of which may act as glucose sensors. Colesevelam is provided as a powder for oral solution and as 625-mg tablets; dyspepsia, abdominal pain, and nausea affecting up to 10% of treated patients. increase plasma triglycerides Pregnancy category B drug & has no contraindications in patients with renal or liver disease. Therapeutic Uses. T reatment of hypercholesterolemia and may be used for treatment of type 2 diabetes as an adjunct to diet and exercise. In clinical trials, colesevelam reduced A1c by 0.5% when added to metformin, sulfonylurea, or insulin treatment in type 2 diabetic patients.

48. B r omo cri pt i ne Approved for the treatment of type 2 diabetes Bromocriptine is an established treatment of parkinson disease and hyperprolactinemia Effects on blood glucose are modest and may reflect an action in the CNS. The dose range for bromocriptine is 1.6 to 4.8 mg, taken with food in the morning within 3 h of awakening. Side effects include nausea, fatigue, dizziness,

49. COMBINATION ANTIDIABETICS 1. Thiazolidinedione + Biguanide DPP-4 inhibitors + Biguanide SGLT2 inhibitor + Biguanide DPP-4 inhibitor + SGLT2 inhibitor GLP-1 agonist + Degludec insulin GLP-1 agonist + Glargine insulin 2. 3. 4. 5. 6.

50. Dual PPAR agonists: Current Status Saroglitazar Only drug approved till date for Diabetic dyslipidaemia Indigenously developed NCE by any Indian company Approved for use in India by the DCGI in 2013 Phase II trials for NASH [Non alcoholic steatohepatitis] in US ( june,2016) Diabetic dyslipidemia and hypertriglyceridemia in T2DM not controlled by statin therapy

51. O T H ERS Muraglitazar Meta-analysis of the phase 2 and 3 clinical trials revealed that it was associated with a greater incidence of MI, stroke, TIA and CHF when compared to placebo or pioglitazone Aleglitazar : Abandoned due to CAD Tesaglitazar: no longer studied, discontinued: renal toxicity

52. Newer potential targets in DM

53. IRTK (Insulin receptor tyrosine kinase and insulin mimetics

54. New potential targets of carbohydrate metabolism

55. New potential targets of lipid metabolism

56. New drugs for complications & vaccines Arxxant (also known as ruboxistaurin) has been submitted to the FDA (Food and Drug Administration) for approval in treating diabetic eye disease . Failed Diabetes vaccines Recombinant Human Glutamic Acid Decarboxylase-65 (rhGAD65) Phase 3 , Antibodies against GAD - 80–90% type 1 DM To slow or prevent autoimmune destruction of pancreatic islet cells amongst recent-onset type 1 diabetes mellitus ,subcutaneously - disappointing results. In 2013, a new trial in combination with vitamin D and the anti-inflammatory drug Ibuprofen

57. Emerging Therapies for Diabetes : what does our Goodman.G say ? Immunomodulatory approaches : To prevent or block the autoimmune process central to type 1 diabetes, Activators of GK, glucagon antagonists, and inhibitors of 11β-hydroxysteroid dehydrogenase [inactive cortisone to active cortisol] are being investigated as novel therapies for type 2 diabetes Advances in protein chemistry have allowed the development of peptides that activate more than one receptor to improve glucose regulation. Most of these incorporate GLP-1 receptor agonism with the capacity to activate receptors for glucagon, GIP, or gastrin. These compounds have been potent in pre-clinical models and are now in human trials . Some drugs developed for type 2 diabetes are being tested as adjunctive therapy for type 1 diabetes

58. Insulin Pumps : CSII Dexcom G5 Mobile Continuous Glucose Monitoring Syst em, Approved December 20, 2016 [Sensor, transmitter , compatible smart phone,or a smart watch ] FreeStyle Libre Flash Glucose Monitoring System , Approved September 27, 2017 [sensor plus mobile reader ] InPen syst e m[ sma r t i nsu li n p e n] : FDA a pprov e d i n 2017 for a pp l e i OS and for android version in 2018 , is the first reusable insulin injector pen Newer Insulin delivery systems & glucose monitors

59. Insulin & Pregnancy category [ Not used after 2015 ] INSULIN P RE G NANCY CATEGORY Regular B[U-100,500] LOW RISK Aspart B LOW RISK Lispro B [U- 100,200] LOW RISK Glulisine C NO HUMAN DATA NPH B LOW RISK Glargine NO HU M AN D AT A [P r e v C] NO WELL CONTROLLED CLINICAL STUDIES Detemir B LOW RISK Degludec C [U-100 ,200] NO HUMAN DATA Inhaled insulin C NO HUMAN DATA

60. To summarise Diabetes is a metabolic disorder Discovery of insulin : major breakthrough Progressed from animal insulins to recombinant insulins - insulin analogs - inhaled insulins Not far off from oral insulins & regrowth of beta cells In Type 2 Insulin secretagogues , sensitizers ,newer GLP 1 analogs ,DPP 4 INHIBITORS , SGLT 1 inhibitors, pramlintide ,colesevelam, bromocriptine and the other

61. REFERENCES The Pharmacological Basis of Therapeutics – Goodman & Gilman Rang & Dales Pharmacology Essentials of Medical Pharmacology – KD tripathi Internet - Journals

62. NOTHING LIKE DIET ,EXERCISE & ADHERENCE TO LIFE STYLE CHANGES thank you