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Aaditya Recent Advances in Diabetes Mellitus
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Aaditya Recent Advances in Diabetes Mellitus



Some of the recent advances in diabetes mellitus including newer insulin preparations and other oral hypoglycaemic agents.

Some of the recent advances in diabetes mellitus including newer insulin preparations and other oral hypoglycaemic agents.



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Aaditya Recent Advances in Diabetes Mellitus Aaditya Recent Advances in Diabetes Mellitus Presentation Transcript

  • Dr Udupa 11/5/2011 INTRODUCTION Definition: “Metabolic disorder characterized by hyperglycemia, glycosuria, hyperlipemia, negative nitrogen balance and sometimes ketonemia.” Classification: ( Expert Committee,2003) Type I - IDDM (Insulin Dependant) Type II - NIDDM (Non- Insulin Dependant) Type III - Others (MODY) Type IV - Gestational 2
  • Dr Udupa 11/5/2011PHARMACOTHERAPY OF DM Non-pharmacologic Rx:  Diet  Exercise Pharmacological Rx:  Insulins  Oral anti-diabetic drugs  Recent developments Emerging non-pharmaco. Rx:  Islet cell transplant  Gene therapy 3
  • Dr Udupa 4 11/5/2011CURRENT THERAPY OF DIABETES MELLITUS Drugs increase insulin release OR reduce glucose absorption/increase utilisation. Don’t alter overactivity of glucagon & other hormones that increase hepatic glucose output. Insulin. OHA  Insulin secretogogues- sulfonylureas & meglitinides  Biguanides  Thiazolidinediones  α-glucosidase inhibitors
  • Dr Udupa 5 11/5/2011NEED FOR NEWER THERAPIES Inadequate control of post prandial hyperglycemia(with sulfonylureas, metformin, TZDs ) Weight gain( sulfonylureas, meglitinides, TZDs & insulin ) Loss of efficacy ( all agents ) Pathophysiology of insulin resistance remains unaltered Insulin- Hypoglycemia , Resistance
  • Dr Udupa 11/5/2011LIMITATIONS OF REGULAR HUMAN INSULIN Slower onset of activity Patient inconvenience Safety concerns Prolonged duration of action Late post-prandial hypoglycemia Risk of hyperinsulinemia 7
  • Dr Udupa 11/5/2011HIGHLY PURIFIED INSULIN PREPARATIONS Why purified ? Single peak Insulins: 50-200 ppm proinsulin Actrapid, Lentard Monocomponent Insulins: 20 ppm proinsulin Actrapid MC, Monotard MC Advantages of Monocomponent Insulins: Immunogenicity similar to human insulin greater stability less allergic 8
  • Dr Udupa 11/5/2011HUMAN INSULINS By recombinant DNA technology Benefits- more water soluble more rapid absorption Special indications- insulin resistance allergy inj. site lipodystrophy short time crisis during pregnancy Examples: Human Actrapid, Human Insulitard. 9
  • Preparation Source Dr Udupa 11/5/2011Rapid-acting insulins Insulin Lispro, Human analog Insulin Aspart Human analog Insulin Glulisine Human analogShort-acting insulins Regular Human Insulin HumanIntermediate-acting insulins NPH Humulin HumanPremixed insulins (% NPH/ % regular) Humulin 70/30 and 50/50 Human (Lilly) 50/50 NPL, Lispro (Lilly) Human analogLong-acting insulins Insulin detemir, Human analog 10 Insulin glargine, Human analog
  • NEWER INSULINSInsulin Onset peak DurationRapid acting: 5-15 min 30-90 min 5 hrs-lispro-aspart-glulisineShort acting: 30-60 min 2-3 hrs 5-8 hrs-Reglar ins.Long acting: 2-4 hrs peakless 20-24 hrs-glargineInhaled insulinOral / rectal insulin 11/5/2011 Dr Udupa 11
  • Dr Udupa 11/5/2011 INSULIN LISPRO (HUMALOG) Ist commercially available analogue At posn 28 of β-chain– lysine At posn 29 of β-chain– proline By s.c., 15 min before meal Rapid absorption from s.c. due to dissociation into monomers –shorter duration Glucose control significantly improved Available as 100 U/ ml. 12
  • Dr Udupa 11/5/2011INSULIN ASPART (NOVOLOG) At position 28 of β-chain – aspartate replaces proline Produced by rDNA from saccharomyces cerevisiae Similar effects as that of lispro Faster onset & shorter duration Given 10 min before meal by s.c. C/I: hypoglycemia & hypersensitivity. 13
  • Dr Udupa 11/5/2011INSULIN GLULISINE (APIDRA) By rDNA technology from E. coli (k-12). At position 29 – glutamate for lysine At position 3 - lysine for asparagine Given 15 min before meal by s.c. , peak in 1 hr. ADR: gen. well tolerated hypoglycemia, comprised cardiac disease. Approved for use in type 1 & 2 DM. Used in combination with basal insulin 14
  • Dr Udupa 11/5/2011INSULIN GLARGINE (LANTUS) First long acting insulin analogue approved At position 21 of A-chain- asparagine by glycine 2 arginine added to c- terminus of β-chain Has acidic pH of 4 Results in less hypoglycemia & sustained “peakless” absorption profile No effect of exercise & site of injection on absorption C/I: hypersensitivity 15
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  • Dr Udupa 11/5/2011 NEWER INSULIN DELIVERY DEVICES Insulin syringes Pen devices Jet injectors Insulin pumps-CSII Implantable pumps Buccal insulin Insulin patch External artificial pancreas Inhaled insulin Liposome entrapped insulin 17
  • Dr Udupa 11/5/2011 INHALED INSULIN (EXUBERA) Inhalable insulin was available from September 2006 to October 2007 in the United States Pharmacological properties:  more rapid increase in insulin conc.  faster onset than s.c. peak at 2 hrs: duration  6 hrs- intraindividual reproducibility of glycemic response  decrease in s. triglyceride levels 18
  • Dr Udupa 11/5/2011EFFICACY & SAFETY HbA1c values < 8% in 83% pts Mean HbA1c values were reduced & maintained Hypoglycemia Weight gain Greater decline in pulmonary function Cough within seconds of inhalation Lung Cancer concerns 19
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  • Dr Udupa 11/5/2011NEWER INSULIN DELIVERY METHODS Jet Injector: High-pressure narrow jet of the injection liquid instead of a hypodermic needle to penetrate the epidermis. Buccal spray launched in India in 2009. Claims to get absorbed through the buccal mucosa. 21
  • Dr Udupa 11/5/2011NEWER INSULIN DELIVERY METHODS Insulin patch 22
  • Dr Udupa 11/5/2011INSULIN PUMPS 23
  • Dr Udupa 11/5/2011INCRETIN MIMETICS Insulin has been shown to be released more effectively through an oral glucose load than intravenously and this is known as the incretin effect. Enhance the incretin pathway in two ways  ↑ Glucagon-like Polypeptide 1 (GLP-1)  ↓Dipeptidyl peptidase (DPP-IV) 25
  • Dr Udupa 11/5/2011Human ileum, GLP-1producing L-cells Capillaries, DPP-IV (Di- Peptidyl Peptidase-IV) 27
  • Dr Udupa 11/5/2011 GLUCAGON-LIKE POLYPEPTIDE 1 ANALOGUES Exenatide:  Saliva of the Gila monster  1 st Incretin therapy. Approved as SC injection, to treat Metformin/sulfonylurea treated T2DM, getting suboptimal response  Suppresses high glucagon  suppress hepatic glucose output  Preserves β-cell reserves  Central loss of appetite. Control of bodyweight  Reduces HbA1c by 1-1.3% S.C. inj. b.d. for 1 year 28
  • Dr Udupa 11/5/2011EXENATIDE- A D R Nausea in 44%, Vomiting, Diarrhea. Combination with Insulin/secretogogue leads to Hypoglycemia. C/I : T1DM, T2DM with Beta Cell Failure, Diabetic ketoacidosis , Renal impairment , GIT disease , Pregnancy , Lactation. Pancreatitis . 29
  •  National Institute for Health and Clinical Dr Udupa 11/5/2011 Excellence (NICE) Guidelines:  Exenatide is not recommended for routine use in T2DM Individual Fulfils One Of The Following Criteria:  Has a body mass index (BMI) > 35 kg/m2  Has specific problems of a psychological, biochemical or physical nature arising from high body weight  Has inadequate glucose control (HbA1c >7.5%) with conventional oral agents  If another high cost medication such as a TZD or insulin would otherwise be started. 30
  • Dr Udupa 11/5/2011PRAMLINTIDE- GLP-1 AGONIST Synthetic analogue of a Gut Hormone, Amylin Pramlintide suppresses Glucagon release. Approved Pre-Prandially [with Insulin] in T1&T2, is a PP Glucose modulator. Delays Gastric Emptying. Central Anorectic effects. Reduces HbA1c by 0.39-0.62% [6 weeks] Peak action 20 Min. Duration-150 Min. Mealtime Insulin Dose reduced by 50%. 31
  • Dr Udupa 11/5/2011 LIRAGLUTIDE EXENATIDE Once daily Twice daily Peakless PeakGood effect on HbA1c & FBG Good effect on HbA1c & FBG Weight loss Weight loss No antibodies antibodies No inj site reactions Inj site reactions 32
  • Dr Udupa 11/5/2011DIPEPTIDYL PEPTIDASE INHIBITORS This class of agent works by enhancing the sensitivity of β-cells to glucose, which causes enhanced glucose dependent insulin secretion. It has also been shown to improve markers of β cell function. Can be used in combination with metformin, sulfonylureas, or even as monotherapy 33
  • Dr Udupa 11/5/2011VILDAGLIPTIN Expands β-cell mass Decreases fasting & PP BGL Reduces HbA1c in T2DM by 0.50-1% & controls Glucose Levels in poorly controlled Addition of Insulin can lead to Hypoglycemia. Single dose reduces Glucose by inhibiting EGP [Endogenous glucose production] . 34
  • Dr Udupa 11/5/2011VILDAGLIPTIN Absorbed rapidly [Tmax = 1Hr ] Bioavailability 85% T1/2=90 Min But DPP- 4 Inhibition continued for 10 Hrs , Hence OD/BD administration. Glucose Excursions significantly reduced with Vildagliptin & Insulin levels increased. ADR  Headache , Dizziness , Increased sweating , Nasopharingitis ,Cough .  Hyperinsulinemic hypoglycemia .  Nesidioblastosis 35
  • Dr Udupa 11/5/2011GLP-1 AGONISTS VS DPP-4 INHIBITORS  Parenteral .Twice daily  Oral , Once daily .  Alternative to Insulin  1st line/Add on  HbA1c Reduction  HbA1c Reduction.  Weight loss  Prevent Weight gain ,independent  Predominantly Nausea  Nausea Absent  GLP-1 R stimulation  All above due to depends on Agonist modest stabilisation of [Exenatide] level PP levels of GLP-  Slow Gastric Emtying 1[Vildagliptin]  No Effect 36
  • Dr Udupa 11/5/2011 CANNABINOID-1 RECEPTOR BLOCKERS Cannabinoid-1 receptors appear to regulate energy balance and body composition Blocking the action of these receptors is an attractive target for treating obesity, diabetes, and the metabolic syndrome Jbilo O, et al, Faseb J, 2005;19:1567-1569 37
  • Dr Udupa 11/5/2011RIMONABANT Weight loss and improved insulin sensitivity 20 mg once a day before breakfast Phase 3 trials and is licensed for use in patients who have a BMI >30 kg/sqm or BMI >27 kg/sqm with an additional risk factor such as dyslipidaemia 38
  • Dr Udupa 11/5/2011PPAR MODULATORS PPAR alpha- increases HDL cholesterol PPAR gamma- insulin sensitization PPAR beta/delta- inflammation/ obesity Dual PPAR agonists:  Muraglitazar  Naveglitazar  Tesaglitazar  Farglitazar Pan- PPAR Activator- Bezafibrate 39
  • RATIONALE FOR DUAL PPAR -α/γ Dr Udupa 11/5/2011 AGONISTS Muraglitazar TZDs : Rosiglitazone; ; Pioglitazone Tesaglitazar PPARgPPARa(liver, vascular wall) (fat, muscle)  “Master Regulation: of Reduced triglycerides adipocyte differentiation Increases circulating HDL  Modulates glucose Improved LDL buoyancy metabolism & insulin sensitivity Glucose intolerance Dyslipidemia and Type 2 diabetes 40
  • Dr Udupa 11/5/2011DUAL PPAR AGONISTS: SAFETY ISSUES  Several earlier glitazars were discontinued because of serious safety issue  Includes ragaglitazar and farglitazar, among others  Safety issues were different for each drug1  Muraglitazar  Increased risk of death, nonfatal MI, and nonfatal stroke2  Unlikely that further studies will be done  Tesagalitazar  Increased serum creatinine and decreased glomerular filtration rate  Development discoutinued May 2006 41
  • Dr Udupa 11/5/2011SGLT2 INHIBITORS Sodium Glucose Co-transporter (SGLT)-2 inhibitors SGLT2 mediates 90% of filtered glucose reabsorption in the convoluted segment of the proximal renal tubule Dapagliflozin Canagliflozin Remogliflozin etabonate Sergliflozin 42
  • Dr Udupa 11/5/2011 Potential Clinical Advantages  SGLT2 is expressed exclusively in the kidney  SGLT2 function is independent of insulin  Increased GLUCOSE EXCRETION Negative energy balance Weight loss  Improvement in both FBG and PPB  Low incidence of hypoglycemia Predicted Clinical Limitations  Increasedurine volume  Sodium loss  Long-term safety not yet studied 43
  • Dr Udupa 11/5/2011CLINICAL DATA FOR DAPAGLIFLOZIN Orally effective SGLT-2 selective Half life= 11.2-16.6hrs…. Suitable for once daily dosing Dose dependent increase in glycosuria BSL and HbA1c reduction comparable to metformin; Weight loss more than metformin Effective in combination with metformin and other antidiabetics 44
  • Dr Udupa 11/5/2011RUBOXISTAURIN (ARXXANT) Protein kinase C- β inhibitor drug under investigation To reduce occurrence of vision loss in patients with non-proliferative diabetic retinopathy. DRUGS ACTING ON INTERMEDIARY METABOLISM TO ↓ HEP. GLUCOSE OUTPUT: Acipimox, bezafibrate- ↓ FA levels Etomoxir- ↓ FA oxidation 45
  • Dr Udupa 11/5/2011ALDOSE REDUCTASE INHIBITORS Enhanced polyol pathway – diabetic peripheral neuropathy ARI blocks polyol pathway Delays progression & ameliorate symptoms of diabetic neuropathy Examples :  Epalrestat  Ranirestat  Fidarestat  Zinarestat 46
  • Dr Udupa 11/5/2011 PEGAPTINIB (MACUGEN) & RANIBIZUMAB Pegaptinib: Selective Vascular Endothelial Growth Factor antagonist (VEGF Antagonist) For Rx of age related macular degeneration associated with diabetes 0.3 mg every 6 weeks intravitreous inj ADR: anterior chamber inflammation, cataract, blurred vision, endophthalmitis Ranibizumab- recombinant humanised monoclonal antibody that neutralizes all active forms of VEGF-A 47
  • Dr Udupa 11/5/2011OTHER EMERGING DRUGS Glucagon antagonist: skyrin, oxyskyrin, octreotide β-3 adrenoreceptor agonists Endogenous cannabinoid modulator- Rimonabant Protein kinase C inhibitors : Calphostin, staurosporine Insulin like growth factors (IGF) Morpholinoguanidine 48
  • Dr Udupa 11/5/2011MISCELLANEOUS THERAPIES INGAP (Islet NeuroGenesis Assisted Protein) Thyroxyl insulin Phosphodiesterase inhibitors Growth hormone fragments RXR (Retinoid X Receptor ) agonist Glucose 6 phosphatase inhibitors Trace elements: vanadium (decreases EGF), zinc, chromium, magnesium,selenium 49
  • Dr Udupa 11/5/2011HERBAL REMEDIES Gymnema sylvestre Pterocarpous marsupium (vijaysar) – trials by ICMR Momordica charantia (karela) Trigonella faenum (methi) Marine product- CDR-MOES-D123 50
  • Dr Udupa 11/5/2011GYMNEMA SYLVESTRE Indian ayurvedic plant vastly studied Also called gur-mar = sugar destroyer Active ingredient gymnemic acid As sugar controller & insulin secretagogue 51
  • Dr Udupa 11/5/2011 GENE AND CELL-REPLACEMENT THERAPY IN THE TREATMENT OF TYPE 1 DIABETES Gene Therapy  (Insulin) gene therapy will  introduction of a foreign gene into any cell type in the body, allowing it to produce insulin May be:  insulin gene itself, perhaps under control of a tissue-specific promoter  a gene encoding a factor that in turn activates the insulin gene Induction of stem-cell differentiation into ß-cells by means of molecular intervention 53
  • Dr Udupa 11/5/2011 GENE AND CELL-REPLACEMENT THERAPY IN THE TREATMENT OF TYPE 1 DIABETES Challenges:  To ensure adequate insulin response after glucose load  Any newly created insulin-secreting cell will have to be able to adapt to alterations in insulin requirements that accompany changes with exercise, body weight, and aging  Ensure that newly created or implanted (surrogate) ß-cells are protected in some way from recognition by the immune system and in particular from autoimmune destruction 54
  • Dr Udupa 11/5/2011 ISLET CELL TRANSPLANTATION Average-size person (70 kg), a typical transplant requires about one million islets, isolated from two donor pancreases Donor pancreas isolated enzymatically digested purified infused via the portal vein into the liver. Daclizumab, Sirolimus And Tacrolimus Limitations:  Low donor pool  High incidence of failure of immunosuppressive regimen 55
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