Newer anti diabetic drugs

Newer anti diabetic drugs

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  Newer Anti Diabetic Drugs
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  Diabetes – Globalscenario 2015 2040 WORLD 416 million WORLD 642 million people living with diabetes Middle East and North Africa 85% South East Asia 64% South and Central America 55% Western Pacific 46% North America and Caribbean 30% Europe 33% Africa 93% 54% *The IDF Atlas, 7th edition, 2015
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  Diabetes – Indianscenario 2014 2030 INDIA 67 million INDIA 87 million people living with diabetes *Diabetes Res Clin Pract 2010;87:4-14.
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  peripheral glucose uptake hepatic glucose production pancreatic insulin secretion pancreatic glucagon secretion gut carbohydrate delivery & absorption incretin effect HYPERGLYCEMIA ? Adapted from:Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 Multiple, Complex Pathophysiological Abnormalities in T2DM _ _ + renal glucose excretion
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  peripheral glucose uptake hepatic glucose production pancreatic insulin secretion pancreatic glucagon secretion gut carbohydrate delivery & absorption incretin effect HYPERGLYCEMIA ? _ _ + renal glucose excretion DA agonists T ZD sMetformin S U sGlinides DPP-4 inhibitors GLP-1R agonists A G I s Amylin mimetics Insulin Bile acid sequestrants SGLT2 Inhibitors Multiple, Complex Pathophysiological Abnormalities in T2DM Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
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  OADs • Insulin Secretagogues –Sulphonylureas – Glibenclamide, Glicliazide, Glipizide, Glimepiride – Non SU secretagogues – Repaglinide, Nateglinide • Insulin Sensitizers – Biguanides – Metformin, Phenformin – Thiazolidinediones– Pioglitazone, Rosiglitazone • Alpha-Glucosidase Inhibitors: Acarbose, Voglibose, Miglitol • DPP-4 Inhibitors: Sitagliptin, Vildagliptin, Saxagliptin, Linagliptin • SGLT 2 Inhibitors: Empagliflozin, Canagliflozin, Dapagliflozin • Others: Pramlintide, Bromocriptine, Colesevelam • Insulins – Ultrashort acting: Glulisine, Aspart, Lispro – Short acting: Regular Insulin – Intermediate acting: NPH – Long acting: Glargine, Degludec, Detemer • GLP-1 analogues: Exenatine, Lixisenatide, Liraglutide Injectables
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  Approval Timeline 1996 • Acarbose •Glimepiride • Miglitol • Lispro 1997 • Glipizide • Glyburide • Repaglinide 1999 • Pioglitazone • Rosiglitazone 2000 • Glargine • Aspart http://www.fda.gov/
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  Approval Timeline 2001 • 30/70Aspart 2002 • Rosi + Met • Glipi + Met 2005 • Exenatide • Pramlintide • Pio + Met 2006 • Sitagliptin http://www.fda.gov/
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  Approval Timeline 2008 • Colesevelam •Vildagliptin 2009 • Bromocript • Saxagliptin 2010 • Liraglutide 2011 • Linagliptin http://www.fda.gov/
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  Approval Timeline 2012 • Anagliptin •Teneligliptin • Exenatide-ER 2013 • Lixisenatide • Canagliflozin • Degludec,Ryz • Metreleptin • Alogliptin 2014 • Dapa, Empa • Ipra,Tofo,Luse • Albi,dulagluti • Afrezza 2015 • IDegLira • Evogliptin • Omari,Trela • U-300 http://www.fda.gov/
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  Drugs in Pipeline NDA Aleglitazar Phase3 Ranolazine, GPR 40 agonist (Fasiglifam), Oral insulin Phase 2 Glucokinase activators (MK-0941) PTP 1B Inhibitors (ISIS –PTP1BRX ) Tetrahydrocannabivarin (THCV) (GWP42004) Phase 1 GPR 119 agonists
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  Drugs in Tank Cannabinoi d-1receptor antagonists Acetyl-CoA carboxylase- 1 and -2 inhibitors GPR40 GPR119 GKAs 11β-HSD1 inhibitor PTP1B inhibitor GSK -3β inhibitors Glucagon receptor antagonists GLP-1/IgG1- Fc fusion construct Rimonabant Succinobuco GLP1RA Intranasal Once monthly DAPD DPP4Is SGLT2Is Dual PPARs FGF 21 (LY) Vanadyl (II) thiamine Hcl Fructose 1, 6 bisphosphatse inhibitors
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  Newer targets • uncOCN: –undercarboxylated form of Osteocalcin (uncOCN) seems to have positive effects on the metabolic syndrome, including improvement of insulin resistance, β-cell function and dyslipidemia. • INDY Gene (‘I’m not dead yet’): – Its deletion mimics aspects of dietary restriction and protects again adiposity and insulin resistance in mice • VEGF-B Blocker: 2H10 • ABHD6: α/β hydrolase domain-6: breaks down monoacylglycerol and thus negatively controls insulin release. Inhibition may help in treating diabetes. • FFAR3: β cell short-chain fatty acid receptors
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  For Discussion • NewerInsulins: – U-300, Oral insulin, Smart Insulin patches • DPP4 Inhibitors: Once weekly • GLP 1 RA: Once Monthly and Yearly • PTP1B Inhibitors • GK activators, GPR 40, GPR 119 agonists • Dual PPAR agonists • Islet cell transplantation • Artificial Pancreas
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  Glargine U-300 • Three-foldmore concentrated formulation of Glargine • Reduced volume (1/3) and reduced surface area (1/2) of subcutaneous depot • Slower and more constant rate of absorption • Gla-300 provided sustained glycemic control with a lower risk of hypoglycemia compared with Gla-100
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  Glargine U-300 Flatter PKProfile More Prolonged PD Profile 0 6 12 18 24 30 36 0 1 2 3 4 5 DOSE 0.4 U.kg -1 U300 U100 GIR-mg.kg -1 .min -1 TIME - hour Glucose Infusion Rate 0 6 12 18 24 30 36 0 5 10 15 20 25 30 LLOQ 5.02 µU.mL -1 SC INJECTION INSULIN-µU.mL -1 TIME - hour U100 0.4 U.kg -1 U300 0.4 U.kg -1 LOESS 0.15 Gla-300 Gla-100 Serum Insulin Glargine Concentration Gla-300 Gla-100
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  Oral Insulin
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  DAPD
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  DAPD
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  PTP 1B Inhibitors
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  PTP 1B Inhibitors
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  PTP 1B Inhibitors •PTP 1B acts as a negative regulator for both insulin and leptin signaling • Inhibition of PTP 1B could address both Diabetes and Obesity • Traditional therapeutics cannot specifically target PTP 1B • Anti sense based oligonucleotides inhibit the expression and activity of PTP 1B gene without affecting other highly related Tyrosine Phosphatases
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  PTP 1B Inhibitors
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  PTP 1B Inhibitors •A phase 2 program in T2DM with PTP 1B Inhibitor (ISIS –PTP1BRX ) showed • Reduction in HbA1C by 0.7% • Reduction in weight by 2.7 Kg. • No Hypoglycemia • No change in renal/hepatic function • No GI Side effects http://www.easdvirtualmeeting.org/resources/isis-ptp-1brx-a-novel-ptp-1b-antisense-inhibitor- improves-hba1c-and-body-weight-in-patients-with-type-2-diabetes-on-metformin- sulphonylurea--3
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  Glucokinase Activators
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  GPR 119, GPR40 agonists
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  GPR 119, GPR40 agonists
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  Dual PPAR α/γagonists
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  Islet cell transplantation •The two types of pancreatic islet transplantation are – auto-transplantation – allo-transplantation • Pancreatic islet auto-transplantation – Performed following total pancreatectomy – Patients with type 1 diabetes cannot receive pancreatic islet auto-transplantation. – The surgeon first removes the pancreas and then extracts and purifies islets from the pancreas. – Within hours, the islets are infused through a catheter into the patient's liver. – Goal is to give the body healthy islets to make insulin.
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  Islet cell transplantation •Pancreatic islet allo-transplantation – islets from the pancreas of a deceased organ donor are purified, processed, and transferred into another person. – Currently experimental (not approved for therapeutic purpose). – Transplant patients typically receive two infusions with an average of 400,000 to 500,000 islets per infusion. – In most cases, islet cells from several different donors are needed. – The islets are infused, into the portal vein. – Pancreatic islet allo-transplantation is performed in type 1 diabetes.
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  Islet cell transplantation •Islet transplantation is an efficient treatment for type 1 diabetes • Beta cells are removed from a donor's pancreas and transferred into a person with diabetes. • As with all organ and tissue transplants, rejection of the donor cells is the greatest challenge. • Patients have to be on immuno-suppresssants life long, which may increase chances of infection and some cancers.
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  Islet cell transplantation
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  Islet cell transplantation •Recent data of a 5-yr post transplant followup: – Prevent severe hypoglycemia in nearly 90% of the recipients at five years – HbA1c levels were ≤ 7% in 84% of patients at 12 months, 70% of patients at 48 months, and 59% of patients at 60 months after islet transplantation. Diabetes Care. 2015 Sep;38(9):1714-22
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  Artificial Pancreas • Artificial/Bionicpancreas: – Dual-chambered – Two separate pumps for delivering both insulin and glucagon, – A continuous glucose monitor (CGM) – A control algorithm built into an iPhone app. • The bihormonal "bionic pancreas" continues to perform well in clinical trials and could reach the US market by 2018.
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  Artificial Pancreas
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  Convergence Toward Automationand Smartness I n s u l i n M o n i t o r i n g HCP Self Management Automation 1922 Insulin & syringes 1979 Pumps 1983 Pens Connectivity 1926 Clinic Monitoring 1971 Home Monitors Data Management Advice/Feedback Open Loop D e l i v e r y Closed Loop We are here Continuous Monitors There is Smart Insulins
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  • Smart insulinis defined as a pharmaceutical preparation which contains an inbuilt sensor mechanism to assess ambient glycaemia, and ensures release of insulin based upon this information. • It avoids both hypoglycaemia dips and hyperglycaemia peaks, while ensuring euglycaemia. Smart insulins
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  • As longback as 1979, Brownlee and Cerami reported the synthesis of a stable, biologically active glycosylated insulin derivative, combined with a lectin called concavalin A. • This synthetic ligand-bound insulin releases active insulin in a quantity proportional to the amount of glucose present • This approach, though currently far from perfection, has the potential to revolutionize insulin therapy. Smart insulins
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  Conventional – Protein BindingLigands – Bulk Hydrogel Matrix – Phenyl Boronic Acid • Nano-Technology Based Smart Insulins • Nano-Membranes • Microgel (Smart Sponge) • Nano-Network Smart insulins
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  • Every smartinsulin has to have two components: • a glucose sensor, and • an insulin delivery device. • In the recently developed nano — network, exposure to hyperglycaemia leads to enzymatic catalysis of insulin nanoparticles, and allows release of insulin. • The duration of action of these nano-networks is 10 days in type 1 mice, and has been noted to last up to 14 days in some animal subjects. Smart insulins Basic Principle
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  Smart insulins Basic Principle Schematicof the Glucose responsive vesicles(GRV)-containing Micro Needle MN-array patch (smart insulin patch) for in vivo insulin delivery triggered by a hyperglycemic state to release more insulin.
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  • The fieldseems to be a promising area for innovation. • Patents have been drawn for glucose-responsive insulin formulations, including microgels, amphilic hydrogels, and thermo- sensitive polymers. • Patents are also filed for implantation insulin-producing devices which contain porcine endocrine cells contained in immuno- isolatory membranes. • All these research paths have potential to reach fructification. • Insulin secretion follows a nonlinear pattern. • Any inorganic or non-living insulin secretory apparatus would not be able to replicate the work of an organic, live islet of Langerhans. Smart insulins Pros and cons
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  • Recently anautonomous drug release system, based upon chemo-mechanical energy conversions, which works as an Organic Engine, without using external energy source, has been demonstrated to provide glycaemic control. • This innovation has helped allay these fears. Smart insulins are an exciting development in diabetes care. • While it may take many years before they reach clinical use, recent advances in the area suggest that smart insulins will soon become a reality. Smart insulins
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