DPP-4 inhibitors their potential transient and serious side effects

Views:
 
     
 

Presentation Description

The GLP-1–related drugs arrived in clinical practice with much fanfare and anticipation. DPP- 4 enzyme is a ubiquitous cell-membrane protein, expressed in many tissues, including lymphocytes, which has raised some concerns about the long-term effects of DPP-4 inhibitors, especially on immune function. Data consistent with case reports and animal studies indicate an increased risk for pancreatitis with GLP-1-based therapy and also raise caution about the potential long-term actions of these drugs to promote pancreatic and thyroid cancers. This lecture will review the incretin-based therapies with focus on their benefits and their potential transient and serious side effects.

Comments

Presentation Transcript

PowerPoint Presentation:

Dr. Abdulameer Abdullah Al- ashbal Consultant Physician Almustansiriya medical college , Department of Medicine ; Alyermouk Teaching Hospital Incretin -Based Therapies for the Treatment of Type 2 Diabetes: Update on the Benefits and Risks

PowerPoint Presentation:

Dr. Abdulameer Abdullah Al- ashbal Consultant Physician The gastrointestinal tract has a crucial role in the control of energy homeostasis through its role in the digestion, absorption, and assimilation of ingested nutrients.

PowerPoint Presentation:

Dr. Abdulameer Abdullah Al- ashbal Consultant Physician The role of Insulin in glucose homeostasis is a firmly established concept and forms the cornerstone of discussions of the pathophysiolgy of diabetes.

PowerPoint Presentation:

However, how glucose enters the blood stream has profound effects on magnitude of stimulatory effect of glucose on insulin secetrion .

PowerPoint Presentation:

The concept of gastrointestinal hormones (The incretin concept) 1-2 The observation that in response to hyperglycemic stimuli, oral glucose elicits a greater insulin response than intravenous glucose , is termed , which accounts for up to 60% of postprandial insulin release in healthy people “ The Incretin Effect “ Elrick H, et al. J Clin Endocrinol Metab 1964 ; 24: 1076–1082. McIntyre N, et al. Lancet 1964 ; 2: 20–21.

PowerPoint Presentation:

Glucose Gut-derived signals The gut Insulin release The parenteral route Energy administeration via Glucose Insulin release (Insulin secretagogue ) (Potent insulin secretagogues )  (Insulin secretagogue ) The incretin effect

PowerPoint Presentation:

* Perley MI,et al. J Clin Invest. 1967 ; 46:1954-1962. Time (min) Plasma Insulin (µU/mL) The incretin effect *

PowerPoint Presentation:

firmly implicated gastrointestinal factors * as important mediators of insulin secretion after oral glucose And this finding * Mcintyre N, et al. J Clin Endocrinol Metab , 1965 25:1317–1324.

PowerPoint Presentation:

These factors have come to be termed “ Incretins “ ( INtestine seCRETtion Insulin) and their role on glucose homeostasis has led to a novel class of based on the function and physiology of two endogenous dominant incretin hormones incretin -based antihyperglycemic agents Zunz E, et al. Arch Int Physiol Biochim 1929 ; 31: 20–44.

PowerPoint Presentation:

These two native incretin hormones are : & that principally responsible for the incretin effect 1-8 . The incretin hormones Glucagon-like peptide-1 (GLP-1) Glucose-dependent insulinotropic peptide (GIP ) Bell GI, et al. Nature 1983 ;302 :716 -718 Heinrich C. et al. Endocrinology 1984: 115:2176-2181 Mojsov S, et al. I Biol Chem 1986; 261:11880-11889 Novak U, et al. European Journal of Biochemistry 1987; 164:553-558 Holst JJ, et al. FEBS Lett 1987; 211:169-174 Kreymann B, et al. Lancet. 1987;2:1300-4 Ørskov C ,et al . Endocrinology 1986 ;119 :1467-1475 Mojsov S ,et al . J Clin Invest 1987; 79 :616-619

PowerPoint Presentation:

ProGIP (K-cells of the intestinal mucosa)  Gene * The incretin hormones Glucose-dependent insulinotropic peptide (GIP ) * Takeda J, et al.Proc Natl Acad Sci U S A 1987 ; 84:7005–7008

PowerPoint Presentation:

Glucagon Proglucagon (L-cells of the intestinal mucosa)   Glucagon-like peptide-1 (GLP-1) gene * gene * Orskov C, et al. En­docrinology 1986 ; 119:1467—1475. The incretin hormones

PowerPoint Presentation:

GLP-1 -secreting enteroendocrine L-cells are located predominantly in the ileum and colon 1-3 . GIP -secreting enteroendocrine K-cells are concentrated in the duodenum and proximal jejunum 1-6 . These native hormones are secreted at low basal levels in the fasting state and their circulating levels increase rapidly and transiently following food ingestion 1-5 . Inagaki N, et al. Mol Endocrinol 1989; 3: 1014–1021. Takeda J, et al. Proc Natl Acad Sci USA 1987; 84: 7005–7008. Brown JC, et al. J Physiol 1970; 209: 57–64. Dupre J, et al. J Clin Endocrinol Metab 1973; 37: 826–828. Adrian TE,et al. Diabetologia 1978; 14: 413–417. Taminato T, et al. Diabetes 1977; 26: 480–484. Bell GI,et al. Nature 1983; 302: 716–718. Schmidt WE,et al. Diabetologia 1985; 28: 704–707. Kreymann B, et al. Lancet 1987; 2: 1300–1304. JF et al. Diabetes Metab 2005;31:233-242 Drucker DJ.Diabetes Care 2003; 26:1929-2940 Orskov C,et al. Diabetes 1994 ;43:535-53 Damholt , et al. Endocrinology 1999 ;140, 4800-4808 Holst , J. J. Physiol. Rev. 87: 1409-1439 2007; doi:10.1152/physrev.00034.2006 The incretin hormones

PowerPoint Presentation:

On a rapid time scale, typically occurring when a meal is digested and absorbed, nutrients and the incretin hormones,GLP-1 and GIP, Synergize in the acute stimulation of insulin secretion (exocytosis of insulin secretory granules) * * Jia X, et al . Am J Physiol 1995 ;268: E645–E651 Interactions between nutrients and GIP and GLP- 1

Incretin Receptors (GIP Receptors):

Incretin Receptors ( GIP Receptors ) The human gipr gene 1-4 is localized to chromosome 19, band q13.3. is expressed in both α and β cells in pancreatic islets , And in other tissues : GI tract, adipose tissue, adrenal cortex, pituitary, heart, testis, endothelium of major blood vessels, bone, trachea, spleen, thymus, lung, kidney, thyroid, and several brain areas. Usdin TB, et al. Endocrinology ,1993; 133: 2861-2870. Yasuda K, et al. Biochem Biophys Res Commun ,1994;205: 1556-1562. McIntosh CH, et al. Acta Physiol Scand , 1996;157: 361-365. Yip RG, et al. Endocrinology ,1998;139: 4004-4007.

Incretin Receptors (glp-1 Receptors):

Incretin Receptors ( glp-1 Receptors ) The human glp-1r gene 1-5 is located on chromosome 6p21. Its genetic expression: may be almost exclusively restricted to the β cells and is present in cells lining the pancreatic ducts in a variety of other tissues: thyroid C cells, kidney, lung, heart, gastrointestinal track, skin, pituitary, and multiple regions of the peripheral and central nervous system. Stoffel M, et al. Diabetes, 1993; 42: 1215-1218. Thorens B . Proc Natl Acad Sci U S A , 1992;89: 8641-8645. Thorens B, et al. Diabetes, 1993; 42: 1678-1682. Tibaduiza EC, et al. J Biol Chem , 2001; 276: 37787-37793. Dillon JS, et al. Endocrinology, 1993; 133: 1907-1910.

PowerPoint Presentation:

2.8 mmol/L Glucose 10 mmol/L Glucose 10 mmol/L Glucose 2.8 mmol/L Glucose Insulin Release (% of total content) Glucose-dependency of the insulin stimulatory effect of glucagon-like peptide-1 GLP-1 (7-36) amide (pmol/L) * Goke R, et al. Res Exp Med (Berl). 1993; 193:97-103

PowerPoint Presentation:

THE ENZYME DIPEPTIDYL PEPTIDASE-4 (DPP-4 or DPP-IV) Or CD 26 ; EC 34145

PowerPoint Presentation:

In 1993 it was demonstrated that Dipeptidyl -peptidase - 4 (DPP -IV ) enzyme mediates the inactivation of G L P-1 and GIP by removing the two N-terminal amino acids of the hormones. * Mentlein R, et al. Eur J Biochem 1993; 214:829–35. Bruckley D, et al Regul. Pept. 1992, 40, 117 Dipeptidyl-peptidase - 4 (DPP -IV ) enzyme*

PowerPoint Presentation:

Nutrients in the gut lumen Portal circulation (Liver) 25% of the GLP- 1 Incretin Secretion L-cells- intestinal villus 100% of the GLP- 1 Systemic circulation 10—15% of the GLP- 1 The pancreas and the brain 10—15% or less of the GLP- 1 Soluble plasma DPP-IV enzyme Luminal Endothelial cells DPP-IV** enzyme **DPP-IV:Dipeptidyl peptidase-IV Holst J J,et al.Diabetologia 2005 48: 612-615 Soluble plasma DPP-IV enzyme Endocrine pathway for the actions of GLP- 1*

PowerPoint Presentation:

The inactivation enzyme DPP-IV Active GLP- 1 (7-36 ) and active GIP (1-42 amide) Biologically Biologically Inactive GLP- 1 (3-42 ) and Inactive GIP (9-36 amide ) (Half-life of 1-1.5 min) (Half-life of 7 min) (Half-life of 17 min) (Half-life of 4-5 min) Inactivation of GLP-1 and GIP by Dipeptidyl peptidase-IV (DPP-IV) enzyme (1-11) Nauck M, et al . Diabetologia 1986; 29: 46–52. Mentlein R, et al. Eur J Biochem 1993; 214:829–35. Vilsbøll T,et al. J Clin Endocrinol Metab 2003; 88: 220–4. Deacon CF, et al. J Clin Endocrinol Metab 2000; 85:3575-3581 Deacon CF,et al. Am J Physiol 1996; 271:E458-E464 Bruckley D, et al Regul . Pept . 1992, 40, 117. Deacon C, et al . Diabetes 1995; 44, 1126-1131. Kieffer TJ, et al. Endocrinology 1995;136, 3585-3596. Deacon CF, et al. Clin . Endocrinol Metab1995; 80, 952-957 Deacon, C.F, et al . J.Endocrinol 2002 ;172, 355-362 Mentlein R, Et al. Eur J Biochem 1993; 214: 829–35.

PowerPoint Presentation:

GLP-1 DPP-IV DPP-IV GLP-1 * Histochemistry by C. Ørskov , the Panum Institute GLP-1 (yellow) released by enteroendocrine L-cells, diffuses to the capillaries, where it is inactivated by DPP-4 enzyme (red)*

PowerPoint Presentation:

The glucose-lowering actions of GIP The secretion of Normal or increased GLP-1 reduced GIP GLP-1 much weaker or absent (resistance) preserved In type 2 diabetes The incretin hormones and Pathophysiology of Type 2 DM 1-12 Nauck MA, et al. J Clin Invest 1993;91:301–307 Rachman J,et al. Diabetes 1996;45:1524–1530 Ahre´n B, et al. Horm Metab Res 2004;36:867–876 Vilsbøll T, et al. Diabetes 2001;50:609–613J Clin Endocrinol Metab 2001;86:3717–3723. J Clin Endocrinol Metab 2003;88:220–224. Diabet Med 2000;17:713–719 Clin . Invest. 1993;91:301–307. Regul.Pept 1994;51:63-74. Metabolism.1987; 36:677-682. Vilsbell T, et al.Diabetologia 2002;45 : 1111 –1119. Nauck MA, et al.Diabetologia 1993;36:741–744

PowerPoint Presentation:

abolished severely reduced* (From normal 60% to < 10%)** or Consequently in patients with Type 2 diabetes, the incretin effect is either resulting in inappropriately low insulin secretion following oral ingestion of nutrients * . * Tronier B, et al . Diabetes Clin Pract1985;[Suppl 1]:S568. Nauck M , et al. Diabetologia 1986;29:46-52. Diabet Med 2000;17:713–719. ** Mentlein R, et al. Eur J Biochem 1993; 214: 829–35. Rask E, et al. Metabolism 2004; 53 : 624 –631. The incretin hormones and Pathophysiology of Type 2 DM

PowerPoint Presentation:

Type 2 diabetes Increased glucagon secretion Increased hepatic glucose production Increased Insulin resistance Impaired incretin effect Decreased secretion of GLP-1 Impaired response to GIP Decreased insulin secretion Increased gastric-emptying rate Pathophysiological changes in Type 2 diabetes* DeFronzo RA. Diabetes Rev1997 ;5:177 – 26. Shah P, et al. I Clin Endocrinol Metab 2000 ;85:4053-4059. Ahr é n B, et al. Diabetologia 2001 ;44:19982-1103. LeRoith D. Am J Med 2002;113 ( Suppl 6A)3S- 11S. Toft -Nielsen MB, et al. Diabetes Care 1999;22:1137-1143. Vilsboll T, et al. Diabetes 2001;50:609-613.

PowerPoint Presentation:

The lost efficacy of GIP precludes its application as a therapeutic agent. While the preserved effect of GLP- 1 has inspired attempts to treat Type 2 diabetes with it * ٭ Hoist II, et al ? Bio Drugs 2002; 16:175-181 The unique antidiabetic effects of Glucagon-like peptide-1

PowerPoint Presentation:

Because GLP-1 is rapidly inactivated by the enzyme DPP-4 , modulating its & has become a major focus of investigation for treating type 2 diabetes by Approaches to enhance incretin effects Level activity one of major three approaches, which are known as GLP-1 - based therapies or incretin - based therapies The preserved effects of GLP- 1 has inspired attempts to treat Type 2 diabetes with it 1-4 Mentlein R. Regul Pept 1999; 85:9 -24. Deacon CE, et al. Clin Endocrinol Metab 1995; 80:952-957. Vilsboll T. J Clin Endocrinol Metab , 2003;82706 -2713. Egan JM,. J Clin Endocrinol Metab 2002;87:3768 -3773.

PowerPoint Presentation:

The current approaches to enhance incretin action in patients with type 2 diabetes 1) GLP-1 receptor agonists * : as Exendin -4 or Exenatide ( Half-life of 2-4 h ) ( synthetic exendin-4 ) ( Byetta ®) 2) GLP-1 analogues *: as liraglutide ( Half-life of 12-14 h ) by conjugation of GLP-1 to circulating albumin ( Victoza ®) Incretin mimetics (used by SC injection) DDP-4 degradation-resistant and can produce GLP-1 levels that are more than 5 times a patient's physiologic levels. * Amori RE, et al.JAMA.2007;298:194-206 Liraglutide: Blonde L., et al. Can J Diabetes. 2008;32 (Supp):A107

PowerPoint Presentation:

The Gila Monster Lizard Exendin-4 GLP-1 analogue, exendin-4, first found in the saliva of the Gila monster Lizard

PowerPoint Presentation:

The current approaches to enhance incretin action in patients with type 2 diabetes augment the concentration of endogenously released both GIP and GLP-1 and normalize GLP-1 level in type 2 diabetes and can result in an approximate 2-fold increase in GLP-1 levels. Incretin enhancers ( Gliptins ) (used Orally) Inhibitors of DPP-IV * : Sitagliptin ( Januvia ®) , Viltagliptin ( Galvus ®) saxagliptin ( Onglyza ® ) * Pospisilik JA, et al . Diabetes 2002; 51: 2677-2683 Fonseca VA ,et al. Am J Med.2010; 123(7):S2 -S10. Linagliptin ( Tradjenta ®) Alogliptin ( Nesina ® )

PowerPoint Presentation:

GLP-1 receptor agonist Decreased glucagon secretion Increased insulin secretion Prolonged gastric emptying Decreased food intake Decreased blood glucose Weight loss Increased insulin sensitivity Effects of GLP-1 R agonists ( Gliptins ) on glucose metabolism 1-10 (HbA1c ↓ 0.6 – 1.0%) Pancreatic islet cells Brubaker PL . Trends Endocrinol Metab,2007; 18:240–245 Lovshin JA, et al. Nat Rev Endocrinol . 2009; 5:262–269 Brubaker PL. Trends Endocrinol Metab ,2007;18:240–245 Lovshin JA, et al. Nat Rev Endocrinol , 2009;5:262–269 Drucker DJ,et al . Lancet 2006; 368: 1696–705. Willms B, et al. J Clin Endocrinol Metab 1996; 81: 327–32. Nauck MA, et al. Am J Physiol 1997; 273: E981–8. Maljaars J, et al.Aliment Pharmacol Ther 2007; 26 (Suppl. 2): 241–50. Gutniak M, et al. N Engl J Med 1992; 326:1316-22. Degn KB, et al.Diabetes 2004; 53: 1187–94.

PowerPoint Presentation:

VRS-859 (GLP-1 R agonist SC monthly ; 2011) ITCA 650 ( Exentide Cont. SC delivery for 3 months ; 2011 ) Exendin-4 (Natural GLP-1 ) ; 2002 Exenatide (Synthetic exendin-4 ) ( Byetta ®) SC once or twice/d ;2005 Exenatide LAR ® ( Bydureon ( exenatide extended-release), ; SC once-weekly ); 2012 ( Liraglutide ) ( Victoza ®) (Naturally occurring GLP-1 analogue) ; SC once or twice / d ;2010 CJC-1131 AVE-0010 ZP-1O Albugon ® Albiglutide ® Taspoglutide ® ( GLP-1 analogue; SC once-weekly; 2011 ) Lixisenatide GLP-1 R agonist; SC once / d ; 2010 Current incretin mimetics (GLP-1 R agonists; GLP-1 analogues) used by injection for type 2 diabetes 1-10 LY 2189265 (LY) GLP-1 analogue; SC once-weekly ; 2011) Amori RE, et al.JAMA.2007;298:194-206 Exentide LAR (Once weekly):Drucker DJ, et al. Lancet 2008;372:1240-1250. Liraglutide: Blonde L., et al. Can J Diabetes. 2008;32 (Supp):A107 Grunberger G, et al.Diabetologia 2011;54 {Suppl 1] S318: No. 788. Clland JL, et al. Diabetologia 2011; 54[Suppl 1] S 318:No. 787. Alessi T, et al. Diabetologia 2011; 54 [Suppl 1] S319 :No. 789. Boll G, et al. Diabetologia 2011; 54[Suppl 1] S 316 : No.784. Ratner RE, et al>Diabetologia 2011; 54 [Suppl 1] S317 :No. 785. Rosenstock J, et al. Diabetologia 2011;54 [Suppl 1] S 317 : No. 786. Dahms J, et al. Diabetologia 2011;54 [Suppl 1] S 319 : No. 790. Albiglutide once-weekly

PowerPoint Presentation:

Control GLP-1 analogues Risk Ratio (95% CI), Incretin vs. Control Adverse events Mean % (95% CI) Achieving Control Mean % (95% CI) Achieving Control 7.0 (4.0-12.0) 10.0 (8.1-29.1) 2.30 (1.08-4.88) Hypoglycemia Exenatide vs. Placebo Injection 2.3 (1.3-4.0) 2.3 (1.3-4.1) 1.02 (1.46-2.26) Exenatide vs. Insulin 12.6 (9.0-17.3) 32.9 (25.4-41.4) 1.92 (2.02-4.24) Nausea All GLP-1 analoques vs. Comparator 13.4 (9.5-18.5) 41.9 (36.4-47.7) 3.17 (2.16-4.64) Exenatide vs. Comparator 5.7 (1.8-16.2) 5.6 (3.1-10.1) 0.89 (0.27-3.01) Liraglutide vs. Placebo Injection 4.0 (3.1-5.1) 11.6 (9.1-14.6) 3.32 (2.51-4.41) Vomiting All GLP-1 analoques vs. Comparator 4.0 (3.1-5.1) 14.1 (12.5-15.9) 3.52 (2.64-4.70) Exenatide vs. Comparator 3.6 (0.9-13.4) 2.3 (1.1-4.7) 0.62 (0.13-2.91) Liraglutide vs. Placebo Injection 4.9 (3.7-6.6) 4.9 (3.6-6.7) 10.2 (7.9-13.0) 11.0 (8.8-13.6) 2.23 (1.72-2.89) 2.27 (1.75-2.94) Diarrhea All GLP-1 analoques vs. Comparator Exenatide vs. Comparator Summary of adverse events in patients with type 2 diabetes treated with GLP-1 analogues ( Exenatide and Liraglutide )* * Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206. DPP4: dipeptidyl peptidase 4 ; Comparator :placebo or oral hypoglycemic agent or insulin; CI :confidence interval

PowerPoint Presentation:

* Nachnani J S et al. Diabetologia (2010) 53:153–159. Exendin-4-treated patients: a Vascular thickening (arrow) was seen in exocrine pancreas . Lumen patency was significantly increased with exendin-4 vs controls and more inflammatory cells were present in the adventitia. b Acinar structure disruption and pyknotic nuclei at arrows. No significant damage in islets of Langerhans . c More severe acinar structure disruption involving large acinar section. d Severe acinar destruction and fibrosis. Controls : e, f No damage, acinar pancreas and islets of Langerhans (Exocrine and endocrine pancreas) Photographs of pancreatic tissue sections in rats treated with exendin-4 and controls*

PowerPoint Presentation:

Postmarketing data have shown an increase in acute pancreatitis, including fatal and nonfatal hemorrhagic or necrotizing pancreatitis. In August 2008, the FDA described 36 patients with pancreatitis related to exenatide use. Pancreatitis was also seen in clinical studies of the GLP-1 agonist liraglutide. Byetta . [Package Insert]. San Diego, CA: Amylin Pharmaceuticals, Inc. 2009. FDA alert. Available at: http://www.fda.gov/Drugs/DrugSafety/ostmarketDrugSafetyInformationforPatientsandProviders/ucm124713.htm. Updated August 2008. Cure P, et al. N Engl J Med. 2008;358:1969–1972. Buse JB, et al.(LEAD-6). Lancet 2009; 374: 39– 47 * Exenatide ( Byetta ®) and liraglutide ( Victoza ®) and Acute pancreatitis warning*

PowerPoint Presentation:

Liraglutide stimulates C-cells in rodents, causing an increase in calcitonin and there were few cases of medullary thyroid cancer in these animals and not in humans*. GLP-1 Receptor Agonists Activate Rodent Thyroid C-Cells Causing Calcitonin Release and C-Cell Proliferation * Bjerre Knudsen L et al. Endocrinology 2010;151:1473-1486

PowerPoint Presentation:

Previous studies with rat thyroid C-cell lines and thyroid tissues have shown that activation of the GLP-1 receptor leads to calcitonin secretion * . Plasma calcitonin is a specific biomarker for both C-cell activation and increased C-cell number ** , and changes in calcitonin levels are used in the diagnosis of C-cell disease in humans *** . * Crespel A, et al. Endocrinology 1996;137:3674–3680 Lamari Y, et al. FEBS Lett 1996;393:248–252 Vertongen P, et al. Endocrinology 1996;135:1537–1542 ** Kurosawa M, et al. Arch Gerontol Geriatr 1988;7:229–238 *** Wolfe HJ, et al. N Engl J Med 1973;289:437–441 Exenatide ( Byetta ®) and liraglutide ( Victoza ®) and medullary thyroid cancer (MTC) concerns* Hence, potentially sustained use of Liraglutide might increase the risk for medullary thyroid cancer in human which it did in rodents. however, long-term clinical studies of sufficient size and duration regarding cancer and incretin therapeutics have not yet been completed.

PowerPoint Presentation:

Hence, potentially sustained use of Liraglutide might increase the risk for medullary thyroid cancer in human which it did in rodents. Long-term clinical studies of sufficient size and duration regarding cancer and incretin therapeutics have not yet been completed. Patients should be counseled regarding the risk and symptoms of MTC. Exenatide ( Byetta ®) and liraglutide ( Victoza ®) and medullary thyroid cancer (MTC) concerns* Hence, potentially sustained use of Liraglutide might increase the risk for medullary thyroid cancer in human which it did in rodents. however, long-term clinical studies of sufficient size and duration regarding cancer and incretin therapeutics have not yet been completed.

PowerPoint Presentation:

Overview of current DPP-4 inhibitors (Gliptins) used orally for type 2 diabetes 1-4 Sitagliptin ; Januvia ® 2007 Vildagliptin ; Galvus ® 2008 Saxagliptin ; Onglyza ® 2009 Denagliptin ; Melagliptin ; Alogliptin Dutogliptin ; NVP DPP728 Valine pyrrolidide Linagliptin ; Ondero ® Ile- thiazolidide PSN 9301 Mentlein R. Regul Pept 1999; 85:9 -24. Deacon CE, et al. Clin Endocrinol Metab 1995; 80:952-957. Vilsboll T. J Clin Endocrinol Metab , 2003;82706 -2713. Egan JM,. J Clin Endocrinol Metab 2002;87:3768 -3773.

PowerPoint Presentation:

DPP-IV inhibitors ( Gliptins )   GLP-1 Decreased glucagon secretion Increased insulin secretion Prolonged gastric emptying * Decreased food intake * Decreased blood glucose (HbA1c↓ 0.7% [ 0.5 – 0.8%] ) Weight loss Increased insulin sensitivity * Potential effects to slow gastric emptying and increase satiety probably contribute little to the therapeutic efficacy of DPP-4 inhibitors , therefore they are weight-neutral or may cause slight gains in weight Pancreatic islet cells Effects of DPP-IV inhibitors ( Gliptins ) on glucose metabolism 1-6 Willms B, et al. J Clin Endocrinol Metab 1996; 81: 327–32. Nauck MA, et al. Am J Physiol 1997; 273: E981–8. Maljaars J, et al.Aliment Pharmacol Ther 2007; 26 (Suppl. 2): 241–50. Gutniak M, et al. N Engl J Med 1992; 326:1316-22. Degn KB, et al.Diabetes 2004; 53: 1187–94. Richter B, et al. Cochrane Database Syst Rev 2008; ?????: CD006739.

PowerPoint Presentation:

GLP-1R agonists DPP-IV inhibitors Administration Injection Oral Mechanism of actions Pure GLP-1 effect GLP-1 + GIP Pharmacological levels of GLP-1 Physiological levels of GLP-1  Insulin secretion +++ +  Glucagon secretion ++ ++ Gastric emptying Inhibited +/- Weight loss Yes No Expansion of β -cell mass in preclinical studies Yes Yes Nausea and vomiting Yes No (or less) Pancreatitis Yes Yes Potential immunogenicity Yes No Specificity lack specificity strictly Specific GLP-1R agonists vs. DPP-IV inhibitors

PowerPoint Presentation:

Control DDP-4 inhibitors Risk Ratio (95% CI), Incretin vs. Control Adverse events Mean % (95% CI) Achieving Control Mean % (95% CI) Achieving Control 1.4 (0.6-3.4) 1.6 (0.7-3.2) 0.97(0.50-1.86) Hypoglycemia All DDP4 inhibitors vs comparator 1.5 (0.2-8.5) 1.8 (0.9-3.3) 0.92 (0.30-2.87) Sitagliptin vs comparator 1.2 (0.3-5.7) ( 1.4 ( 0.4-4.8 0.84 (0.50-1.19) Vildagliptin vs comparator Nausea 3.1 (2.0-4.7) 1.4 (0.7-2.4) 5.2 (3.6-7.4) 2.7 (2.1-3.4) 2.1 (1.4-3.0) 3.4 (2.6-4.6) 0.89 (0.58-1.36) 1.46 (0.88-2.43) 0.57 (0.37-0.88) All DDP4 inhibitors vs comparator Sitagliptin vs comparator Vildagliptin vs comparator 1.5 (0.9-2.6) 1.2 (0.8-1.9) NR 1.3 (0.8-2.2) 1.1 (0.6-2.0) NR 0.69 (0.42-1.15) 0.86 (0.45-1.65) 0.49 (0.21-1.1.11) Vomiting All DDP4 inhibitors vs comparator Sitagliptin vs comparator Vildagliptin vs comparator 4.0 (1.8-4.6) 2.8 (1.8-4.6) 9.9 (2.7-30.7) 3.8 (2.8-5.1) 3.6 (2.5-5.1) 4.0 (2.0-8.0) 0.80 (0.42-1.54) 1.21 (0.81-1.80) 0.34 (0.14-0.80) Diarrhea All DDP4 inhibitors vs comparator Sitagliptin vs comparator Vildagliptin vs comparator Summary of adverse events in patients with type 2 diabetes treated with DDP-4 inhibitors (Sitagliptin and Vildagliptin)* * Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206. DPP4: dipeptidyl peptidase 4 ; Comparator :placebo or oral hypoglycemic agent or insulin; CI :confidence interval

PowerPoint Presentation:

DPP- 4 is a ubiquitous cell-membrane protein, expressed in many tissues, including lymphocytes , which has raised some concerns about the long-term effects of DPP4 inhibitors, especially on immune function. DPP-4 inactivates many peptides and is identical to the T cell activation antigen CD26 , so its inhibition potentially can affect many pathways. Thus, long term safety is unknown. * Drucker DJ, et al. Lancet. 2006;368(9548):1696-1705 Fleicher B. Immunol Today 1994 ;15 :180 –184 Kieffer TJ, et al. Endocrinology 1995 ;136 :3585 –3596 Marguet D, et al. Proc Natl Acad Sci U S A 2000 97 :6874 –6879 Long-term effects of DPP-4 inhibitors on immune function of patients with type 2 diabetes*

PowerPoint Presentation:

Studies analysis showed an increased risk of infections. Post-marketing reports of anaphylaxis , angioedema , rash , urticaria and exfoliative skin conditions such as Stevens-Johnson syndrome have occurred with sitagliptin (Januvia), up to 3 months after starting treatment. It has also been suggested that immunomodulatory effects of DPP-4 inhibition might increase risk for all cancers including pancreatic and thyroid cancer **. * Drucker DJ, et al. Lancet. 2006;368(9548):1696-1705. ** Havre PA, et al. Front Biosci 2008;13:1634–1645. Matteucci E, Giampietro O. Curr Med Chem 2009;16:2943–2951. Other adverse events in patients with type 2 diabetes treated with DPP4 inhibitors (i.e. Sitagliptin:Januvia )*

PowerPoint Presentation:

Control DDP-4 inhibitors Risk Ratio (95% CI), Incretin vs. Control Adverse events Mean % (95% CI) Achieving Control Mean % (95% CI) Achieving Control 3.2 (1.7-5.7) 2.6 (1.7-3.9) NR 2.4 (1.8-3.2) 2.5 (1.8-3.3) NR 0.73 (0.36-1.45) 0.92 (0.47-1.80) 0.32 (0.16-0.66) Abdominal pain All DDP4 inhibitors vs comparator Sitagliptin vs comparator Vildagliptin vs comparator 2.4 (1.7-3.5) 2.6 (1.8-3.9) 1.7 (0.7-4.1) 2.9 (2.1-4.0) 2.5 (1.7-3.5) 4.8 (2.6-8.6) 1.07 (0.65-1.78) 0.95 (0.54-1.78) 1.86 (0.57-6.11) Couph All DDP4 inhibitors vs comparator Sitagliptin vs comparator Vildagliptin vs comparator 4.4 (3.4-5.8) 5.3 (3.7-7.4) 6.1 (5.0-7.4) 4.1 (3.3-5.1) 4.0 (3.1-5.1) 4.2 (2.5-7.1) 0.87 (0.64-1.19) 0.95 (0.65-1.39) 0.73 (0.42-1.27) Influenza All DDP4 inhibitors vs comparator Sitagliptin vs comparator Vildagliptin vs comparator 4.5 (3.0-6.7) 7.3 (6.0-8.9) 6.4 (4.9-8.4) 6.4 (5.1-7.8) 5.3 (3.5-7.9) 7.3 (5.8-9.3) 1.17 (0.98-1.40) 1.38 (1.06-1.81) 1.02 (0.80-1.29) Nasopharyngitis All DDP4 inhibitors vs comparator Sitagliptin vs comparator Vildagliptin vs comparator * Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206. DPP4: dipeptidyl peptidase 4 ; Comparator :placebo or oral hypoglycemic agent or insulin; CI :confidence interval Adverse events in patients with type 2 diabetes treated with DDP-4 inhibitors ( Sitagliptin and Viltagliptin )*

PowerPoint Presentation:

Control DDP-4 inhibitors Risk Ratio (95% CI), Incretin vs. Control Adverse events Mean % (95% CI) Achieving Control Mean % (95% CI) Achieving Control 6.4 (4.9-8.4) 4.7 (2.8-8.0) 8.0 (6.5-9.8) 6.3 (5.1-7.7) 5.7 (4.0-8.0) 6.8 (5.3-8.6) 0.99 (0.81-1.21) 1.09 (0.84-1.43) 0.88 (0.65-1.18) Upper respiratory tract infection All DDP4 inhibitors vs comparator Sitagliptin vs comparator Vildagliptin vs comparator 3.4 (2.4-4.8) 2.5 (1.6-3.9) 5.4 (3.1-9.2) 2.0 (1.3-3.1) 2.2 (1.4-3.4) 1.2 (0.3-4.1) 0.61 (0.34-1.12) 0.81 (0.41-1.58) 0.20 (0.05-0.78) Sinusitis All DDP4 inhibitors vs comparator Sitagliptin vs comparator Vildagliptin vs comparator 2.4 (1.8-3.2) 2.6 (1.9-3.5) 1.3 (0.5-3.3) 3.2 (2.3-4.5) 3.1 (2.1-4.6) 3.6 (1.5-8.3) 1.52 (1.04-2.21) 1.42 (0.95-2.11) 2.72 (0.85-8.68) Urinary tract infection All DDP4 inhibitors vs comparator Sitagliptin vs comparator Vildagliptin vs comparator 3.9 (3.1-4.8) 3.1 (1.9-4.9) 4.4 (3.4-5.6) 5.1 (4.1-6.4) 3.6 (2.9-4.5) 6.3 (5.0-8.0) 1.38 (1.10-1.72) 1.24 (0.82-1.87) 1.47 (1.12-1.94) Headache All DDP4 inhibitors vs comparator Sitagliptin vs comparator Vildagliptin vs comparator Adverse events in patients with type 2 diabetes treated with DDP-4 inhibitors ( Sitagliptin and Viltagliptin )* * Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206. DPP4: dipeptidyl peptidase 4 ; Comparator :placebo ororal hypoglycemic agent or insulin; CI :confidence interval

PowerPoint Presentation:

Drug regulatory agencies are unlikely to receive data on drug safety that are independent of industry ties. Moreover, university-based medicine institutions have not viewed the problem of drug surveillance as a worthy academic pursuit. Until surveillance tools devoid of industry influence have been established to provide more robust data, such dilemmas of uncertainty regarding adverse effects will remain unsolved.” Drug regulatory agencies and university-based medicine Institutions and drug surveillance ( industry influence)

PowerPoint Presentation:

** Matveyenko AV et al.Diabetes 2009 ;58 : 1604-1615. Increased ductal cell turnover and ductal metaplasia are well-characterized risk factors for pancreatic ductal cancer and pancreatitis 1-4 . Parsa I, et al. Cancer Res 1985; 45: 1285– 1290 Wagner M, et al. Genes Dev 2001; 15: 286– 293 Wagner M, et al. Gastroenterology 2002; 122: 1898– 1912 Lowenfels AB, et al. N Engl J Med 1993; 328: 1433– 1437. Representative images of increased exocrine pancreatic ductal cell replication in HIP* Rats treated with sitagliptin “ Januvia ” for 12 weeks** * HIP: H uman I slet amyloid P olypeptide transgenic rats, a model for type 2 diabetes

PowerPoint Presentation:

*Matveyenko AV et al. Diabetes 2009 ;58 : 1604-1615. Necrotizing pancreatitis in a HIP rat treated with sitagliptin “ Januvia ” for 12 weeks*

PowerPoint Presentation:

In 2009, FDA has completed a review of 88 cases of acute pancreatitis in patients using sitagliptin or sitagliptin / metformin . The cases were reported to FDA’s Adverse Event Reporting System (AERS) between October 2006 and February 2009. Hospitalization: 66% of the patients, 4 to the intensive care unit. Two cases of hemorrhagic or necrotizing pancreatitis. 21% of pancreatitis cases occurred within 30 days of starting sitagliptin , sitagliptin / metformin . The most common adverse events were abdominal pain, nausea and vomiting. Sitagliptin or sitagliptin/metformin (marketed as Januvia and Janumet) Acute pancreatitis warning FDA , U.S. Food and Drug Adminstration

PowerPoint Presentation:

Odds ratio of test vs control events (pancreatitis pancreatic and thyroid cancer, or any cancer) for exenatide , sitagliptin , and other therapies *. * Elashoff R, et al. Gastroenterology. 2011 Jul;141(1):150-6. Source : Larry L. Hillblom Islet Research Center at David Geffen School of Medicine and Department of Biomathematics, University of California These data are consistent with case reports and animal studies and indicating an increased risk for pancreatitis with GLP-1-based therapy. The findings also raise caution about the potential long-term actions of these drugs to promote pancreatic cancer. Conflicts of Interest The authors disclose no conflicts. Funding Supported by the Larry L. Hillblom Foundation.

PowerPoint Presentation:

* Elashoff M,et al. Gastroenterology.2011 Jul;141(1):150-6. These data are consistent with case reports and animal studies and indicating an increased risk for pancreatitis with GLP-1-based therapy. The findings also raise caution about the potential long-term actions of these drugs to promote pancreatic cancer. The odds ratio of an adverse report of pancreatitis, pancreatic and thyroid cancer, or any cancer associated with exenatide and/or sitagliptin therapy vs other therapies*.

PowerPoint Presentation:

In 2009, FDA has asked the manufacturer of these products to revise the prescribing information to include: post-marketing reports of acute pancreatitis. Patients should carefully be monitored for pancreatitis after initiation or dose increases of these drugs. These drugs should be used with caution in patients with a history of pancreatitis. Considerations for Healthcare Professionals regarding the use of sitagliptin ( Januvia )

PowerPoint Presentation:

Be aware of the signs and symptoms of pancreatitis such as nausea, vomiting, anorexia, and persistent severe abdominal pain, sometimes radiating to the back. Discontinue these drugs if pancreatitis is suspected. If pancreatitis is suspected in a patient, supportive medical care should be instituted. The patient should be monitored closely with appropriate laboratory studies such as serum and urine amylase, amylase/creatinine clearance ratio, electrolytes, serum calcium, glucose, and lipase. Inform patients of the signs and symptoms of acute pancreatitis. Considerations for Healthcare Professionals regarding the use of sitagliptin and sitagliptin/metformin (Januvia and Janumet)

Cochrane Database of Systematic Reviews 2008 on DPP-4 inhibitors for type 2 diabetes mellitus*:

Cochrane Database of Systematic Reviews 2008 on DPP-4 inhibitors for type 2 diabetes mellitus* DPP-4 inhibitors have some theoretical advantages over existing therapies with oral antidiabetic compounds but should currently be restricted to individual patients. Long-term data especially on cardiovascular outcomes and safety are urgently needed before widespread use of these agents. More information on the benefit-risk ratio of DPP-4 inhibitor treatment is necessary especially analysing adverse effects on parameters of immune function. Also, long-term data are needed investigating patient-oriented parameters like health related quality of life, diabetic complications and all cause mortality. * Richter B, Bandeira-Echtler E, Bergerhoff K, Lerch C. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2008, Issue 2. Art. No.: CD006739. DOI: 10.1002/14651858.CD006739.pub2

Example of conflict of interests or Competing interests:

Example of conflict of interests or Competing interests BMC Endocr Disord. 2010; 10: 7. Published online 2010 April 22. doi: 10.1186/1472-6823- 10-7 Safety and tolerability of sitagliptin in clinical studies: a pooled analysis of data from 10,246 patients with type 2 diabetes Debora Williams-Herman ; Samuel S Engel ; Elizabeth Round ; Jeremy Johnson; Gregory T Golm ; Hua Guo ; Bret J Musser ; Michael J Davies ; Keith D Kaufman: ; Barry J Goldstein Received February 10, 2010; Accepted April 22, 2010. Conclusions : In this updated pooled safety analysis of data from 10,246 patients with type 2 diabetes, sitagliptin 100 mg/day was generally well tolerated in clinical trials of up to 2 years in duration. Disclosures All authors are employed by Merck Sharp & Dohme , Corp., a subsidiary of Merck & Co., Inc., the manufacturer of sitagliptin and may have company stock or stock options.

PowerPoint Presentation:

A Systematic Assessment of Cardiovascular Outcomes in the Saxagliptin Drug Development Program for Type 2 Diabetes DOI: 10.3810/pgm.2010.05.2138 Conclusion : No increased risk of CV death/MI/stroke was observed in patients randomly assigned saxagliptin across a broad drug development program. Although this systematic overview has inherent and important limitations, the data support a potential reduction in CV events with saxagliptin. The hypothesis of CV protection with saxagliptin will be tested prospectively in a large randomized clinical outcome trial evaluating saxagliptin compared with standard of care in patients with type 2 diabetes at increased risk for CV events. Conflict of Interest s Statement s Robert Frederich, MD, PhD, Fred Fiedorek, MD, Mark Donovan, PhD, Niklas Berglind, BSc, Roland Chen, MD, and Robert Wolf, MD are employed by Bristol-Myers Squibb. Susan Harris , MS is employed by AstraZeneca. John H. Alexander , MD, MHS, FACC provided consulting or other services, and received honoraria from, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CSL Behring, Duke Private Diagnostic Clinic, Duke Health System, and Regado Biosciences. John H. Alexander also received research grant or contract funding from Bristol-Myers Squibb, Duke Health System, Medtronic Japan, Merck and Company, National Institutes of Health, Pfizer, and Regado Biosciences. Kenneth W. Mahaffey , MD provided consulting or other services, received honoraria, or received research grant or contract funding from, or provided educational activities or lectures for, Adolor Corp, Alexion, Amgen Inc., Amylin Inc., Argolyn, AstraZeneca, Bayer HealthCare, Boehringer Ingelheim, Brigham & Women’s Hospital, Bristol-Myers Squibb, CardioKinetix Inc., Cierra, Cordis, Daiichi Sankyo, Duke University School of Medicine, Edwards Lifesciences, Eli Lilly, Elsevier (AHJ), Forest Laboratories, Genentech, GlaxoSmithKline, Guidant Corporation, Innocoll Pharmaceuticals, Johnson & Johnson, KCI Medical, Luitpold Pharmaceutical, Medtronic Inc., Merck and Company, Momenta Pharmaceutical, Novartis, Pfizer, Portola Pharmaceutical, Proctor and Gamble, Pozen, Regado Biosciences, sanofi-aventis, Schering-Plough Corp., Scios Inc., The Medicines Company, WebMD, and William Beaumont Hospital. Example of conflict of interests or Competing interests

PowerPoint Presentation:

Sitagliptin : review of preclinical and clinical data regarding incidence of pancreatitis S S Engel, D E Williams-Herman, G T Golm , R J Clay, S V Machotka , K D Kaufman, and B J Goldstein Int J Clin Pract . 2010 June; 64(7): 984–990. Conclusions Preclinical and clinical trial data with sitagliptin to date do not indicate an increased risk of pancreatitis in patients with T2DM treated with sitagliptin . Disclosures All authors are employees of Merck & Co., Inc., the manufacturer of sitagliptin and may have stock or stock options in the company. Received February 2010; Accepted February 2010. Example of conflict of interests or Competing interests

PowerPoint Presentation:

Dore DD, et alCurrent Medical Research and Opinion. 2009;25 :1019-1027. Curr Med Res Opin. 2009 Apr;25(4):1019-27. Dore DD , Seeger JD , Arnold Chan K . Source i3 Drug Safety, 950 Winter Street, Waltham, MA 02451, USA. [email protected] CONCLUSIONS: These data do not provide evidence for an association of acute pancreatitis among initiators of exenatide or sitagliptin compared to met/gly initiators. These results are limited by the data available in an administrative, healthcare database. Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide . Declaration of interest: Funding for this research was provided to i3 Drug safety by Amylin Pharmaceuticals, , Inc., which has a global agreement with Eli Lilly and Company to collaborate on the development and commercialization of exentide . D.D.D., J. D.S. and K.A.C. are employees of i3 Drug Safety. Example of conflict of interests or Competing interests

PowerPoint Presentation:

Acute Pancreatitis in Type 2 Diabetes Treated With Exenatide or Sitagliptin A retrospective observational pharmacy claims analysis Rajesh Garg , MD 1 , William Chen , PHD, MPH 2 and Merri Pendergrass , MD, PHD 2 , 3 CONCLUSIONS Our study demonstrated increased incidence of acute pancreatitis in diabetic versus nondiabetic patients but did not find an association between the use of exenatide or sitagliptin and acute pancreatitis. The limitations of this observational claims-based analysis cannot exclude the possibility of an increased risk. Despite these limitations, these data provide valuable information for practicing clinicians weighing potential reported benefits versus risks, including the FDA warning of increased pancreatitis. Declaration of interest: No potential conflicts of interest relevant to this article were reported. Garg R, et al. Diabetes Care November 2010 vol. 33 :2349 - 2354 Example of conflict of interests or Competing interests

PowerPoint Presentation:

Many side effects, drug interactions, and effectiveness can not be detected when drugs are approved. They may be found only after drugs have been used by millions of people and for a long time. In addition, available reports were sponsored by pharmaceutical companies and arguably have a limited capacity to detect adverse outcomes*. Drug regulatory agencies are unlikely to receive data on drug safety (i.e. an administrative, healthcare database.) that are independent of industry ties . Moreover, university-based medicine institutions have not viewed the problem of drug surveillance as a worthy academic pursuit. Until surveillance tools devoid of industry influence have been established to provide more robust data, such dilemmas of uncertainty regarding adverse effects will remain unsolved.” * Dore DD, et al. Curr Med Res Opin 2009;25:1019–1027. Williams-Herman D,et al. BMC Endocr Disord 2008;8:14. Drug surveillance and a real world approach for drugs

PowerPoint Presentation:

* Butler PC, et al. Diabetologia (2010) 53:1–6. Animal studies: ** Nachnani JS, et al. Diabetologia 2009; doi:10.1007/s00125-009 Matveyenko AV, et al .Diabetes 2009;58:1604–1615 Although, the GLP-1–based therapies arrived in clinical practice with much fanfare and anticipation*, ** the use of these drugs has not been formally recommended by all expert panels.

PowerPoint Presentation:

Theoretical model to explain currently available observations with increased risks for acute pancreatitis and pancreatic cancer in individuals with Obesity & Type 2 diabetes GLP-1 Rx ? Metformin Rx(insulin Rx) decreased increased Pancreatic cancer Acute pancreatitis . Diabetologia 2009;52:1699–1708. Nat Clin Pract Gastroenterol Hepatol 2004; 1: 46– 52 . Shetty S, et al. J Manag Care Pharm 2005;11:559–564. Coughlin SS, et al. Am J Epidemiol 2004;159:1160–1167 Monami M, et al. Diabetes Care 2008;31:1455–1460. Denker PS, et al. Diabetes Care 2006; 29: 471 Cure P, et al. N Engl J Med 2008; 358: 1969– 1970 Tripathy NR, et al. J Assoc Physicians India 2008; 56: 987– 988 Parnaud G, et al. Diabetologia 2008; 51: 91– 100 Vainio H, Bianchini F. IARC handbooks of cancer prevention. Volume 6: Weight control and physical activity. Lyon, France: IARC Press, 2002. Polednak AP. Cancer Detection and Prevention 2003; 27(6):415–421. Calle EE, et al. New England Journal of Medicine 2003; 348(17):1625–1638. Evans JM, et al.BMJ 2005;330 1304–1305. Luo Z, et al. Trends in Pharmacological Sciences 2005;26 69–76. McCarty MF. Medical Hypotheses 2004;63 334–339. Ruderman N,et al. Nature Reviews. Drug Discovery 2004;3 340–351. Alimova IN, et al. Cell Cycle 2009;8 909–915. Cazzaniga M, et al. Cancer Epidemiology, Biomarkers and Prevention 2009;18 701–705.

PowerPoint Presentation:

Butler PC, et al. Diabetologia (2010) 53:1–6. Nachnani JS, et al. Diabetologia 2009; doi:10.1007/s00125-009 Matveyenko AV, et al .Diabetes 2009;58:1604–1615 The GLP-1–based therapies arrived in clinical practice with much fanfare and anticipation. *

PowerPoint Presentation:

to assume that new drugs are better (‘Never be the first, or the last, to use a new drug.’ ) to use pharmaceuticals to treat a non-pharmaceutical problem; to repeat prescriptions that serve no rational purpose; to use one drug to counter the side effects produced by another; to overestimate the benefits of your intervention; to pursue the mirage of longevity beyond the realms of common sense; and to reduce the quality of the life you are trying to improve. Suggested seven deadly sins of drug prescription And this sin is to assume that: new drugs are better Never be the first, or the last, to use a new drug We control the market for products that we neither pay for nor consume, and whose unwanted consequences are experienced by other people

PowerPoint Presentation:

Thank you

authorStream Live Help