Diese Präsentation wurde erfolgreich gemeldet.
Wir verwenden Ihre LinkedIn Profilangaben und Informationen zu Ihren Aktivitäten, um Anzeigen zu personalisieren und Ihnen relevantere Inhalte anzuzeigen. Sie können Ihre Anzeigeneinstellungen jederzeit ändern.
Incretin-Based Therapies for the  Treatment of Type 2 Diabetes: Update on the Benefits and RisksDr. Abdulameer Abdullah Al...
No financial relationships with   any commercial interests
The gastrointestinal tract              has a crucial role in the control of                     energy homeostasis       ...
The role of                                         Insulin                                           in         glucose h...
However,                how   glucose enters the blood stream                has profound effects on             magnitude...
The observation that in response to          hyperglycemic stimuli,1.E                              En lrick              ...
The incretin effect             Energy administeration      The gut        via                                    The pare...
Plasma Insulin (µU/mL)   The incretin effect*                                                Time (min)* Perley MI,et al. ...
And                                    this finding                              m                              L         ...
These factors have come to be termed            “Incretins“         (INtestine seCRETtion Insulin)                      an...
These two native incretin hormones are :  Glucagon-like peptide-1         (GLP-1)                          1.   Bell GI, e...
(K-cells of the intestinal mucosa)                              *   Takeda J, et al.Proc Natl Acad Sci U S A 1987; 84:700...
(L-cells of the intestinal mucosa)                                                                       * Orskov C, et ...
      GLP-1 -secreting enteroendocrine    L-cells are located predominantly in      the ileum and colon1-3.       GIP-se...
Interactions between                        nutrients and GIP and GLP- 1   On a rapid time scale, typically occurring when...
Incretin Receptors (GIP Receptors)               The human       gipr gene                        1-4 is localized to chr...
Incretin Receptors (glp-1 Receptors)                  The human      glp-1r gene                            1-5is located...
Molecular mechanisms underlying the insulinotropic    effects of GIP and GLP-1 on Pancreatic beta cell*                   ...
Glucose-dependency of the insulin stimulatory      effect of glucagon-like peptide-1                                      ...
Dipeptidyl-peptidase -IV (DPP -IV ) enzymeA subset of prolyl oligopeptidases, includingdipeptidyl-peptidase IV (DPP IV ) o...
Dipeptidyl-peptidase - 4                      *DPP -IV ) enzyme) In 1993 it was demonstrated that ( Dipeptidyl-peptidase -...
Endocrine pathway for the actions of GLP- 1*    Nutrients                                  Incretin Secretionin the gut lu...
Inactivation of GLP-1 and GIP by Dipeptidyl peptidase-IV (DPP-IV) enzyme((1-11                                            ...
GLP-1 (yellow) released by enteroendocrine L-cells,             diffuses to the capillaries, where it is inactivated by   ...
The incretin hormones and   Pathophysiology of Type 2 DM                                                                  ...
The incretin hormones and Pathophysiology                                    of Type 2 DM              Consequently in pat...
Pathophysiological changes in Type 2 diabetes1-6                                              1.                          ...
The unique antidiabetic effects of  Glucagon-like peptide-1                            The lost efficacy of GIP           ...
Approaches to enhance incretin effectsThe preserved effects of GLP- 1 has inspired attempts to              treat Type 2 d...
The current approaches to enhance incretin         action in patients with type 2 diabetes    1) GLP-1 receptor agonists *...
GLP-1 analogue, exendin-4,         first found in the saliva of the Gila monster LizardThe Gila Monster Lizard            ...
The current approaches to enhance incretin    action in patients with type 2 diabetes•       Inhibitors of DPP-IV *:      ...
Effects of GLP-1 R agonists (Gliptins)                on glucose metabolism1-10                             GLP-1 receptor...
Current incretin mimetics            (GLP-1 R agonists; GLP-1 analogues) used by                  injection for type 2 dia...
Photographs of pancreatic tissue sections in rats     treated with exendin-4 and controls*Exendin-4-treated patients:a  Va...
Exenatide (Byetta®) and liraglutide(Victoza®) and  *Acute pancreatitis warning Postmarketing data have shown an increase ...
GLP-1 Receptor Agonists Activate Rodent Thyroid C-Cells  Causing Calcitonin Release and C-Cell ProliferationLiraglutide st...
Exenatide (Byetta®) and liraglutide (Victoza®)    and medullary thyroid cancer (MTC) concerns* Previous studies with rat ...
Exenatide (Byetta®) and liraglutide (Victoza®)and medullary thyroid cancer (MTC) concerns* Hence, potentially sustained u...
Overview of current DPP-4 inhibitors (Gliptins) used                orally for type 2 diabetes 1-4                        ...
Effects of DPP-IV inhibitors (Gliptins)                          on glucose metabolism 1-6DPP-IV inhibitors (Gliptins)  ...
Summary of adverse events in patients with type 2 diabetes treated with GLP-1 analogues (Exenatide and Liraglutide)*      ...
Summary of adverse events in patients with type 2 diabetes treated with DDP-4 inhibitors (Sitagliptin and Vildagliptin)*  ...
Long-term effects of DPP-4 inhibitors on      immune function of patients with type 2 diabetes*    DPP- 4 is a ubiquitous...
Other adverse events in patients with type 2 diabetes  treated with DPP4 inhibitors (i.e. Sitagliptin:Januvia)* Studies a...
Adverse events in patients with type 2 diabetes treatedwith DDP-4 inhibitors (Sitagliptin and Viltagliptin)*              ...
Adverse events in patients with type 2 diabetes  treated with DDP-4 inhibitors (Sitagliptin and Viltagliptin)*            ...
Representative images of increased exocrine pancreatic      ductal cell replication in HIP* Rats treated with sitagliptin ...
Necrotizing pancreatitis in a HIP rat treated with sitagliptin “Januvia” for 12 weeks**Matveyenko AV et al. Diabetes 2009 ...
Sitagliptin or sitagliptin/metformin  marketed as Januvia and Janumet))  Acute pancreatitis warning In 2009, FDA has comp...
Odds ratio of test vs control events (pancreatitis pancreatic and thyroid cancer, or any cancer) for .*exenatide, sitaglip...
Considerations for Healthcare Professionals regarding the use of sitagliptin and sitagliptin/metformin(Januvia and Janumet...
Considerations for Healthcare Professionals     regarding the use of sitagliptin and sitagliptin/metformin    (Januvia and...
Drug surveillance and a real world approach for drugs Many side effects, drug interactions, and effectiveness can not  be...
Comparison between   GLP-1 analogs and DDP-IV inhibiters                SpecificityThe effects of GLP-analogs are strictly...
Undesirable side effects due to other                                 potential endogenous                       DPP-IV su...
Unanswered questions       GLP-1R agonists and DPP-IV inhibitorsFurthermore, GLP-1R agonists exhibit <100% amino acid     ...
Unanswered questions        GLP-1R agonists and DPP-IV inhibitors   DPP-IV, is activated by external stimuli and modulates...
 DPP-4 inhibitors have some theoretical  advantages over existing therapies with  oral antidiabetic compounds but should ...
 Long-term data especially on  cardiovascular outcomes and safety are   urgently needed before widespread use  of these a...
 More information on the benefit-risk  ratio of DPP-4 inhibitor treatment is  necessary especially analysing adverse  eff...
 Also, long-term data are needed  investigating patient-oriented  parameters like health related quality  of life, diabet...
Physician relationships with the industry“Conflict implies that there is a problem orargument, and I don’t believe that th...
Physician relationships with the industry   Clinical practice guidelines are increasingly used in  medical malpractice cas...
Physician relationships with the industryWhat we have to be careful about is thatmany trials are not designed to answer   ...
BMC Endocr Disord. 2010; 10: 7. Published online 2010 April 22. doi: 10.1186/1472-6823-10-7Safety and tolerability of sita...
Example of conflict of interests or Competing       interestsA Systematic Assessment of Cardiovascular Outcomes in the Sax...
Example of conflict of interests or   Competing interestsSitagliptin: review of preclinical and clinical dataregarding inc...
Example of conflict of interests or  Competing interestsUse of a claims-based active drug safety surveillance system to as...
Example of conflict of interests or  Competing interestsAcute Pancreatitis in Type 2 Diabetes Treated With Exenatide orSit...
Although, the GLP-1–based                                                                     therapies arrived in clinica...
Theoretical model to explain currently available observations with increased risks for   d ecr                            ...
Conclusions   Glucagon-like peptide-1-based therapy is gaining widespread use    for type 2 diabetes, although there are ...
JanuviaPotentially extremely   Dangerous and                                       Januvia      expensive                 ...
Suggested seven deadly sins of drug prescription                                And•   toWe control the marketare the firs...
Thank you
Glp 1-based therapies for treatment of type 2 diabetes  update on the benefits and risks
Glp 1-based therapies for treatment of type 2 diabetes  update on the benefits and risks
Nächste SlideShare
Wird geladen in …5
×

Glp 1-based therapies for treatment of type 2 diabetes update on the benefits and risks

GLP-1R agonists lower glycated haemoglobin by about 0.6–1% and induce weight loss. DPP-4 inhibitors reduce glycated haemoglobin by 0.5–0.6% and have no effect on weight. 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.

Ähnliche Bücher

Kostenlos mit einer 30-tägigen Testversion von Scribd

Alle anzeigen

Ähnliche Hörbücher

Kostenlos mit einer 30-tägigen Testversion von Scribd

Alle anzeigen
  • Als Erste(r) kommentieren

Glp 1-based therapies for treatment of type 2 diabetes update on the benefits and risks

  1. 1. Incretin-Based Therapies for the Treatment of Type 2 Diabetes: Update on the Benefits and RisksDr. Abdulameer Abdullah Al-ashbal Ass.Prof. ; Consultant Diabetologist Almustansiriya medical college , Department of Medicine ; Alyermouk Teaching Hospital
  2. 2. No financial relationships with any commercial interests
  3. 3. 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.Dr. Abdulameer Abdullah Al-ashbalAss.Prof. ; Consultant Diabetologist
  4. 4. The role of Insulin in glucose homeostasisis a firmly established concept and forms the cornerstone of discussions of the pathophysiolgy of diabetes. Dr. Abdulameer Abdullah Al-ashbal Ass.Prof. ; Consultant Diabetologist
  5. 5. However, how glucose enters the blood stream has profound effects on magnitude of stimulatory effect of glucose on insulin secetrion.Dr. Abdulameer Abdullah Al-ashbalAss.Prof. ; Consultant Diabetologist
  6. 6. The observation that in response to hyperglycemic stimuli,1.E En lrick do cri H, e •M 19 nol M t al. J oral glucose19 cInty 64; 2 etab Clin 64 ; 2 re N 4: 10 :2 0– , et al 76–1 elicits a greater insulin response than 21 . . Lan 082. cet intravenous glucose, is termed “The Incretin Effect “, which accounts for up to 60% of postprandial insulin release in healthy people
  7. 7. The incretin effect Energy administeration The gut via The parenteral route Glucose Glucose + (Insulin secretagogue) (Insulin secretagogue) Gut-derived signals(Potent insulin secretagogues) Insulin release Insulin release
  8. 8. Plasma Insulin (µU/mL) The incretin effect* Time (min)* Perley MI,et al. J Clin Invest. 1967; 46:1954-1962.
  9. 9. And this finding m L m U P µ u n a I s ( / i l) Time (min) firmly implicated gastrointestinal factors* as important mediators of insulin secretion after oral glucose* Mcintyre N, et al. J Clin Endocrinol Metab , 1965 25:1317–1324.
  10. 10. These factors have come to be termed “Incretins“ (INtestine seCRETtion Insulin) andtheir role on glucose homeostasis has led to Zunz E, et al. Arch Int Physiol Biochim 1929; 31: 20–44. a novel class of incretin-based antihyperglycemic agents based on the function and physiology of two endogenous dominant incretin hormones
  11. 11. These two native incretin hormones are : Glucagon-like peptide-1 (GLP-1) 1. Bell GI, et al. Nature 1983 ; 302 :716 -718 2. Heinrich C. et al. Endocrinology 1984: 115:2176-2181 3. Mojsov S, et al. I Biol Chem 1986; 261:11880-11889 4. Novak U, et al. European Journal of Biochemistry 1987; 164:553-558 5. Holst JJ, et al. FEBS Lett 1987; 211:169-174 6. Kreymann B, et al. Lancet. 1987;2:1300-4 7. Ørskov C ,et al . Endocrinology 1986 ;119 :1467-1475 8. Mojsov S ,et al . J Clin Invest 1987; 79 :616-619 that principally responsible for the incretin effect 1-8.
  12. 12. (K-cells of the intestinal mucosa) * Takeda J, et al.Proc Natl Acad Sci U S A 1987; 84:7005–7008
  13. 13. (L-cells of the intestinal mucosa)  * Orskov C, et al. En-docrinology 1986; 119:1467—1475.
  14. 14.  GLP-1 -secreting enteroendocrine L-cells are located predominantly in the ileum and colon1-3. GIP-secreting enteroendocrine K-cells are concentrated in 1. Bell GI,et al. Nature 1983; 302: 716–718. the duodenum and proximal jejunum1-6. 2. Schmidt WE,et al. Diabetologia 1985; 28: 1. JF et al. Diabetes Metab 704–707. 2005;31:233-242 3. Kreymann B, et al. 2. Drucker DJ.Diabetes Care Lancet 1987; 2: 1300– 1304. These native hormones are secreted 2003; 26:1929-2940 3. Orskov C,et al. Diabetes Insulin 1994 ;43:535-53 4. Damholt, et al. at low basal levels in the fasting 1. Inagaki N, et al. Mol m P Endocrinology 1999 ;140, a s l Endocrinol 1989; 3: 1014– 4800-4808 n a o r e c s 1021. t i 5. Holst, J. J. Physiol. Rev. 87: state and their circulating levels 2. Takeda J, et al. Proc Natl 1409-1439 2007; doi:10.1152/physrev.00034.2006 Acad Sci USA 1987; 84: GLP-1 7005–7008. 3. Brown JC, et al. J Physiol increase rapidly and transiently m P 1970; 209: 57–64. a s l 4. Dupre J, et al. J Clin n a o r e c s t i Endocrinol Metab 1973; following food ingestion1-5 . 5. 37: 826–828. Adrian TE,et al. Diabetologia 1978; 14: GIP m P a s 413–417. l n a o r e c 6. Taminato T, et al. Diabetes s t i 1977; 26: 480–484. Hours
  15. 15. Interactions between nutrients and GIP and GLP- 1 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
  16. 16. Incretin Receptors (GIP Receptors) The human gipr gene 1-4 is localized to chromosome 19, band 1.q13.3. Usd i End n TB, e o 286 crinolo al. t is expressed in both α and β cells in 2. 1 g Yas -2870. y ,199 u 3; 1 Biop da K, e 33: hy s t al . 3. 1994;2 Res C Biochpancreatic islets, McI Phy 0 o ntos 5: 1556 mmun m h siol CH, e 1562. - e , 4. 361-36 Scand t al. Ac And in other tissues: GI tract, adipose tissue, Yip 5 R G, . , 19 t 96; 1 a E nd 57: ocri et al.adrenal cortex, pituitary, heart, testis, endothelium of major blood 400 n 4-40 ology 07. , 199 8; 13vessels, bone, trachea, spleen, thymus, lung, kidney, thyroid, and 9:several brain areas.
  17. 17. Incretin Receptors (glp-1 Receptors) The human glp-1r gene 1-5is located on chromosome 6p21. 1.Its genetic expression:2 42Stoffel M . : Th 1215 , et a o 3. U S rens -1218 l. Dia Th A , 1 B . Pr . bet es, may be almost exclusively restricted to the β cells and is 4. ore 199 ns 992;8 oc Na B, 199 3; Tib 3; 42 et a 9: 86 tl Acapresent in cells lining the pancreatic ducts Ch aduiz : 167 l. Di 41-86 d Sc e 8 a i 5. 377 m, 2 a EC, -168 betes 45. in a variety of other tissues: thyroid C cells, kidney, lung, 0 Dil 87-3 01; 2 et al. . lon 779 76: J B 2 , 199 3 io l 3 ; 1 J S, e t .heart, gastrointestinal track, skin, pituitary, and multiple regions 33: al. 190 Endof the peripheral and central nervous system. 7-1 ocri 910 nol . ogy ,
  18. 18. Molecular mechanisms underlying the insulinotropic effects of GIP and GLP-1 on Pancreatic beta cell* GIPR GLP-1RInsulin * Seino Y et al .J Diabetes Invest 2010,2040-1124)
  19. 19. Glucose-dependency of the insulin stimulatory effect of glucagon-like peptide-1 10 mmol/L Glucose 2.8 mmol/L Glucose Insulin Release (% of total content) 10 mmol/L Glucose 2.8 mmol/L Glucose GLP-1 (7-36) amide (pmol/L)*Goke R, et al. Res Exp Med (Berl). 1993; 193:97-103
  20. 20. Dipeptidyl-peptidase -IV (DPP -IV ) enzymeA subset of prolyl oligopeptidases, includingdipeptidyl-peptidase IV (DPP IV ) or CD26, specifically cleave off N-terminal dipeptides from substrates having proline or alanine in amino acid position 2.
  21. 21. Dipeptidyl-peptidase - 4 *DPP -IV ) enzyme) In 1993 it was demonstrated that ( Dipeptidyl-peptidase - 4 (DPP -IV enzyme mediates the inactivation of GLP-1 and GIPby 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
  22. 22. Endocrine pathway for the actions of GLP- 1* Nutrients Incretin Secretionin the gut lumen L-cells- intestinal villus 100% of the GLP- 1 Luminal Endothelial cells DPP-IV** enzyme Portal circulation (Liver) 25% of the GLP- 1 Soluble plasma DPP-IV enzyme Systemic circulation 10—15% of the GLP- 1 Soluble plasma DPP-IV enzyme The pancreas and the brain 10—15% or less of the GLP- 1 Holst J J,et al.Diabetologia 2005 48: 612-615 **DPP-IV:Dipeptidyl peptidase-IV
  23. 23. Inactivation of GLP-1 and GIP by Dipeptidyl peptidase-IV (DPP-IV) enzyme((1-11 1. Na u 2. 46– ck M Me 5 2 . , et al. 3. 214 ntlein Di a :82 R, b et Vil 9 – 3 et a olo 200 sbøll 5. l. E gia (Half-life of 7 min) 4. ur 198 (Half-life of 1-1.5 min) De 3; 8 T,e JB 6; 2 aco 8: 2 t al ioc 9: 5. Me 2 .J h em tab n CF, 0–4. Clin 199 De 20 et En 6. 271 acon 00; 8 al. J doc rin 3; C Bru :E45 CF,et 5:357 lin E ol M 8 7. 117 ckley -E46 al. A 5-358 ndoc et a b D, 4 mJ 1 rin De . et a Ph y ol aco lR sio 8. 112 n C eg u l 1 Kie 6-113 , et a l. P 996 9. 199 ffer 1. l. D ep t ; TJ, i ab . 19 The inactivation enzyme De 5;136 et et e s1 92, a 40, 10. Me con C , 358 al. En 995 ; 44 De tab19 F, et 5-359 docri , a nol 11. 172 con, 95; 80 al. Cl 6. ogy , 3 5 C. F , 95 in. DPP-IV Me 5 ,e 2 En 214 ntlein -362 t al . -957 docri 829 : R, J.E nol –35 Et ndo . al . c ri n Eu ol 2 rJ 002 Bio che ; m1 993 ;(Half-life of 4-5 min) (Half-life of 17 min)
  24. 24. GLP-1 (yellow) released by enteroendocrine L-cells, diffuses to the capillaries, where it is inactivated by DPP-4 enzyme (red)* -IVDPP GLP-1 GLP-1 DP P-IV* Histochemistry by C. Ørskov, the Panum Institute
  25. 25. The incretin hormones and Pathophysiology of Type 2 DM 1-12 In type 2 diabetes 1. 2. Na 19 uck 3. Ra 93;9 MA 19 chm 1:3 , et The secretion of 5. 4. The glucose-lowering Ah 96;4 an 01– al. J 20 re´ 5:1 J,et 307 Clin Vil 04;3 n B, 524 al. D In ve 61 sbø 6:8 et a –153 iab actions of st 3J ll T 67 l. ete 6. Cli , e –8 Ho 0 s 37 n En t a 76 rm 7. J C 23. doc l. D Me 22 lin rin ia b tab 8. 4. En ol ete Re 9. D do Me s2 s Cli iab cri tab 00 10 n et no 20 1; 11 . Re . Inv Me lM eta 01 50 :6 . Me l.g u es d 2 ;8 6: 09 Vil ta Pe t. 00 b2 37 – 12 . 11 el sb bo pt 199 0;1 00 3; 17 li 1 3; 7 – Na 11 – l T, sm.1 994 91: :713 88 :2 19 uc 11 et 98 ;5 30 –7 20 1 93 k M 19. al.D 7; 3 :63 1–30 19 – ;3 A, iab 6: -74 7. GIP GLP-1 6: 74 et a eto 677 . GIP GLP-1 1– l.D 74 iab 4 eto log -68 ia 2 20 . Normal log 02 much weaker ia ;4 preserved 5:or increased reduced or absent (resistance)
  26. 26. The incretin hormones and Pathophysiology of Type 2 DM Consequently in patients with Type 2 diabetes, the incretin effect is either severely reduced* abolished or (From normal 60% to < 10%)** resulting ininappropriately low insulin secretion following oral ingestion of nutrients*. .Tronier B, et al . Diabetes Clin Pract1985;]Suppl 1[:S568 * ** Mentlein R, et al. Eur J Biochem 1993; 214: 829–35. Nauck M , et al. Diabetologia 1986;29:46-52. Rask E, et al. Metabolism 2004; 53 : 624 –631. Diabet Med 2000;17:713–719.
  27. 27. Pathophysiological changes in Type 2 diabetes1-6 1. 2. Degr Increased Increased glucagon 3. Sh on 20 age zo R 01 P, Deranged adipocyte A ;85 et A. D hepatic glucose secretion 37 hfen :805 al. I iabe 4. :19 B, 3 Le 86 et -805 lin E es Re Ro -11 al. C t biology 6 8. nd v19 5. C)8S ek D 13. Diab production 19 Ni els - 13S m 6. 98; on M . .A JM eto log ia ocr ino 98 ;9 l M :97 eta 7–2 Vi 22 B, ed 20 b 6. lsg :11 20 02 ell 37 et al. 02 ; T, -11 D ;11 et i al. 43. abete 3( Su Di sC pp ab lIncreased ete s2 00 2;8 are 0:5Insulin 09 -51 resistance Type 2 diabetes 3. Increased gastric-emptying rate Impaired incretin effect Decreased insulin 2.Decreased secretion of GLP-1 secretion 3.Impaired response to GIP
  28. 28. The unique antidiabetic effects of Glucagon-like peptide-1 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
  29. 29. Approaches to enhance incretin effectsThe preserved effects of GLP- 1 has inspired attempts to treat Type 2 diabetes with it 1-4 Because 1.M e GLP-1 is rapidly inactivated9byein R 19 ntl 2.D 9; 8 eac 5:9 . Reg the enzyme DPP-4, Endo on CE -24. ul Pep DPP-4 c 80 ri ,e t 3. V :952- nol M t al. modulating its ils 957 eta Clin En boll . b1 Level & activity doc T. J 995 2 0 0 ri n ; 4.E 3;82 ol M Clin g 7 e En an JM 06 -2 tab , has become a major focus of investigation d 200 ocrin ,. J Cl 13. 7 2 ; 8 o l M in for treating type 2 diabetes by 7:3 768 etab -37 73. one of major three approaches, which are known as GLP-1 - based therapies or incretin - based therapies
  30. 30. The current approaches to enhance incretin action in patients with type 2 diabetes 1) GLP-1 receptor agonists *: as Exendin -4 or DDP-4 degradation-resistant and Exenatide can produce GLP-1 (Half-life of 2-4 h) levels that are more than (synthetic exendin-4) (Byetta ®) 5 times a patients physiologic levels. 2) GLP-1 analogues *: as liraglutide (Half-life of 12-14 h) by conjugation of GLP-1 Incretin mimetics (used by SC to circulating albumin injection) (Victoza ®)• * Amori RE, et al.JAMA.2007;298:194-206• Liraglutide: Blonde L., et al. Can J Diabetes. 2008;32 (Supp):A107
  31. 31. GLP-1 analogue, exendin-4, first found in the saliva of the Gila monster LizardThe Gila Monster Lizard -4 en din Ex
  32. 32. The current approaches to enhance incretin action in patients with type 2 diabetes• Inhibitors of DPP-IV *: augment the concentration of endogenously released Sitagliptin (Januvia ®) both GIP and GLP-1 and normalize GLP-1 level in type 2 ,Viltagliptin (Galvus ®) diabetes and can result in an approximate 2-fold increase in saxagliptin (Onglyza ®) GLP-1 levels. Linagliptin (Tradjenta ®) Alogliptin (Nesina ® ) Incretin enhancers* Pospisilik JA, et al . Diabetes 2002; 51: 2677-2683 (Gliptins) Fonseca VA ,et al. Am J Med.2010; 123(7):S2 -S10. (used Orally)
  33. 33. Effects of GLP-1 R agonists (Gliptins) on glucose metabolism1-10 GLP-1 receptor agonist Pancreatic islet cells 1. Brubaker PL . Trends Endocrinol Metab,2007; 18:240–245Decreased food Prolonged gastric Increased insulin Decreased glucagon 2. Lovshin JA, et al. Nat Rev Endocrinol. 2009; 5:262–269 intake emptying secretion 3. Brubaker PL. Trends Endocrinolsecretion Metab ,2007;18:240–245 4. Lovshin JA, et al. Nat Rev Endocrinol , 2009;5:262–269 5. Drucker DJ,et al. Lancet 2006; 368: 1696–705. 6. Willms B, et al. J Clin Endocrinol Metab 1996; 81: 327–32. 7. Nauck MA, et al. Am J Physiol 1997; Weight loss 273: E981–8. 8. Maljaars J, et al.Aliment Pharmacol Ther Decreased blood glucose 2007; 26 (Suppl. 2): 241–50. 9. Gutniak M, et al. N Engl J Med 1992; 326:1316-22. ↓ ( 0.6 – 0.8%HbA1c) 10. Degn KB, et al.Diabetes 2004; 53: 1187– 94. Increased insulin sensitivity
  34. 34. Current incretin mimetics (GLP-1 R agonists; GLP-1 analogues) used by injection for type 2 diabetes 1-10 1. 2. Am Ex o r et enti i RE Exendin-4 ZP-1O 3. Li al. L de L , et (Natural GLP-1 ) ; rag an A al. 2002CJC-1131 4. Dia lut ce R ( JAMAlbugon ® 5. G be id t 2 O Exenatide {S runb tes. e: B 008 nce .20 A 2 l ;37 we 07 Cl uppl erge 008 ond (Synthetic exendin-4 ) 2 ek ;29 AVE-0010 54 lan 1[ r G ;32 e L :1(Byetta ®) : ly 6. A u ]S d J S3 , e (S ., e 240- ):D 8 19 L 1 t 1 ru 4 u SCt once or twice/d Albiglutide ® 7. ]S less ppl 1 , et 8: N al.D pp): al. C 250 cke -206 u i a an . rD Bo ppl T, e [ S l. D o. 7 iabe A10 ;2005 J J, 1 3 i 8 t 7 Lixisenatide 8. 54]S ll G, [ S3 t al. 18:N abet 8. olog GLP-1 R agonist; 9. ]Sup r Ra up et 19 Dia o. olo tne pl al. :N be 78 gia (Liraglutide) ia 20 11 1[ D o . to l 7 . 20 ;54 SC once / d ; Ro pl RE S iab 78 og 11 (Victoza ®) ]S sen 1[ , et 316 eto 9. ia 2 10 up s S3 a ; (Naturally occurring 2010 . D pl toc 17 l> : N logi 01 1; GLP-1 analogue) ; ]S ahm 1[ k J, :N Diab o.78 a 20 54 LY 2189265 (LY) up pl s J S 31 et o. 7 eto 4. 11 SC once or twice / d 1[ , e 7 al. 85 lo ; ;2010 GLP-1 analogue; S 3 t al. : No Dia . gia 1 9 D ia . 7 be 20 SC once-weekly ; : N be 86. tolo 11 ;5 2011) ITCA 650 tolog o. gia 4 Exenatide 79 20 (Exentide 0. a 20 VRS-859 LAR ® i 11 ;54 Taspoglutide ® Albiglutide Cont. SC delivery 11 (GLP-1 R agonist ;5 4 (Bydureon (GLP-1 analogue; for 3 months ; SC monthly ; SC once-weekly; once-weekly 2011 ) 2011) (exenatide extended-release), SC once-weekly ); 2011) 2012
  35. 35. Photographs of pancreatic tissue sections in rats treated with exendin-4 and controls*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) * Nachnani J S et al. Diabetologia (2010) 53:153–159.
  36. 36. Exenatide (Byetta®) and liraglutide(Victoza®) and *Acute pancreatitis warning 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. * 1. Byetta. ]Package Insert[. San Diego, CA: Amylin Pharmaceuticals, Inc. 2009. 2. 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
  37. 37. GLP-1 Receptor Agonists Activate Rodent Thyroid C-Cells Causing Calcitonin Release and C-Cell ProliferationLiraglutide stimulates C-cells in rodents, causingan increase in calcitoninand there were few casesof medullary thyroidcancer in these animalsand not in humans*.* Bjerre Knudsen L et al. Endocrinology 2010;151:1473-1486
  38. 38. Exenatide (Byetta®) and liraglutide (Victoza®) and medullary thyroid cancer (MTC) concerns* 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
  39. 39. 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. 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.
  40. 40. Overview of current DPP-4 inhibitors (Gliptins) used orally for type 2 diabetes 1-4 1.PSN 9301 2. M 85 entle Sitagliptin; Sitagliptin De :9 -2 in R En aco 4. . R eg Januvia ® 2007 3. 80 doc n CE ul Ile- :95 rin , Pe thiazolidide Vi 2 4. M lsbo -95 Me l. Eg etab ll T 7. ol et a tab Cli Sitagliptin +metformin pt 19 99 19 n ; M an J , 20 . J C eta M 03 li b 2 ,. J ;82 n E 00 Cl 70 nd 95 ; Janumet ® 2007 Valine 2;8 in 6 - oc pyrrolidide 7:3 En 271 rino 76 doc 3. l 8 - ri n Sitagliptin +simvastatin 37 ol 73 . Juvisync ® 2011 NVP DPP728 Vildagliptin; Galvus ® 2008 Dutogliptin;Melagliptin; Saxagliptin; Alogliptin Linagliptin; Onglyza ® 2009 (Nesina ® 2012 ) (Tradjenta ®2012) ®2012Denagliptin;
  41. 41. Effects of DPP-IV inhibitors (Gliptins) on glucose metabolism 1-6DPP-IV inhibitors (Gliptins)  GLP-1 1. Wi llm Na 2. sB Pancreatic uck ,e 3. 19 M Me t al. islet cells Ma 97; 2 A, tab 1 J Cli Ph ljaar : E 73 et a 99 n E l. 6; nd 4. 2): arma s J, e 981– Am 81: ocri 32 no Gu 241– col T t al.A 8. J Phy 7– l Decreased food Prolonged gastrick 50. her 2 lime tn 5. 1992 ia M Increased insulin sio 32. l De ; 3 , et 00 nt 7; Decreased glucagon intake* 6. 118 * emptying7gn KB26:131 al. N secretion 26 (Su secretion Ric –9 , et 6-2 En pp Da hter 4. al. 2. Di gl JM l. tab B, CD as abe ed 00 e S et al. tes 20 67 39 yst R Coch 04 ;5 . ev ran 3: 20 e 08 ;? ??? ?: Weight loss Decreased blood glucose (HbA1c↓ 0.7% ] 0.5 – 0.6%[ )* Potential effects to slow gastric emptying and increase satiety probably contribute littleIncreased insulin efficacy of DPP-4 inhibitors , therefore they to the therapeutic are weight-neutralsensitivity or may cause slight gains in weight
  42. 42. Summary of adverse events in patients with type 2 diabetes treated with GLP-1 analogues (Exenatide and Liraglutide)* GLP-1 analogues Control Adverse events Risk Ratio (95% CI), Incretin Mean % (95% CI) Mean % (95% CI) vs. Control Achieving Control Achieving ControlHypoglycemiaExenatide vs. Placebo Injection (1.08-4.88) 2.30 (8.1-29.1) 10.0 (4.0-12.0) 7.0Exenatide vs. Insulin (1.46-2.26) 1.02 (1.3-4.1) 2.3 (1.3-4.0) 2.3NauseaAll GLP-1 analoques vs. Comparator (2.02-4.24) 1.92 (25.4-41.4) 32.9 (9.0-17.3) 12.6Exenatide vs. Comparator (2.16-4.64) 3.17 (36.4-47.7) 41.9 (9.5-18.5) 13.4Liraglutide vs. Placebo Injection (0.27-3.01) 0.89 (3.1-10.1) 5.6 (1.8-16.2) 5.7VomitingAll GLP-1 analoques vs. Comparator (2.51-4.41) 3.32 (9.1-14.6) 11.6 (3.1-5.1) 4.0Exenatide vs. Comparator (2.64-4.70) 3.52 (12.5-15.9) 14.1 (3.1-5.1) 4.0Liraglutide vs. Placebo Injection (0.13-2.91) 0.62 (1.1-4.7) 2.3 (0.9-13.4) 3.6DiarrheaAll GLP-1 analoques vs. Comparator (1.72-2.89) 2.23 (7.9-13.0) 10.2 (3.7-6.6) 4.9Exenatide vs. Comparator (1.75-2.94) 2.27 (8.8-13.6) 11.0 (3.6-6.7) 4.9DPP4: dipeptidyl peptidase 4 ; Comparator :placebo or oral hypoglycemic agent or insulin; CI :confidence interval* Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206.
  43. 43. Summary of adverse events in patients with type 2 diabetes treated with DDP-4 inhibitors (Sitagliptin and Vildagliptin)* DDP-4 inhibitors Control Risk Ratio (95% CI), Adverse events Incretin Mean % (95% CI) Mean % (95% CI) Achieving Control Achieving Control vs. ControlHypoglycemiaAll DDP4 inhibitors vs comparator (0.50-1.86)0.97 1.6 (0.7-3.2) 1.4 (0.6-3.4)Sitagliptin vs comparator (0.30-2.87) 0.92 (0.9-3.3) 1.8 (0.2-8.5) 1.5Vildagliptin vs comparator (0.50-1.19) 0.84 0.4-4.8) 1.4) (0.3-5.7) 1.2NauseaAll DDP4 inhibitors vs comparator 0.89 (0.58-1.36) 2.7 (2.1-3.4) 3.1 (2.0-4.7)Sitagliptin vs comparator 1.46 (0.88-2.43) 2.1 (1.4-3.0) 1.4 (0.7-2.4)Vildagliptin vs comparator 0.57 (0.37-0.88) (2.6-4.6) 3.4 5.2 (3.6-7.4)VomitingAll DDP4 inhibitors vs comparator (0.42-1.15) 0.69 1.3 (0.8-2.2) 1.5 (0.9-2.6)Sitagliptin vs comparator (0.45-1.65) 0.86 1.1 (0.6-2.0) 1.2 (0.8-1.9)Vildagliptin vs comparator 0.49 (0.21-1.1.11) NR NRDiarrheaAll DDP4 inhibitors vs comparator 0.80 (0.42-1.54) (2.8-5.1) 3.8 4.0 (1.8-4.6)Sitagliptin vs comparator 1.21 (0.81-1.80) 3.6 (2.5-5.1) 2.8 (1.8-4.6)Vildagliptin vs comparator 0.34 (0.14-0.80) 4.0 (2.0-8.0) 9.9 (2.7-30.7)DPP4: dipeptidyl peptidase 4 ; Comparator :placebo or oral hypoglycemic agent or insulin; CI :confidence interval* Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206.
  44. 44. Long-term effects of DPP-4 inhibitors on immune function of patients with type 2 diabetes*  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
  45. 45. Other adverse events in patients with type 2 diabetes treated with DPP4 inhibitors (i.e. Sitagliptin:Januvia)* 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.
  46. 46. Adverse events in patients with type 2 diabetes treatedwith DDP-4 inhibitors (Sitagliptin and Viltagliptin)* DDP-4 inhibitors Control Adverse events Risk Ratio (95% CI), Mean % (95% CI) Mean % (95% CI) Incretin vs. Control Achieving Control Achieving ControlAbdominal painAll DDP4 inhibitors vs comparator 0.73 (0.36-1.45) 2.4 (1.8-3.2) 3.2 (1.7-5.7)Sitagliptin vs comparator 0.92 (0.47-1.80) 2.5 (1.8-3.3) 2.6 (1.7-3.9) Vildagliptin vs comparator 0.32 (0.16-0.66) NR NRCouphAll DDP4 inhibitors vs comparator 1.07 (0.65-1.78) 2.9 (2.1-4.0) 2.4 (1.7-3.5)Sitagliptin vs comparator 0.95 (0.54-1.78) 2.5 (1.7-3.5) 2.6 (1.8-3.9) Vildagliptin vs comparator 1.86 (0.57-6.11) 4.8 (2.6-8.6) 1.7 (0.7-4.1)InfluenzaAll DDP4 inhibitors vs comparator 0.87 (0.64-1.19) 4.1 (3.3-5.1) 4.4 (3.4-5.8)Sitagliptin vs comparator 0.95 (0.65-1.39) 4.0 (3.1-5.1) 5.3 (3.7-7.4) Vildagliptin vs comparator 0.73 (0.42-1.27) 4.2 (2.5-7.1) 6.1 (5.0-7.4)NasopharyngitisAll DDP4 inhibitors vs comparator 1.17 (0.98-1.40) 6.4 (5.1-7.8) 4.5 (3.0-6.7)Sitagliptin vs comparator 1.38 (1.06-1.81) (3.5-7.9) 5.3 7.3 (6.0-8.9) Vildagliptin vs comparator 1.02 (0.80-1.29) (5.8-9.3) 7.3 6.4 (4.9-8.4) DPP4: dipeptidyl peptidase 4 ; Comparator :placebo or oral hypoglycemic agent or insulin; CI :confidence interval * Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206.
  47. 47. Adverse events in patients with type 2 diabetes treated with DDP-4 inhibitors (Sitagliptin and Viltagliptin)* DDP-4 inhibitors Control Adverse events Risk Ratio (95% CI), Mean % (95% CI) Mean % (95% CI) Incretin vs. Control Achieving Control Achieving ControlUpper respiratory tract infectionAll DDP4 inhibitors vs comparator 0.99 (0.81-1.21) 6.3 (5.1-7.7) 6.4 (4.9-8.4)Sitagliptin vs comparator 1.09 (0.84-1.43) 5.7 (4.0-8.0) 4.7 (2.8-8.0) Vildagliptin vs comparator 0.88 (0.65-1.18) 6.8 (5.3-8.6) 8.0 (6.5-9.8)SinusitisAll DDP4 inhibitors vs comparator 0.61 (0.34-1.12) 2.0 (1.3-3.1) 3.4 (2.4-4.8)Sitagliptin vs comparator 0.81 (0.41-1.58) 2.2 (1.4-3.4) 2.5 (1.6-3.9) Vildagliptin vs comparator 0.20 (0.05-0.78) 1.2 (0.3-4.1) 5.4 (3.1-9.2)Urinary tract infectionAll DDP4 inhibitors vs comparator 1.52 (1.04-2.21) 3.2 (2.3-4.5) 2.4 (1.8-3.2)Sitagliptin vs comparator 1.42 (0.95-2.11) 3.1 (2.1-4.6) 2.6 (1.9-3.5) Vildagliptin vs comparator 2.72 (0.85-8.68) 3.6 (1.5-8.3) 1.3 (0.5-3.3)HeadacheAll DDP4 inhibitors vs comparator 1.38 (1.10-1.72) 5.1 (4.1-6.4) 3.9 (3.1-4.8)Sitagliptin vs comparator 1.24 (0.82-1.87) 3.6 (2.9-4.5) 3.1 (1.9-4.9) Vildagliptin vs comparator 1.47 (1.12-1.94) 6.3 (5.0-8.0) 4.4 (3.4-5.6)DPP4: dipeptidyl peptidase 4 ; Comparator :placebo ororal hypoglycemic agent or insulin; CI :confidence interval* Amori RE, et al. Efficacy and Safety of Incretin Therapy in Type 2 Diabetes Systematic Review and Meta-analysis. JAMA. 2007;298:194-206.
  48. 48. Representative images of increased exocrine pancreatic ductal cell replication in HIP* Rats treated with sitagliptin **Januvia” for 12 weeks”Increased ductal cellturnover and ductalmetaplasia are well-characterized risk factors forpancreatic ductal cancer andpancreatitis 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.* HIP:Human Islet amyloid Polypeptide transgenic rats, a model for type 2 diabetes** Matveyenko AV et al.Diabetes 2009 ;58 : 1604-1615.
  49. 49. Necrotizing pancreatitis in a HIP rat treated with sitagliptin “Januvia” for 12 weeks**Matveyenko AV et al. Diabetes 2009 ;58 : 1604-1615.
  50. 50. Sitagliptin or sitagliptin/metformin marketed as Januvia and Janumet)) Acute pancreatitis warning 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. FDA , U.S. Food and Drug Adminstration
  51. 51. Odds ratio of test vs control events (pancreatitis pancreatic and thyroid cancer, or any cancer) for .*exenatide, sitagliptin, and other therapies These data are consistent with case reports and animal studies and indicating an increased risk for pancreatitis with GLP-1- of Interest Conflicts based therapy. The authors disclose no The findings also raise caution conflicts. about the potential long-term actions of these drugs toFunding promote pancreatic cancer.by the Larry L. Supported Hillblom Foundation.* 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
  52. 52. Considerations for Healthcare Professionals regarding the use of sitagliptin and sitagliptin/metformin(Januvia and Janumet) In 2009, FDA has asked the manufacturer of these products to revise the prescribinginformation 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.
  53. 53. Considerations for Healthcare Professionals regarding the use of sitagliptin and sitagliptin/metformin (Januvia and Janumet) 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.
  54. 54. Drug surveillance and a real world approach for drugs 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 ofindustry 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.
  55. 55. Comparison between GLP-1 analogs and DDP-IV inhibiters SpecificityThe effects of GLP-analogs are strictly Specific whilethe DDP-IV inhibiters lack specificity
  56. 56. Undesirable side effects due to other potential endogenous DPP-IV substrates identified in kinetic studies Among the additional substrates identified in kinetic studies* are a number of neuropeptides, including: Pituitary adenylylate cyclase–activating polpeptide (PACAP), Vasoactive intestinal polypeptide (VIP), Gastrin-releasing peptide (GRP), Neuropeptide Y (NPY), and Growth hormone–releasing hormone (GHRH), Other regulatory peptides (such as GLP-2 and peptide YY [PYY]), A number of chemokines and cytokines.*Lambeir AM, et al. Crit Rev Clin Lab Sci,2003 40 :209 -294
  57. 57. Unanswered questions GLP-1R agonists and DPP-IV inhibitorsFurthermore, GLP-1R agonists exhibit <100% amino acid identity with the native peptide. The immunogenic potential raises the specter of immunoneutralizing antibodies in some patients, which may lead to reduction in therapeutic efficacy or potential exacerbation of diabetes if the antibodies cross-react with endogenous GLP-1
  58. 58. Unanswered questions GLP-1R agonists and DPP-IV inhibitors DPP-IV, is activated by external stimuli and modulates T-cell activation, producing pleiotropic effects in experimental inflammatory and neoplastic disorders.Global genetic inactivation of CD26 in mice is associated with subtle but detectable abnormalities in cytokine and immunoglobulin secretion *. Whether highly selective inhibition of of DPP-IV will adversely perturb immune-related activity in human subjects is unclear; hence,the long-term safety of sustained DPP-IV inhibition merits careful scrutiny.
  59. 59.  DPP-4 inhibitors have some theoretical advantages over existing therapies with oral antidiabetic compounds but should currently be restricted to individual patients. * 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
  60. 60.  Long-term data especially on cardiovascular outcomes and safety are urgently needed before widespread use of these agents. * 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
  61. 61.  More information on the benefit-risk ratio of DPP-4 inhibitor treatment is necessary especially analysing adverse effects on parameters of immune function. * 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
  62. 62.  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
  63. 63. Physician relationships with the industry“Conflict implies that there is a problem orargument, and I don’t believe that theserelationships are a conflict at all,”  Transparency  Conflicts of interest  Harm to:- Professional reputations (prescribing and professional behavior )- Scientific research- Guideline credibility- Patients (patient care ).
  64. 64. Physician relationships with the industry Clinical practice guidelines are increasingly used in medical malpractice cases and are forming the basis of many of the pay-for-performance initiativesthese relationships affect the prescribing and professional behavior of physicians. Continuing medical education programs sponsored by a drug company were more likely to highlight the drug company’s product.A Journal of the American Medical Association review published by Wazana and colleagues in2000
  65. 65. Physician relationships with the industryWhat we have to be careful about is thatmany trials are not designed to answer a scientific question, but rather to answer a marketing question Therefore“Conflicts of interest are not universally bad, but they’re not universally good.”
  66. 66. BMC Endocr Disord. 2010; 10: 7. Published online 2010 April 22. doi: 10.1186/1472-6823-10-7Safety and tolerability of sitagliptin in clinical studies:a pooled analysis of data from 10,246 patients with Disclosures All authors are employed by Merck Sharp &type 2 diabetes Dohme, Corp.,Debora Williams-Herman ; Samuel S Engel ; Elizabeth Round ; Jeremy Johnson; Gregory T Golm; Hua Guo ;Bret J Musser ; Michael J Davies ; Keith D Kaufman: ; of Merck & Co., Inc., a subsidiary Barry J GoldsteinReceived February 10, 2010; Accepted April manufacturer of sitagliptin the 22, 2010.Conclusions : In this updated stock or safety analysis of and may have company pooleddata from 10,246 patients withstock options. type 2 diabetes, sitagliptin 100mg/day was generally well tolerated in clinical trials ofup to 2 years in duration.
  67. 67. Example of conflict of interests or Competing interestsA Systematic Assessment of Cardiovascular Outcomes in the SaxagliptinDrug Development Program for Type 2 DiabetesDOI: 10.3810/pgm.2010.05.2138 No increased, riskPhD, Fred Fiedorek,Conclusion:Conflict of Interests Statements MD, Mark Donovan, PhD, Niklas Berglind, BSc, Robert Frederich MD,of CV death/MI/stroke was observed MD are employed by Bristol-Myers Squibb. Roland Chen, MD, and Robert Wolf,in patients randomly assigned is employed by AstraZeneca. Susan Harris, MSsaxagliptin across a broad drug , MD, MHS, FACC provided consulting or other services, and received honoraria from, John H. Alexanderdevelopment program. Although this Ingelheim, Bristol-Myers Squibb, CSL Behring, Duke Private AstraZeneca, Boehringersystematic overview Diagnostic Clinic, Duke Health System, and Regado Biosciences. has inherent andimportant limitations, the H. support a Johndata Alexander also received research grant or contract funding from Bristol-Myers Squibb, Duke withpotential reduction in CV eventsHealth System, Medtronic Japan, Merck and Company, National Institutes of Health, Pfizer, and Regado Biosciences.saxagliptin. The hypothesis of CV protection , MD provided consulting or other services, received honoraria, or received Kenneth W. Mahaffeywith saxagliptin willresearch grant or contract funding from, or provided educational activities or lectures for, Adolor Corp, Alexion, be tested prospectively ina large randomized clinical Inc., Amylin Inc., Argolyn, AstraZeneca, Bayer HealthCare, Boehringer Amgen outcome trialevaluating saxagliptin compared with standard Hospital, Bristol-Myers Squibb, CardioKinetix Inc., Ingelheim, Brigham & Women’sof care in patients with type 2 diabetes at Sankyo, Duke University School of Medicine, Edwards Cierra, Cordis, Daiichiincreased risk for CV events. Eli Lilly, Elsevier (AHJ), Forest Laboratories, Genentech, Lifesciences, 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.
  68. 68. Example of conflict of interests or Competing interestsSitagliptin: review of preclinical and clinical dataregarding incidence of pancreatitisS S Engel, D E Williams-Herman, G T Golm, R J Clay, S V Machotka, K D Kaufman, and B J GoldsteinInt J Clin Pract. 2010 June; 64(7): 984–990. Disclosures All authors are Conclusions employees of Merck & Co., Inc., Preclinical the manufacturerdata with sitagliptin to date and clinical trial of sitagliptin and may have stock or stock options do not indicate an the company. of pancreatitis in in increased risk patients with T2DM treated with sitagliptin. Received February 2010; Accepted February 2010.
  69. 69. Example of conflict of interests or Competing interestsUse of a claims-based active drug safety surveillance system to assess therisk of acute pancreatitis with exenatide or sitagliptin compared tometformin or glyburide.Dore DD, et al. Current Medical Research and Opinion. 2009;25 :1019-1027. Declaration of interest:CONCLUSIONS: Funding for this research was provided to i3 Drug data do notThesesafety by Amylin Pharmaceuticals, , Inc.,for an has provide evidence whichassociation of agreement with Eli Lilly and Company toof a global acute pancreatitis among initiators collaborate on the development andexenatide or sitagliptinof exentide. D.D.D., J. D.S. and commercialization compared to met/gly initiators.These results are limited by the data available in an K.A.C. are employees of i3 Drug Safety.administrative, healthcare database.
  70. 70. Example of conflict of interests or Competing interestsAcute Pancreatitis in Type 2 Diabetes Treated With Exenatide orSitagliptinA retrospective observational pharmacy claims analysis•Rajesh Garg MD1,•William Chen, PHD, MPH2 and Declaration of interest:•Merri Pendergrass MD, PHD2 No potential conflicts ofGarg R, et al. Diabetes Care November 2010 vol. 33 :2349-2354 interest relevant to CONCLUSIONSarticle were reported. this 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.
  71. 71. Although, the GLP-1–based therapies arrived in clinical practice with much fanfare and anticipation*, *** 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
  72. 72. Theoretical model to explain currently available observations with increased risks for d ecr ed ease acute pancreatitis and pancreatic cancer in individuals with reas d Obesity & Type 2 diabetes incMetformin Rx(insulin Rx) GLP-1 Rx ? 1. Va i of c nio H con anc , Bi er anc 2. Fra trol an preve hini F Pol nce d p ntio . IA edn : IAR hysic n. Vo RC h 08. 3. Pre ak C P al a lum and –17 l Cal ventio AP. C ress, 2 ctivity e 6: W book 1 699 Hepato s ;52: terol 1. Me le EE, n 200 a Evans JM, et al.BMJ 2005;330 ncer D 02. 0 . Ly e on, ight a 20 09 en o 3; 2 dic ine et al. 7 et to logi t Gastr Pha rm 1304–1305. 200 New (6):4 ection abe Prac are 2. Luo Z, et al. Trends in 3; 34 Eng 15– 42 and . Di in 2. ag C 1. Nat Cl : 46– 5 J Man iol 8(1 Pharmacological Sciences 2005;26 and J 1. l 1 . dem 7):1 625 ourn 2. 2004; S, et al1. 64. Denker pi et al. Diabetes Care J E PS, 69–76. –16 al o tty 9–5 . Am 3. Acute McCarty MF. Medical Hypotheses 2004;63 334–339. 38. f She ;11:55 , et al 2006; 29:s471re 3. 2005 in SS –1167 bete C gh a l 2. 60 CureaP, et al. N Engl J Med 2008; 1 Di Cou 59:1 t al. 1969– 1970 358: pancreatitis 4. Ruderman N,et al. Nature Reviews. Drug Discovery 2004;3 340–351. 4. 2004;1 i M, e 1460. nam 3. 55–Tripathy NR, et al. J Assoc Mo ;31:14 Physicians India 2008; 56: 987– 988 5 . 8 5. Alimova IN, et al. Cell Cycle 200 4. Parnaud G, et al. Diabetologia 2009;8 909–915. 6. Cazzaniga M, et al. Cancer 2008; 51: 91– 100 Epidemiology, Biomarkers and Prevention 2009;18 701–705. Pancreatic cancer
  73. 73. Conclusions Glucagon-like peptide-1-based therapy is gaining widespread use for type 2 diabetes, although there are concerns about risks for pancreatitis and pancreatic and thyroid cancers. DPP-4 inhibitors have some theoretical advantages over existing therapies with oral antidiabetic compounds but should currently be restricted to individual patients. There are also concerns that DPP-4 inhibitors could cause cancer, given their effects on immune function. No data are yet available on whether these new agents affect hard endpoints such as cardiovascular disease, morbidity, and mortality.
  74. 74. JanuviaPotentially extremely Dangerous and Januvia expensive Mildly effective in some patients Janus Jan The image of the Roman god, Janus whose prime characteristic of facing in two directions, seems very appropriate for the similarly named drug Januvia,
  75. 75. Suggested seven deadly sins of drug prescription And• toWe control the marketare the first,we neither Never be better (‘Never be the first, assume that new drugs for products that or the last, to use sin is to assume that: this a new drug.’ consume, pay for nor ) or the last,• new drugs are are experienced by and better to use pharmaceuticals to treat a non-pharmaceutical problem; whose unwanted consequences drug•• to use a peoplenew to repeat prescriptions that serve no rational purpose; to use one drug to counter the side effects produced by another; other• 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.
  76. 76. Thank you

×