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

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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 ...

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.

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  • a consequence of guilt by association rather than a drug effect or what is known as class effect Among adverse drug reactions, pancreatitis is often-ignored because of the difficulty in implicating a drug as its cause. The physician should have a high index of suspicion for DIP. (There is a possible association between exenatide use and acute pancreatitis. Background and Data Summary:  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 was reported in 58/88 (66%) of the patients, 4 of whom were admitted to the intensive care unit (ICU). Two cases of hemorrhagic or necrotizing pancreatitis were identified in the review and both required an extended stay in the hospital with medical management in the ICU. The most common adverse events reported in the 88 cases were abdominal pain, nausea and vomiting. Additionally, the analysis found that 19 of the 88 reported cases (21%) of pancreatitis occurred within 30 days of starting sitagliptin or sitagliptin/metformin.  Furthermore, 47 of the 88 cases (53%) resolved once sitagliptin was discontinued. It is important to note that 45 cases (51%) were associated with at least one other risk factor for developing pancreatitis, such as diabetes, obesity, high cholesterol and/or high triglycerides. Based on the temporal relationship of initiating sitagliptin or sitagliptin/metformin and development of acute pancreatitis in the reviewed cases, FDA believes there may be an association between these events. Because acute pancreatitis is associated with considerable morbidity and mortality, and early recognition is important in reducing adverse health outcomes, FDA is recommending revisions to the prescribing information to alert healthcare professionals to this potentially serious adverse drug event. }}}}}     From the Background and Data Summary part of that document: 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 was reported in 58/88 (66%) of the patients, 4 of whom were admitted to the intensive care unit (ICU). Two cases of hemorrhagic or necrotizing pancreatitis were identified in the review and both required an extended stay in the hospital with medical management in the ICU. The most common adverse events reported in the 88 cases were abdominal pain, nausea and vomiting. Additionally, the analysis found that 19 of the 88 reported cases (21%) of pancreatitis occurred within 30 days of starting sitagliptin or sitagliptin/metformin.  Furthermore, 47 of the 88 cases (53%) resolved once sitagliptin was discontinued. It is important to note that 45 cases (51%) were associated with at least one other risk factor for developing pancreatitis, such as diabetes, obesity, high cholesterol and/or high triglycerides. Based on the temporal relationship of initiating sitagliptin or sitagliptin/metformin and development of acute pancreatitis in the reviewed cases, FDA believes there may be an association between these events.... (There is a possible association pancreatitis with exenatide was 1.7 cases/1000 patientbetween exenatide use and acute pancreatitis. The incidence of acute in clinical development studies and 0.2/1000 patient years during postmarketing surveillance. By comparison, the incidence was 3.0/1000 patient years with placebo and 2.0/1000 patient years with insulin. (Aust Prescr 2008;31:104–8) ) Perhaps of most concern, increased ductal cell turnover and ductal metaplasia are also well-characterized risk factors for pancreatic ductal cancer ( 31 , 44 , 45 ), 31. Parsa I, Longnecker DS, Scarpelli DG, Pour P, Reddy JK, Lefkowitz M : Ductal metaplasia of human exocrine pancreas and its association with carcinoma. Cancer Res 1985; 45: 1285– 1290 44. Wagner M, Greten FR, Weber CK, Koschnick S, Mattfeldt T, Deppert W, Kern H, Adler G, Schmid RM : A murine tumor progression model for pancreatic cancer recapitulating the genetic alterations of the human disease. Genes Dev 2001; 15: 286– 293 45. Wagner M, Weber CK, Bressau F, Greten FR, Stagge V, Ebert M, Leach SD, Adler G, Schmid RM : Transgenic overexpression of amphiregulin induces a mitogenic response selectively in pancreatic duct cells. Gastroenterology 2002; 122: 1898– 1912 46. Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, Dimagno EP, Andren-Sandberg A, Domellof L : Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 1993; 328: 1433– 1437   as is pancreatitis ( 46 ). 46. Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR, Dimagno EP, Andren-Sandberg A, Domellof L : Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 1993; 328: Class I medications (medications implicated in greater than 20 reported cases of acute pancreatitis with at least one documented case following reexposure): didanosine, asparaginase, azathioprine, valproic acid, pentavalent antimonials, pentamidine, mercaptopurine, mesalamine, estrogen preparations, opiates, tetracycline, cytarabine, steroids, trimethoprim/sulfamethoxazole, sulfasalazine, furosemide, and sulindac.   Class II medications (medications implicated in more than 10 cases of acute pancreatitis): rifampin, lamivudine, octreotide, carbamazepine, acetaminophen, phenformin, interferon alfa-2b, enalapril, hydrochlorothiazide, cisplatin, erythromycin, and cyclopenthiazide. Class III medications (all medications reported to be associated with pancreatitis).
  • To provide more specific and comprehensive guidance to academic institutions on conflict of interest policies, the Association of American Medical Colleges ( AAMC, 2001 , 2002 , 2008c ), the Association of American Universities ( AAU, 2001 ), AAMC and AAU jointly ( AAMC-AAU, 2008 ), and the Council on Government Relations ( COGR, 2002 ) have issued several reports with recommendations. Policies on Conflict of Interest: Overview and Evidence Current conflict of interest policies and practices have evolved over more than four decades of increasing relationships with industry in medical education, research, and practice. The increase has been accompanied by intensifying discussions about how the risks and the expected benefits of these relationships should be evaluated and balanced.
  • Furthermore, DPP-IV, also known as the lymphocyte cell surface transmembrane-signaling molecule CD26, is activated by external stimuli and modulates T-cell activation, producing pleiotropic effects in experimental inflammatory and neoplastic disorders ( 155 , 170 ). Global genetic inactivation of CD26 in mice is associated with subtle but detectable abnormalities in cytokine and immunoglobulin secretion after mitogen stimulation ( 171 ). Whether highly selective inhibition of the catalytic activity of DPP-IV will adversely perturb immune-related activity in human subjects is unclear; hence, the long-term safety of sustained DPP-IV/CD26 inhibition merits careful scrutiny. Drucker DJ: Therapeutic potential of dipeptidyl peptidase IV inhibitors for the treatment of type 2 diabetes. Expert Opin Investig Drugs 12:87–100, 2003 Gorrell MD, Gysbers V, McCaughan GW: CD26: a multifunctional integral membrane and secreted protein of activated lymphocytes. Scand J Immunol 54:249–264, 2001 Yan S, Marguet D, Dobers J, Reutter W, Fan H: Deficiency of CD26 results in a change of cytokine and immunoglobulin secretion after stimulation by pokeweed mitogen. Eur J Immunol 33:1519–1527, 2003 [Medline] Drucker DJ. Expert Opin Investig Drugs 2003; 12:87–100 Gorrell MD,et al. Scand J Immunol 2001; 54:249–264 Yan S,et al. Eur J Immunol 2003;33:1519–1527
  • 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   DPP-4 inhibitors Cochrane review conclusions abstract : COCHRANE Author ' conclusions 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 new 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. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus Plain Language Summary Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus Dipeptidyl peptidase-4 (DPP-4) inhibitors like sitagliptin and vildagliptin are promising new medicines for the treatment of type 2 diabetes mellitus. They are supposed to improve metabolic control (as measured by lowering blood glucose) without causing severe hypoglycaemia (low blood sugar levels leading to unconsciousness and other symptoms). Altogether 12.864 people took part in 25 studies investigating the new compounds sitagliptin and vildagliptin. Most studies lasted 24 weeks, the longest trials evaluated 52 weeks of treatment. So far, no study reported on patient-oriented parameters like mortality, diabetic complications, costs of treatment and health-related quality of life. When compared to placebo treatment sitagliptin and vildagliptin improved metabolic control. Comparison with other already established blood-glucose lowering drugs did not reveal advantages of DPP-4 treatment. Weight gain was not observed after sitagliptin and vildagliptin therapy. Overall, sitagliptin and vildagliptin were well tolerated, no severe hypoglycaemia was reported in patients taking sitagliptin or vildagliptin. However, all-cause infections increased significantly after sitagliptin treatment but did not reach statistical significance following vildagliptin therapy. Unfortunately, all published randomised controlled trials of at least 12 weeks treatment with sitagliptin and vildagliptin only reported routine laboratory safety measurements. Since the new DPP-4 inhibitors may influence immune function additional long-term data on the safety of these drugs are necessary. Also, cardiovascular outcomes like heart attacks and strokes should not be increased with any antidiabetic therapy but data so far are lacking. Until new information arrives, DPP-4 inhibitors should only be used under controlled conditions and in individual patients. This is a Cochrane review abstract and plain language summary, prepared and maintained by The Cochrane Collaboration, currently published in The Cochrane Database of Systematic Reviews 2011 Issue 10, Copyright © 2011 The Cochrane Collaboration. Published by John Wiley and Sons, Ltd.. The full text of the review is available in The Cochrane Library (ISSN 1464-780X). This record should be cited as: 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 Editorial Group: Metabolic and Endocrine Disorders Group This version first published online: April 16. 2008 Last assessed as up-to-date: January 31. 2008 Abstract Background In type 2 diabetes mellitus there is a progressive loss of beta-cell function. One new approach yielding promising results is the use of the orally active dipeptidyl peptidase-4 (DPP-4) inhibitors like sitagliptin and vildagliptin. Objectives To assess the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Search strategy Studies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library . Selection criteria Studies were included if they were randomised controlled trials in adult people with type 2 diabetes mellitus and had a trial duration of at least 12 weeks. Data collection and analysis Two authors independently assessed risk of bias and extracted data. Pooling of studies was performed by means of fixed-effect meta-analysis. Main results Twenty-five studies of good quality were identified, 11 trials evaluated sitagliptin and 14 trials vildagliptin treatment. Altogether, 6743 patients were randomised in sitagliptin and 6121 patients in vildagliptin studies, respectively. Sitagliptin and vildagliptin studies ranged from 12 to 52 weeks duration. No data were published on mortality, diabetic complications, costs of treatment and health-related quality of life. Sitagliptin and vildagliptin therapy in comparison with placebo resulted in an HbA1c reduction of approximately 0.7% and 0.6%, respectively. Data on comparisons with active comparators were limited but indicated no improved metabolic control following DPP-4 intervention in contrast to other hypoglycaemic agents. Sitagliptin and vildagliptin therapy did not result in weight gain but weight loss was more pronounced following placebo interventions. No definite conclusions could be drawn from published data on sitagliptin and vildagliptin effects on measurements of beta-cell function. Overall, sitagliptin and vildagliptin were well tolerated, no severe hypoglycaemia was reported in patients taking sitagliptin or vildagliptin. All-cause infections increased significantly after sitagliptin treatment but did not reach statistical significance following vildagliptin therapy. All published randomised controlled trials of at least 12 weeks treatment with sitagliptin and vildagliptin only reported routine laboratory safety measurements Authors' conclusions 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 new 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   DPP-4 inhibitors Cochrane review conclusions abstract : COCHRANE Author ' conclusions 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 new 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. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus Plain Language Summary Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus Dipeptidyl peptidase-4 (DPP-4) inhibitors like sitagliptin and vildagliptin are promising new medicines for the treatment of type 2 diabetes mellitus. They are supposed to improve metabolic control (as measured by lowering blood glucose) without causing severe hypoglycaemia (low blood sugar levels leading to unconsciousness and other symptoms). Altogether 12.864 people took part in 25 studies investigating the new compounds sitagliptin and vildagliptin. Most studies lasted 24 weeks, the longest trials evaluated 52 weeks of treatment. So far, no study reported on patient-oriented parameters like mortality, diabetic complications, costs of treatment and health-related quality of life. When compared to placebo treatment sitagliptin and vildagliptin improved metabolic control. Comparison with other already established blood-glucose lowering drugs did not reveal advantages of DPP-4 treatment. Weight gain was not observed after sitagliptin and vildagliptin therapy. Overall, sitagliptin and vildagliptin were well tolerated, no severe hypoglycaemia was reported in patients taking sitagliptin or vildagliptin. However, all-cause infections increased significantly after sitagliptin treatment but did not reach statistical significance following vildagliptin therapy. Unfortunately, all published randomised controlled trials of at least 12 weeks treatment with sitagliptin and vildagliptin only reported routine laboratory safety measurements. Since the new DPP-4 inhibitors may influence immune function additional long-term data on the safety of these drugs are necessary. Also, cardiovascular outcomes like heart attacks and strokes should not be increased with any antidiabetic therapy but data so far are lacking. Until new information arrives, DPP-4 inhibitors should only be used under controlled conditions and in individual patients. This is a Cochrane review abstract and plain language summary, prepared and maintained by The Cochrane Collaboration, currently published in The Cochrane Database of Systematic Reviews 2011 Issue 10, Copyright © 2011 The Cochrane Collaboration. Published by John Wiley and Sons, Ltd.. The full text of the review is available in The Cochrane Library (ISSN 1464-780X). This record should be cited as: 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 Editorial Group: Metabolic and Endocrine Disorders Group This version first published online: April 16. 2008 Last assessed as up-to-date: January 31. 2008 Abstract Background In type 2 diabetes mellitus there is a progressive loss of beta-cell function. One new approach yielding promising results is the use of the orally active dipeptidyl peptidase-4 (DPP-4) inhibitors like sitagliptin and vildagliptin. Objectives To assess the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Search strategy Studies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library . Selection criteria Studies were included if they were randomised controlled trials in adult people with type 2 diabetes mellitus and had a trial duration of at least 12 weeks. Data collection and analysis Two authors independently assessed risk of bias and extracted data. Pooling of studies was performed by means of fixed-effect meta-analysis. Main results Twenty-five studies of good quality were identified, 11 trials evaluated sitagliptin and 14 trials vildagliptin treatment. Altogether, 6743 patients were randomised in sitagliptin and 6121 patients in vildagliptin studies, respectively. Sitagliptin and vildagliptin studies ranged from 12 to 52 weeks duration. No data were published on mortality, diabetic complications, costs of treatment and health-related quality of life. Sitagliptin and vildagliptin therapy in comparison with placebo resulted in an HbA1c reduction of approximately 0.7% and 0.6%, respectively. Data on comparisons with active comparators were limited but indicated no improved metabolic control following DPP-4 intervention in contrast to other hypoglycaemic agents. Sitagliptin and vildagliptin therapy did not result in weight gain but weight loss was more pronounced following placebo interventions. No definite conclusions could be drawn from published data on sitagliptin and vildagliptin effects on measurements of beta-cell function. Overall, sitagliptin and vildagliptin were well tolerated, no severe hypoglycaemia was reported in patients taking sitagliptin or vildagliptin. All-cause infections increased significantly after sitagliptin treatment but did not reach statistical significance following vildagliptin therapy. All published randomised controlled trials of at least 12 weeks treatment with sitagliptin and vildagliptin only reported routine laboratory safety measurements Authors' conclusions 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 new 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   DPP-4 inhibitors Cochrane review conclusions abstract : COCHRANE Author ' conclusions 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 new 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. Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus Plain Language Summary Dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus Dipeptidyl peptidase-4 (DPP-4) inhibitors like sitagliptin and vildagliptin are promising new medicines for the treatment of type 2 diabetes mellitus. They are supposed to improve metabolic control (as measured by lowering blood glucose) without causing severe hypoglycaemia (low blood sugar levels leading to unconsciousness and other symptoms). Altogether 12.864 people took part in 25 studies investigating the new compounds sitagliptin and vildagliptin. Most studies lasted 24 weeks, the longest trials evaluated 52 weeks of treatment. So far, no study reported on patient-oriented parameters like mortality, diabetic complications, costs of treatment and health-related quality of life. When compared to placebo treatment sitagliptin and vildagliptin improved metabolic control. Comparison with other already established blood-glucose lowering drugs did not reveal advantages of DPP-4 treatment. Weight gain was not observed after sitagliptin and vildagliptin therapy. Overall, sitagliptin and vildagliptin were well tolerated, no severe hypoglycaemia was reported in patients taking sitagliptin or vildagliptin. However, all-cause infections increased significantly after sitagliptin treatment but did not reach statistical significance following vildagliptin therapy. Unfortunately, all published randomised controlled trials of at least 12 weeks treatment with sitagliptin and vildagliptin only reported routine laboratory safety measurements. Since the new DPP-4 inhibitors may influence immune function additional long-term data on the safety of these drugs are necessary. Also, cardiovascular outcomes like heart attacks and strokes should not be increased with any antidiabetic therapy but data so far are lacking. Until new information arrives, DPP-4 inhibitors should only be used under controlled conditions and in individual patients. This is a Cochrane review abstract and plain language summary, prepared and maintained by The Cochrane Collaboration, currently published in The Cochrane Database of Systematic Reviews 2011 Issue 10, Copyright © 2011 The Cochrane Collaboration. Published by John Wiley and Sons, Ltd.. The full text of the review is available in The Cochrane Library (ISSN 1464-780X). This record should be cited as: 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 Editorial Group: Metabolic and Endocrine Disorders Group This version first published online: April 16. 2008 Last assessed as up-to-date: January 31. 2008 Abstract Background In type 2 diabetes mellitus there is a progressive loss of beta-cell function. One new approach yielding promising results is the use of the orally active dipeptidyl peptidase-4 (DPP-4) inhibitors like sitagliptin and vildagliptin. Objectives To assess the effects of dipeptidyl peptidase-4 (DPP-4) inhibitors for type 2 diabetes mellitus. Search strategy Studies were obtained from computerised searches of MEDLINE, EMBASE and The Cochrane Library . Selection criteria Studies were included if they were randomised controlled trials in adult people with type 2 diabetes mellitus and had a trial duration of at least 12 weeks. Data collection and analysis Two authors independently assessed risk of bias and extracted data. Pooling of studies was performed by means of fixed-effect meta-analysis. Main results Twenty-five studies of good quality were identified, 11 trials evaluated sitagliptin and 14 trials vildagliptin treatment. Altogether, 6743 patients were randomised in sitagliptin and 6121 patients in vildagliptin studies, respectively. Sitagliptin and vildagliptin studies ranged from 12 to 52 weeks duration. No data were published on mortality, diabetic complications, costs of treatment and health-related quality of life. Sitagliptin and vildagliptin therapy in comparison with placebo resulted in an HbA1c reduction of approximately 0.7% and 0.6%, respectively. Data on comparisons with active comparators were limited but indicated no improved metabolic control following DPP-4 intervention in contrast to other hypoglycaemic agents. Sitagliptin and vildagliptin therapy did not result in weight gain but weight loss was more pronounced following placebo interventions. No definite conclusions could be drawn from published data on sitagliptin and vildagliptin effects on measurements of beta-cell function. Overall, sitagliptin and vildagliptin were well tolerated, no severe hypoglycaemia was reported in patients taking sitagliptin or vildagliptin. All-cause infections increased significantly after sitagliptin treatment but did not reach statistical significance following vildagliptin therapy. All published randomised controlled trials of at least 12 weeks treatment with sitagliptin and vildagliptin only reported routine laboratory safety measurements Authors' conclusions 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 new 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.  
  • “ These conflicts undermine the reliability and credibility of the guidelines,” One of the ways we need to do that is to have a transparent open process and to minimize conflicts of interest.” “ Conflict implies that there is a problem or argument, and we don’t believe that these relationships are a conflict at all,”   said Henry R. Black, MD, clinical professor of medicine at New York University School of Medicine.   “ If anything, it’s a confluence of interest or a synergy of interest. We have the same interest at heart, and that is helping patients.”   According to Steven Nissen, MD, chair of CV medicine at the Cleveland Clinic and a member of the Cardiology Today Editorial Board, there are two primary concerns regarding physician relationships with the industry: the first is that of transparency; the other is the existence of conflicts of interest in areas in which there could be considerable opportunity for harm to be done to professional reputations, guideline credibility and, ultimately, to patients. “ These conflicts undermine the reliability and credibility of the guidelines,” Nissen told Cardiology Today . “I don’t think that disclosure is the antidote here. The antidote is for physicians who are involved in public policy discussions not to accept money for promoting drugs.” The study of guidelines and conflicts of interest is an important one because such clinical practice guidelines may have a great effect on patient care. According to James N. Kirkpatrick, MD, assistant professor of medicine at the University of Pennsylvania and a researcher of the study, clinical practice guidelines are increasingly used in medical malpractice cases and are forming the basis of many of the pay-for-performance initiatives. James N. Kirkpatrick “ It is important that clinical guidelines be something that people can trust,” Kirkpatrick said. “We do have to be more cognizant of conflicts of interest, mainly because of the perception they bring. We have to safeguard the trust of the proven therapies we have. One of the ways we need to do that is to have a transparent open process and to minimize conflicts of interest.” But physician relationships with industry do not just have the potential to affect practice guidelines. They have the potential to affect scientific research and patient care. “ The research shows that relationships between doctors and companies are ubiquitous in every aspect of medical education, medical research and the practice of medicine,” said Eric G. Campbell, PhD, associate professor of medicine at Harvard Medical School. “Conflicts of interest are not universally bad, but they’re not universally good.” Industry relationships Several studies have quantified the relationships between physicians and the industry. A Journal of the American Medical Association review published by Wazana and colleagues in 2000 suggested that these relationships affect the prescribing and professional behavior of physicians. The same study suggested that continuing medical education programs sponsored by a drug company were more likely to highlight the drug company’s product. Eric G. Campbell “ These types of relationships, while beneficial to the industry, are not beneficial to the American public and are actually detrimental,” Campbell said. “Essentially, these programs are meant to serve as a marketing tool to sell drugs. The industry is not to blame, as they are motivated like any other for-profit company. Their primary goal is to sell things, and everything they do revolves around maximizing revenue.” A 2004 study published in The New England Journal of Medicine found that 94% of physicians reported some type of relationship with pharmaceutical companies. The most prevalent relationships involved receiving food in the workplace or receiving drug samples. In addition, 35% of the respondents received reimbursement for costs associated with professional meetings or CME, and 28% received payment for consulting, giving lectures or enrolling patients in trials. Also of note, cardiologists were more than twice as likely as family practitioners to receive payments. Physician relationships with the industry are beneficial in that they typically lead to innovation that leads to new drugs and devices used to enhance patient care. For example, according to Thomas P. Stossel, MD, the American Cancer Society Professor of Medicine at Harvard Medical School, there has been a 50% decrease in CV mortality since new drugs and devices were introduced to help patients with CVD. “ This decline in cardiovascular mortality is 100% because of the tools we got from the industry, and these tools were the result of physicians collaborating with the industry,” Stossel told Cardiology Today . “These relationships lead to improved drugs, devices, imaging modalities and many others. No one can get up and say that these relationships haven’t been overwhelmingly beneficial.” J. Michael Gonzalez-Campoy According to J. Michael Gonzalez-Campoy, MD, PhD, medical director and CEO of the Minnesota Center for Obesity, Metabolism and Endocrinology, physicians who are at the cutting edge of science and who are involved in clinical research are the best suited to author clinical practice guidelines. “ These physicians are paid for their work by third parties, and this is what advanced science,” Gonzalez-Campoy said. “It does not matter if it is the NIH, the Cleveland Clinic or a pharmaceutical company. Excluding the most expert physicians in the field because of their working relationships stands to hurt medicine and patients. It is naive to suggest that physicians should not have fiduciary relationships for the work they do.” Academic physicians should not be expected to do what they do without any compensation, Black said, adding that the problem with current disclosures is that they make no distinction between the types of money received, such as that for a research grant or for honorarium, or speaking at industry-sponsored CME. “ That can be misleading,” he said. “If I get a large grant sponsored by a company or received money to give talks, these would not be distinguished from each other. We have no problem with disclosures — our universities make us disclose and our societies make us disclose — but the nature of the relationships disclosed need to be distinguished.” Research funding Not all relationships between physicians and drug companies are negative. Pharmaceutical companies often provide most of the funding for clinical trials that evaluate potential new treatments for patients. This funding may not be available elsewhere. “ The American people support our academic institutions through research grants and contracts,” Campbell said. “They do that under the assumption that our research will make health services better for the American people. If we refused to accept research funding from drug companies, we would not be able to live up to that expectation. There is an academic and a social contract. We need to work with the industry because we need to translate the results of our research into health care products and services. At the end of the day, we need to be about curing disease, ending suffering and educating the next generation of researchers.” Joel Lexchin According to Joel Lexchin, MD, professor in the School of Health Policy & Management at York University in Toronto, a large body of research supports the notion that when the industry directly funds studies, those studies are about four times more likely to produce positive results than if anyone else funds the research. Although collaborations between industry and researchers can be useful, there should be a firewall between the researchers and industry. “ Industry should give the money to the NIH if they want a trial on a specific drug, and then the NIH would act as a gatekeeper between the researchers and industry,” Lexchin said. “The NIH would peer-review the researcher proposals and select the research team to complete the research. The data would then be analyzed independent of the drug company.” But the distinction between research funding and marketing still can be blurred, Nissen said. “ Relationships between physician and industry that involve doing good scientific work to develop new products that benefit patients are highly desirable,” Nissen said. “But you have to be careful about what that means. Many trials are not designed to answer a scientific question, but rather to answer a marketing question.” Gonzalez-Campoy, however, said the collaboration between physicians and pharmaceutical and biotechnology companies is what has made American medicine great. “ One could not exist without the other,” he said. “In fact, trials are designed not for marketing, but to fulfill regulatory criteria that allow medications and technologies to achieve the permissions and indications needed to come to market and benefit patients. It stands to reason that the compounds and technologies that are safe and effective are the ones that deserve attention.” Black said the basic science research and clinical trials needed to bring a new drug or device to the market requires the expertise of physicians and fosters the collaboration between them and the industry. “ We would be nowhere without the relationships with the industry,” Black said. “The investment that a company makes to take an idea to market is about $1.2 billion.” Uniform standards Most, if not all, medical institutions have policies regarding conflicts of interest, as do medical journals. The issue is that they all have their own guidelines when it comes to reporting conflicts. “ Each journal has different standards, hospitals have different standards and medical schools have different standards,” Lexchin said. “Some of these standards are stricter and some of these standards are looser. A universal policy is a useful goal that would allow everybody to be working from the same page. Investigators would understand what is or is not required from them in terms of disclosing conflicts of interest, and all institutions would then know what kind of information they should be collecting.” A study published in JAMA in 2009 found that among 256 medical journals, 89% had author conflict-of-interest policies. However, a JAMA study published 2 years later found that among 29 meta-analyses of pharmacological treatments published in high-impact biomedical journals, information about the conflicts of interests of the 509 randomized controlled trials used for the meta-analyses was rarely reported. Lexchin and colleagues proposed a standard form for investigators to disclose conflicts of interest in an article published in the open-access journal Open Medicine . But simply declaring conflicts of interest is not sufficient enough to deal with the problem, Lexchin said. “ There is some literature that shows that if doctors simply disclose their relationships with a drug company, others would trust those doctors more because they are being honest about their conflicts,” he said. “Unless you are an expert in the area, you cannot be sure of the accuracy of what these doctors are saying, as they might be biased by their relationships with the company.” Thomas P. Stossel According to Stossel, disclosing the sponsors of the research has always been done as a way to give credit to them for funding the studies. But the call for disclosures has become more involved. “ Disclosure policies are no longer a way to honor the sponsor of a study,” Stossel said. “Instead, it has been turned into a type of confession. I have no problem disclosing, in principle. But in practice, disclosures are being used by the media to embarrass people.” Physician Payment Sunshine Act According to Campbell, for a long time, conflicts of interests have remained hidden because drug companies have not had to disclose how much they pay doctors. But a provision included in the Patient Protection and Affordable Care Act of 2009 will require drug/device companies to disclose all payments and gifts made to physicians. The provision, called the Physician Payment Sunshine Act, requires that payments and gifts of more than $100 be reported to the Department of Health and Human Services. The information will then be reported and maintained in a public database. This includes consulting fees, honoraria, research funding, stock options and travel costs, among others. Several states, including Vermont, Massachusetts and Minnesota, and the District of Columbia have already instituted reporting requirements for physicians receiving payment from drug/device companies. This system for reporting industry payments to physicians was an idea put forth by the Institute of Medicine in its 2009 report, “Conflicts of Interest in Medical Research, Education, and Practice.” The committee also recommended that all medical institutions, including academic medical centers, professional societies, patient advocacy groups and medical journals, establish conflict-of-interest policies that require disclosure and management of individual and institutional financial ties to industry. – by Emily Shafer For more information: Blum J. JAMA. 2009;302:2230-2234. Campbell E. N Engl J Med. 2007;356:1742-1750. Institute of Medicine. Conflict of interest in medical research, education, and practice. April 21, 2009. Available at: www.iom.edu/conflictofinterest . Accessed April 15, 2011. Mendelson T. Arch Intern Med. 2011:177:577-585. Rochon P. Open Med. 2010;4:e69-e91. Roseman M. JAMA. 2011;305:1008-1017. Wazana A. JAMA. 2000;283:373-380. Disclosures: Drs. Black, Campbell, Gonzalez-Campoy, Kirkpatrick, Nissen and Stossel report no relevant financial disclosures. Dr. Lexchin has served as a consultant to a law firm representing the generic company Apotex Inc., a consultant to the Canadian Federal Government in its defense against the challenge to the ban of direct-to-consumer advertising, and as a consultant to a law firm in a suit against Allergan, alleging a death due to an adverse drug reaction. He also is a member of the management board of the group Healthy Skepticism.  
  • “ Conflict implies that there is a problem or argument, and we don’t believe that these relationships are a conflict at all,”   said Henry R. Black, MD, clinical professor of medicine at New York University School of Medicine.   “ If anything, it’s a confluence of interest or a synergy of interest. We have the same interest at heart, and that is helping patients.”   According to Steven Nissen, MD, chair of CV medicine at the Cleveland Clinic and a member of the Cardiology Today Editorial Board, there are two primary concerns regarding physician relationships with the industry: the first is that of transparency; the other is the existence of conflicts of interest in areas in which there could be considerable opportunity for harm to be done to professional reputations, guideline credibility and, ultimately, to patients. “ These conflicts undermine the reliability and credibility of the guidelines,” Nissen told Cardiology Today . “I don’t think that disclosure is the antidote here. The antidote is for physicians who are involved in public policy discussions not to accept money for promoting drugs.” The study of guidelines and conflicts of interest is an important one because such clinical practice guidelines may have a great effect on patient care. According to James N. Kirkpatrick, MD, assistant professor of medicine at the University of Pennsylvania and a researcher of the study, clinical practice guidelines are increasingly used in medical malpractice cases and are forming the basis of many of the pay-for-performance initiatives. James N. Kirkpatrick “ It is important that clinical guidelines be something that people can trust,” Kirkpatrick said. “We do have to be more cognizant of conflicts of interest, mainly because of the perception they bring. We have to safeguard the trust of the proven therapies we have. One of the ways we need to do that is to have a transparent open process and to minimize conflicts of interest.” But physician relationships with industry do not just have the potential to affect practice guidelines. They have the potential to affect scientific research and patient care. “ The research shows that relationships between doctors and companies are ubiquitous in every aspect of medical education, medical research and the practice of medicine,” said Eric G. Campbell, PhD, associate professor of medicine at Harvard Medical School. “Conflicts of interest are not universally bad, but they’re not universally good.” Industry relationships Several studies have quantified the relationships between physicians and the industry. A Journal of the American Medical Association review published by Wazana and colleagues in 2000 suggested that these relationships affect the prescribing and professional behavior of physicians. The same study suggested that continuing medical education programs sponsored by a drug company were more likely to highlight the drug company’s product. Eric G. Campbell “ These types of relationships, while beneficial to the industry, are not beneficial to the American public and are actually detrimental,” Campbell said. “Essentially, these programs are meant to serve as a marketing tool to sell drugs. The industry is not to blame, as they are motivated like any other for-profit company. Their primary goal is to sell things, and everything they do revolves around maximizing revenue.” A 2004 study published in The New England Journal of Medicine found that 94% of physicians reported some type of relationship with pharmaceutical companies. The most prevalent relationships involved receiving food in the workplace or receiving drug samples. In addition, 35% of the respondents received reimbursement for costs associated with professional meetings or CME, and 28% received payment for consulting, giving lectures or enrolling patients in trials. Also of note, cardiologists were more than twice as likely as family practitioners to receive payments. Physician relationships with the industry are beneficial in that they typically lead to innovation that leads to new drugs and devices used to enhance patient care. For example, according to Thomas P. Stossel, MD, the American Cancer Society Professor of Medicine at Harvard Medical School, there has been a 50% decrease in CV mortality since new drugs and devices were introduced to help patients with CVD. “ This decline in cardiovascular mortality is 100% because of the tools we got from the industry, and these tools were the result of physicians collaborating with the industry,” Stossel told Cardiology Today . “These relationships lead to improved drugs, devices, imaging modalities and many others. No one can get up and say that these relationships haven’t been overwhelmingly beneficial.” J. Michael Gonzalez-Campoy According to J. Michael Gonzalez-Campoy, MD, PhD, medical director and CEO of the Minnesota Center for Obesity, Metabolism and Endocrinology, physicians who are at the cutting edge of science and who are involved in clinical research are the best suited to author clinical practice guidelines. “ These physicians are paid for their work by third parties, and this is what advanced science,” Gonzalez-Campoy said. “It does not matter if it is the NIH, the Cleveland Clinic or a pharmaceutical company. Excluding the most expert physicians in the field because of their working relationships stands to hurt medicine and patients. It is naive to suggest that physicians should not have fiduciary relationships for the work they do.” Academic physicians should not be expected to do what they do without any compensation, Black said, adding that the problem with current disclosures is that they make no distinction between the types of money received, such as that for a research grant or for honorarium, or speaking at industry-sponsored CME. “ That can be misleading,” he said. “If I get a large grant sponsored by a company or received money to give talks, these would not be distinguished from each other. We have no problem with disclosures — our universities make us disclose and our societies make us disclose — but the nature of the relationships disclosed need to be distinguished.” Research funding Not all relationships between physicians and drug companies are negative. Pharmaceutical companies often provide most of the funding for clinical trials that evaluate potential new treatments for patients. This funding may not be available elsewhere. “ The American people support our academic institutions through research grants and contracts,” Campbell said. “They do that under the assumption that our research will make health services better for the American people. If we refused to accept research funding from drug companies, we would not be able to live up to that expectation. There is an academic and a social contract. We need to work with the industry because we need to translate the results of our research into health care products and services. At the end of the day, we need to be about curing disease, ending suffering and educating the next generation of researchers.” Joel Lexchin According to Joel Lexchin, MD, professor in the School of Health Policy & Management at York University in Toronto, a large body of research supports the notion that when the industry directly funds studies, those studies are about four times more likely to produce positive results than if anyone else funds the research. Although collaborations between industry and researchers can be useful, there should be a firewall between the researchers and industry. “ Industry should give the money to the NIH if they want a trial on a specific drug, and then the NIH would act as a gatekeeper between the researchers and industry,” Lexchin said. “The NIH would peer-review the researcher proposals and select the research team to complete the research. The data would then be analyzed independent of the drug company.” But the distinction between research funding and marketing still can be blurred, Nissen said. “ Relationships between physician and industry that involve doing good scientific work to develop new products that benefit patients are highly desirable,” Nissen said. “But you have to be careful about what that means. Many trials are not designed to answer a scientific question, but rather to answer a marketing question.” Gonzalez-Campoy, however, said the collaboration between physicians and pharmaceutical and biotechnology companies is what has made American medicine great. “ One could not exist without the other,” he said. “In fact, trials are designed not for marketing, but to fulfill regulatory criteria that allow medications and technologies to achieve the permissions and indications needed to come to market and benefit patients. It stands to reason that the compounds and technologies that are safe and effective are the ones that deserve attention.” Black said the basic science research and clinical trials needed to bring a new drug or device to the market requires the expertise of physicians and fosters the collaboration between them and the industry. “ We would be nowhere without the relationships with the industry,” Black said. “The investment that a company makes to take an idea to market is about $1.2 billion.” Uniform standards Most, if not all, medical institutions have policies regarding conflicts of interest, as do medical journals. The issue is that they all have their own guidelines when it comes to reporting conflicts. “ Each journal has different standards, hospitals have different standards and medical schools have different standards,” Lexchin said. “Some of these standards are stricter and some of these standards are looser. A universal policy is a useful goal that would allow everybody to be working from the same page. Investigators would understand what is or is not required from them in terms of disclosing conflicts of interest, and all institutions would then know what kind of information they should be collecting.” A study published in JAMA in 2009 found that among 256 medical journals, 89% had author conflict-of-interest policies. However, a JAMA study published 2 years later found that among 29 meta-analyses of pharmacological treatments published in high-impact biomedical journals, information about the conflicts of interests of the 509 randomized controlled trials used for the meta-analyses was rarely reported. Lexchin and colleagues proposed a standard form for investigators to disclose conflicts of interest in an article published in the open-access journal Open Medicine . But simply declaring conflicts of interest is not sufficient enough to deal with the problem, Lexchin said. “ There is some literature that shows that if doctors simply disclose their relationships with a drug company, others would trust those doctors more because they are being honest about their conflicts,” he said. “Unless you are an expert in the area, you cannot be sure of the accuracy of what these doctors are saying, as they might be biased by their relationships with the company.” Thomas P. Stossel According to Stossel, disclosing the sponsors of the research has always been done as a way to give credit to them for funding the studies. But the call for disclosures has become more involved. “ Disclosure policies are no longer a way to honor the sponsor of a study,” Stossel said. “Instead, it has been turned into a type of confession. I have no problem disclosing, in principle. But in practice, disclosures are being used by the media to embarrass people.” Physician Payment Sunshine Act According to Campbell, for a long time, conflicts of interests have remained hidden because drug companies have not had to disclose how much they pay doctors. But a provision included in the Patient Protection and Affordable Care Act of 2009 will require drug/device companies to disclose all payments and gifts made to physicians. The provision, called the Physician Payment Sunshine Act, requires that payments and gifts of more than $100 be reported to the Department of Health and Human Services. The information will then be reported and maintained in a public database. This includes consulting fees, honoraria, research funding, stock options and travel costs, among others. Several states, including Vermont, Massachusetts and Minnesota, and the District of Columbia have already instituted reporting requirements for physicians receiving payment from drug/device companies. This system for reporting industry payments to physicians was an idea put forth by the Institute of Medicine in its 2009 report, “Conflicts of Interest in Medical Research, Education, and Practice.” The committee also recommended that all medical institutions, including academic medical centers, professional societies, patient advocacy groups and medical journals, establish conflict-of-interest policies that require disclosure and management of individual and institutional financial ties to industry. – by Emily Shafer For more information: Blum J. JAMA. 2009;302:2230-2234. Campbell E. N Engl J Med. 2007;356:1742-1750. Institute of Medicine. Conflict of interest in medical research, education, and practice. April 21, 2009. Available at: www.iom.edu/conflictofinterest . Accessed April 15, 2011. Mendelson T. Arch Intern Med. 2011:177:577-585. Rochon P. Open Med. 2010;4:e69-e91. Roseman M. JAMA. 2011;305:1008-1017. Wazana A. JAMA. 2000;283:373-380. Disclosures: Drs. Black, Campbell, Gonzalez-Campoy, Kirkpatrick, Nissen and Stossel report no relevant financial disclosures. Dr. Lexchin has served as a consultant to a law firm representing the generic company Apotex Inc., a consultant to the Canadian Federal Government in its defense against the challenge to the ban of direct-to-consumer advertising, and as a consultant to a law firm in a suit against Allergan, alleging a death due to an adverse drug reaction. He also is a member of the management board of the group Healthy Skepticism.  

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 Presentation Transcript

  • 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
  • No financial relationships with any commercial interests
  • 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
  • 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
  • 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
  • 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
  • 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
  • Plasma Insulin (µU/mL) The incretin effect* Time (min)* Perley MI,et al. J Clin Invest. 1967; 46:1954-1962.
  • 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.
  • 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
  • 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.
  • (K-cells of the intestinal mucosa) * Takeda J, et al.Proc Natl Acad Sci U S A 1987; 84:7005–7008
  • (L-cells of the intestinal mucosa)  * Orskov C, et al. En-docrinology 1986; 119:1467—1475.
  •  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
  • 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
  • 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.
  • 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 ,
  • 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)
  • 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
  • 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.
  • 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
  • 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
  • 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)
  • 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
  • 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)
  • 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.
  • 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
  • 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
  • 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
  • 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
  • GLP-1 analogue, exendin-4, first found in the saliva of the Gila monster LizardThe Gila Monster Lizard -4 en din Ex
  • 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)
  • 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
  • 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
  • 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.
  • 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
  • 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
  • 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
  • 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.
  • 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;
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • Necrotizing pancreatitis in a HIP rat treated with sitagliptin “Januvia” for 12 weeks**Matveyenko AV et al. Diabetes 2009 ;58 : 1604-1615.
  • 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
  • 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
  • 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.
  • 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.
  • 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.
  • Comparison between GLP-1 analogs and DDP-IV inhibiters SpecificityThe effects of GLP-analogs are strictly Specific whilethe DDP-IV inhibiters lack specificity
  • 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
  • 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
  • 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.
  •  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
  •  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
  •  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
  •  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
  • 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 ).
  • 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
  • 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.”
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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
  • 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
  • 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.
  • 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,
  • 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.
  • Thank you