Management of T2DM in light of newer evidencesDr.Seenaj Chandran.MD,Dip.Diab31-07-2011Saj Earth Resorts-Cochin

Diabetes – A Global EpidemicOutline:Current recommendationsIncretin based therapiesDPP 4 inhibitors and its scopeSitagliptinCase discussionsComparison of different gliptins in IndiaSafety profile and adverse effectsCurrent ongoing trialsTake home messages

Managing Diabetes

Glycosylated hemoglobin-HbAic most widely used clinical test measurement of blood glycated hemoglobin (also called hemoglobin A1C, glycohemoglobin, and glycosylated hemoglobin [HbA1c]). the average amount of A1C changes in a dynamic way reflects the mean blood glucose concentration over the previous six to eight weeks.  A1C value of 7 percent --150 mg/dLA1C value of 9 percent --210 mg/dL

Oral hypoglycemic agentsBiguanides-Phenformin,MetforminSulfonylureas-Glemepride,glipizide etcMeglitidines-Repaglinide,NateglinideThiazolidinediones-PioglitazoneAlpha-glucosidase inhibitors-Acarbose,VogliboseDPP-4 Inhibitors-Sitagliptin,vildagliptin,Saxagliptin,Lanagliptin

Endocr Pract. 2009;15:540-559Consensus of 14 highly experienced clinicians, clinical researchers, practitioners, and academicians and is based on the AACE/ ACE Diabetes Guidelines & the recent medical literature.Objective: Practical algorithm for management of patients withtype 2 diabetes mellitus that considers “currently approvedClasses” of medications and emphasizes “safety and efficacy”

Algorithm development

Principles followedA1C Goal ≤ 6.5%“Monitor therapy closely (every 2 to 3 months) and to intensify therapy until the goal for A1C has been achieved”Lifestyle (dietary and exercise) modifications are essential for all patients with diabetes. Reduction of obesity or overweight and adjustmentAchieving an A1C of 6.5%When using combinations: Titrate dosesPriority: Safety and efficacy > cost of medications

Management guidelines…..Management of Patients With A1CLevels of 6.5% to 7.5%TripleDualMonotherapyRecommended agents: Metformin, DPP-4i , TZDs, Glinide, SU not recommendedrisk of HYPO & weight gainRecommended order: Metformin +Incretin mimetic → DPP-4i → TZDs → Glinide → SURecommended order: Metformin + Incretin mimetic → DPP-4i TZDs → Glinide → SU

Management guidelinesManagement of Patients With A1CLevels of 7.6% to 9.0%TRIPLEDUALRecommended order: Metformin +Incretin mimetic → DPP-4i → TZDs → SURecommended order: Metformin + Incretin mimetic → DPP-4i → TZDs + TZDs → SUGlinides & AGIs are not considered: limited A1C-lowering potential.

Management guidelinesManagement of Patients With A1CLevels of > 9.0%CombinationRxRecommended order: Metformin + GLP-1± SUMetformin + DPP-4i ± SUMetformin + GLP-1± TZDsMetformin + DPP-4i ± TZDsGlinides & AGIs are not considered: limited A1C-lowering potential.

AACE Treatment Algorithm

In conclusion…..Favors the use of GLP-1 agonists /DPP-4 inhibitors with higher priority: Effectiveness and overall safety profiles.Sulfonylureas - lower priority: Risks of Hypo, weight gain, and improved glycemic for relatively short period (1-2 years).GLP-1 agonists/ DPP-4i: Important agents in regimenTZDs: Effective BUT lower priority: ↑CV risks and bone #AGIs & glinides: Lower priority – limited efficacy.

“HYPOGLYCEMIA”A TOP PRIORITY IN NEWER GUIDELINES“Shift in trend, 2009”Newer classes gaining acceptanceADA→NICE →AACE

The New class-DPP-4 InhibitorsWhat is DPP-4-Dipeptydyl Peptidase-4What is the significanceWhat are the PK propertiesDifferent gliptins availableComparisonYet to come

Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913; Ahrén B. Curr Diab Rep. 2003;2:365–372; Drucker DJ. Diabetes Care. 2003;26:2929–2940; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441; JANUVIA Local Physician Circular, MSD Pharmaceuticals Private Limited, INDIA.The Incretins

GLP1 Glucagon Like Peptide-1 Secretion from L cells of small intestine, Dependent on nutrient presence in the intestine Increases Insulin secretion from the Beta cells, suppress Glucagon secretion from Alpha cells (both glucose dependent), increase satiety, decrease GI motility etc GIP Glucose dependent Insulinotropic Polypeptide Secretion from K cells of small intestine Dependent on nutrient absorption Increases insulin biosynthesis and secretion from beta cells Drucker DJ. Curr Pharm Des 2001; 7:1399-1412

doi:10.1016/j.bcp.2008.07.029 Lambeir, Scharpe, Meester10.1002/ddr.20138, von Geldern, Trevillyan

History of Development of Gliptins1967, DPP-4 enzyme was discovered.The first inhibitors were characterized in the late 1980s and 1990s.Ferring Pharmaceuticals filed for patent on two potent and stable substrate like inhibitors DPP-4 inhibitors which they published in 1995.1995, Edwin B. Villhauer at Novartis started to explore substrate like inhibitors. Vildagliptin (Galvus) was first synthesized in May 1998 and was named after Edwin B. Villhauer. 1999: Merck started a drug development program on DPP-4 inhibitors.Merck stopped working on compounds from the α-amino acid series related to isoleucyl thiazolidide due to lack of selectivity but identified a potent and selective triazolopiperazine series Optimization of these compounds finally led to the discovery of Sitagliptin.

Drugs belonging to DPP4 inhibitor classSitagliptin (FDA approved 2006, marketed by Merck & Co./MSD as Januvia, Ono in Japan as Glactiv)Vildagliptin (marketed in the EU and elsewhere by Novartis as Galvus)Saxagliptin (FDA approved in 2009, marketed as Onglyza by BMS and Astra Zeneca)Linagliptin (being developed by Boehringer Ingelheim),Dutogliptin (being developed by Phenomix Corporation)Gemigliptin (being developed by LG Life Sciences,Korea)Alogliptin (developed by Takeda Pharmaceutical Company, whose FDA application for the product is currently suspended as of June 2009, awaiting Japanese approval)ABT 341 (Abbott Labs)Melogliptin (Glenmark) currently dropped.Denagliptin (GSK) suspendedMK-3102 (Merck/MSD) Once weekly Gliptin, Phase IBerberine, the common herbal dietary supplement, too inhibits dipeptidyl peptidase-4, which at least partly explains its anti-hyperglycemic activities, Gemifloxacin was one of the drug candidates for the development of DPP4 inhibitors

Sitagliptin- A novel Antidiabetic agent

Mechanism of Action of Sitagliptin Restores natural pathway for regulation of α and β Beta cells –Incretin PathwayAdapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913; Ahrén B. Curr Diab Rep. 2003;2:365–372; Drucker DJ. Diabetes Care. 2003;26:2929–2940; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441; JANUVIA Local Physician Circular, MSD Pharmaceuticals Private Limited, INDIA.

Pharmacokinetic & Pharmacodynamic properties of Clinical Importance Once daily dosing Sitagliptin 100 mg given OD provides ~80% inhibition of DPP IV enzyme after 24 hoursNo effect of food on pharmacokinetics parameters Can be administered independent of mealsNo known clinically significant drug-drug interaction80% of drug excreted un-exchanged through kidneys Dose modification needed in moderate to severe renal insufficiencyBy inhibiting DPP-4 enzyme, increases serum levels of intact GLP-1 & GIP Thereby, stimulates Insulin secretion and suppresses Glucagon secretion in a glucose dependent mannerReferences: data on file MSD Pharmaceuticals Pvt. Ltd. , India; JANUVIA Local Physician Circular, MSD Pharmaceuticals Private Limited, INDIA.

Efficacy Results – Phase III Clinical StudiesMultinational, randomized, double-blind, placebo-controlled, parallel-group studies to assess the efficacy of JANUVIA in patients with type 2 diabetes inadequately controlled on specified therapy. The primary efficacy endpoint was change from baseline at end of follow up period in HbA1C.Itamar Raz et al. Current Medical Research and Opinion 2008; 24 (2): 537-550Bernard Charbonnel et al. Diabetes Care. 2006;29:2638–2643Rosenstock et al, Clinical Therapeutics 2006;28(10):1556-1568Hermansen et al, Diabetes Obesity Metabolism 2007* In the entire cohort in K. Hermansen et al , placebo adjusted reduction in HbA1c was -0.74%.

Screening Single-blindplacebo Double-blind treatment period:Sulfonylurea or sitagliptin 100 mg/dayMetformin monotherapyWeek 2:Eligible if HbA1c≥6.5% to ≤10%If on an OHA, D/CContinue/startmetforminDay 1RandomizationWeek 52*Specifically Glipizide 5 mg/day increased to 20 mg/day (dose not up-titrated if finger stick <110 mg/dL or hypoglycemia) OHA = oral antihyperglycemic agent; DC = discontinued; T2DM = type 2 diabetes Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.52-week Sitagliptin vs Sulfonylurea* Add-on Therapy to Metformin Study Active-Comparator (Sulfonylurea) Controlled Add-on to Metformin Study—DesignRandomized, double-blind, parallel-group, active-controlled, non-inferiority study in patients with T2DM (N=1172) Treatment:Sitagliptin 100 mg/day with metformin ≥1500 mg/daySulfonylurea* up to 20 mg/day with metformin ≥1500 mg/dayMetformin (stable dose ≥1500 mg/day)

HbA1c Over Time With Sitagliptin or Glipizide as Add-on Combination With Metformin: Comparable EfficacyA multinational, randomized, double-blind, parallel-group study to assess the effect of adding JANUVIA compared with Glipizide to metformin in patients with type 2 diabetes inadequately controlled with ≥1500 mg daily metformin (HbA1C 6.5% to 10.0%). The primary efficacy analysis assessed whether the study treatments were non-inferior with regard to the HbA1C change from baseline at week 52 using a per-protocol (PP) approach. From - Nauck et al. Diabetes, Obesity & Metabolism 2007; 9: 194-205Mean reduction in patients with baseline HbA1c >9.0% (subgroup results are from a POST-HOC analysis).

Effect on body weight and Incidence of HypoglycemiaA multinational, randomized, double-blind, parallel-group study to assess the effect of adding JANUVIA compared with Glipizide to metformin in patients with type 2 diabetes inadequately controlled with ≥1500 mg daily metformin (HbA1C 6.5% to 10.0%). The primary efficacy analysis assessed whether the study treatments were non-inferior with regard to the HbA1C change from baseline at week 52 using a per-protocol (PP) approach. From - Nauck et al. Diabetes, Obesity & Metabolism 2007; 9: 194-205-2.5 Kg% of patients experiencing at least 1 episode of hypoglycemia over 52 weeksP<0.001

52-week Sitagliptin vs Sulfonylurea* Add-on Therapy to Metformin Study Summary Measures of Clinical Adverse Events in Active-comparator Add-on to Metformin Study *Specifically Glipizide AEs = adverse events All-patients-as-treated population Adapted from Nauck et al. Diabetes Obes Metab. 2007;9:194–205.

JANUVIA® safety summaryJANUVIA® was generally well tolerated in controlled clinical studies as both monotherapy and combination therapy, with discontinuation of therapy due to clinical adverse experiences similar to placebo. In four placebo-controlled clinical studies as both monotherapy and add-on combination therapy with metformin or pioglitazone (both of 24 week duration), there were 1082 patients treated with JANUVIA® 100 mg once daily and 778 patients given placebo. (Two of these studies also included 456 patients treated with JANUVIA® 200 mg daily, two times the recommended daily dose.) There were no drug-related adverse reactions reported that occurred with an incidence of ≥1% in patients receiving JANUVIA® 100 mg. Overall, the safety profile of the 200-mg daily dose was similar to that of the 100-mg daily dose. In a pre-specified pooled analysis of the above studies, the overall incidence of adverse experiences of hypoglycemia in patients treated with JANUVIA® 100 mg was similar to placebo (1.2% vs. 0.9%). Adverse experiences of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required. The incidences of selected gastrointestinal adverse experiences in patients treated with JANUVIA® or placebo were: abdominal pain (JANUVIA®, 2.3%; placebo, 2.1%), nausea (1.4%, 0.6%), vomiting (0.8%, 0.9%), and diarrhea (3.0%, 2.3%). As is typical with other antihyperglycemic agents used in combination with a sulfonylurea, when JANUVIA® was used in combination with a sulfonylurea, a medication known to cause hypoglycemia, the incidence of sulfonylurea-induced hypoglycemia was increased over that of placebo. Therefore, to reduce the risk of sulfonylurea-induced hypoglycemia, a lower dose of sulfonylurea may be considered. The following additional adverse reactions have been identified during post marketing use of JANUVIA®. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypersensitivity reactions include anaphylaxis, angioedema, rash, urticaria, and exfoliative skin conditions, including Stevens-Johnson syndrome, upper respiratory tract infection; naso-pharyngitis. JANUVIA Local Physician Circular, MSD Pharmaceuticals Private Limited, INDIA.

Next to Metformin - Profile of Sitagliptin in the Position

Major Targeted Sites of Oral Drug Classes DPP-4=dipeptidyl peptidase 4; TZDs=thiazolidinediones.Glucose absorptionHepatic glucoseOver productionImpaired insulinsecretionInsulinresistance↓Glucose levelBiguanidesTZDsDPP-4 Inhi.SulfonylureasMeglitinidesDPP-4 Inhi.TZDsBiguanidesα-Glucosidase inhi.BiguanidesRaised glucagonsecretionDPP-4 Inhi.

Co-administration of Sitagliptin and Metformin in Healthy Adults Increased Active GLP-1 Greater Than Either Agent Alone* Values represent geometric mean±SE.PlaceboMetformin 1000 mg Sitagliptin 100 mg Co-administration of sitagliptin 100 mg + metformin 1000 mg Mean AUC ratio*Sita + Met: 4.12Mean AUC ratios*Sita: 1.95 Met: 1.76–201020304050–101234Active GLP-1 Concentrations, pMMealMorning Dose Day 2Time (hours pre/post meal)N=16 healthy subjectsAUC=area under the curveMigoya EM et al. 67th ADA 2007. Oral Presentation OR-0286.Data available on request from Merck & Co., Inc. Please specify 20752937(1)-JMT.Effect on Incretin Axis

Sitagliptin With Metformin Improved 24-Hour Glucose Profile in Patients With Type 2 DiabetesTreatment difference: –32.8 mg/dL (P<0.001)*Glucose (mg/dL)8:00 Day 1Met 1500 mg/day + placebo (n=13)Sitagliptin 50 mg BID + met 1500 mg/day (n=13)13:0019:000:00Day 27:30100120140160180240200220Dose 17:30Dose 218:30BreakfastLunchDinnerPeriod 1Adapted from Brazg R et al. Diabetes Obes Metab. 2007;9:186–193.*Least-squares mean difference in weighted mean glucose To convert mg/dL to mmol/L; divide by 18.

Mean A1C = 8.8%Sitagliptin 50 mg + metformin 1,000 mg bid Metformin 1,000 mg bid Sitagliptin 100 mg qd Sitagliptin 50 mg + metformin 500 mg bid Metformin 500 mg bid LSM A1C Change From Baseline, %–3.5–3.0–2.5–2.0–1.5–1.0–0.50.00.5n=178n=177n=183n=178n=175–0.8a–1.0a–1.3a–1.6a–2.1aOpen labeln=117–2.9bAll patients Treated Populationa LSM placebo adjusted change b LSM change from baseline without adjustment for placebo.bid=twice a day; qd=once a day.24-Week Placebo-Adjusted ResultsA1C Results at 24 WeeksMean A1C = 11.2%Sitagliptin With Metformin Coadministration Initial Therapy Study Goldstein et al. Diabetes Care 2007; 30: 1979-1987

Recent evidences / studies towards newer therapies (DPP-4 inhibitors: Sitagliptin)Newer studiesAdd-on to insulinIn Geriatric population

Effect of Sitagliptin in Patients With T2DM and Inadequate Glycemic Control on Insulin Therapy (With or Without Metformin)Patients with T2DM> 21 years of ageInsulin ≥15 U ± MetforminHbA1c 7.5% & 11%Duration of diabetes: 13 yrs vs. 12 yrsRSita 100 mg qd (n=322)Insulin ≥15 U ± Metformin Placebo (n=319)Insulin ≥15 U ± Metforminx 24 weeksDay 1RandomizationScreeningperiod2 wksWeek 241 weekMetformin & Insulin dose stable for 24 weeksPrimary Outcome Measures: Change From Baseline in HbA1c at Week 24Secondary Outcome Measures: Change From Baseline in FPG , 2-hour PPG, Lipid parameters. Vilsboll et al. November 2009, Diabetes, Obesity and Metabolism. To be published in Feb 2010

AHA=antihyperglycemic agent; FPG=fasting plasma glucose; qd=once a day; R=randomization; T2DM=type 2 diabetes mellitus. *1:1 randomization of sitagliptin vs placebo.Patients with T2DM65 years of ageNot taking AHAHbA1c 7.5% and 11%Taking AHA HbA1c 7% and 10%Diet/exerciserun-in periodRSitagliptin 100 mg qd PlaceboRATIONALE: Hypoglycemia may be especially problematic in the elderlyPrimary Outcome Measures: Change From Baseline in HbA1c at Week 24Secondary Outcome Measures: Change From Baseline in FPG , 2-hour PPG, Rapidity of Onset of Action as Determined by Home Glucose Monitoring After 1 Week x 24 weeksBARZILAI et al. ADA 2009, Publication yet to be released

Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on HbA1c QuintilesAdapted from Monnier L et al. Diabetes Care. 2003;26:881–885.n=58n=58n=58n=58n=58HbA1cContribution, %

24 hours duration of actionIncretins elevated in PP as well as fasting stateBoth PP and Fasting hyperglycemia thus controlled.

ADA 2009 Abstract 540-P

18 weeksBaseline8%0.6%24 weeksBaseline8%0.8% 18 weeksBaseline>9%1.4%104 weeksBaseline8.8%1.1%1. Raz I et al. Diabetologia. 2006;49:2564–2571.2. Aschner P et al. Diabetes Care. 2006;29:2632–2637.

Results(all p<0.001).Observed rapid improvement in glycemic status and good tolerability with no hypoglycemia adverse events in elderly patients given sitagliptin monotherapy.

Patient cases with Sitagliptin

Case 145 Yr old man Ex smoker5 yr History of T2DM and Stable AnginaAt referral his treatment regimen consisted of MF (1000mg BID), Simvastatin 40mg given in the evening, beta blocker and oral nitrates. His HbA1c was 8.3%, FBS 150mg/dl, PBS 230BP 136/78 mmHg, TG 152mg/dl, LDL 85mg/dl, HDL 36mg/dl

Priorities before considering another Anti-hyperglycemic agent for this patientAvoidance of hypoglycemiaAlthough the exact cause of excess mortality in ACCORD is not likely to be known with certainty, the most plausible cause during intensive therapy is Iatrogenic hypoglycemiaCGMS studies show that some patients with diabetes have definite ECG abnormalities during hypoglycemia suggestive of cardiac ischemia.Low cardiac riskHypoglycemia may cause serious morbidity , provoking major vascular events such as stroke, myocardial infarction, acute cardiac failure and ventricular arrhythmia.Other risk factors such as fluid retention and weight gainPotential drug interaction with cardiac medicationZammit et. Al diabetes care, 2005Philip Cryer, Diabetes 2008

Issues with Type 2 DM TherapiesAvandia full prescribing informationAmaryl Full prescribing information

Sitagliptin Phosphate (Sitagliptin)*Highly selective Potent and reversible DPP-4 inhibitor that enhances the secretion and synthesis of insulin as well as glucagon suppression in a glucose dependant manner.Low risk of hypoglycemiaNo cardiac risk associated with SitagliptinNo meaningful drug interactionsSitagliptin full prescribing information

Current Anti-hyperglycemic TreatmentPatient added with Sitagliptin to MetforminAfter 3 Months:FBS: 85PBS: 120HbA1C: 6.2No symptoms of hypoglycemia

Case 250 year old T2 DIABETICOnMF 1 gm 1-0-1T. Glibenclamide 5 mg 2-2-2FBS: 205PPBS: 369HbA1c: 11.6Not accepting insulin

Case 2 (Contd…)Treatment modified:T. Metformin 1 gm 1-0-1T. Sitagliptin 100 mg 1-0-0 T. Glibenclamide 5 mg 1-0-15 days laterc/o hypos and FBS: 66Glibenclamide made to 5 mg 1-0-0Sugars well controlled.

Case 330 year old maleStrong FH of CADOn routine checking RBS: 350BMI: 28Well aware of his risk and wants to avoid it at any costWants best treatmentCost not a problemJob makes him irregular in diet timing with risk of hypoglycemiaWhat will you do…..

Case 3 (Contd..)AdvisedDietExerciseMetformin 1 gm 1-0-1After 2 monthsFBS: 138PPBS: 198Treatment modifiedT. Metformin 1 gm 1-0-1T. Sitagliptin 100 mg 1-0-0

Case 3 (Contd..)One week laterFBS: 78PBS: 82Dose titratedT.Metformin 1 gm 0-0-1T.Sitagliptin 100 mg 1-0-01 month laterFBS: 84PPBS; 96

Case 464 year old male, Arab originOn Inj. Mixtard 30/70: 96 -0-60T. Gliclazide SR 30 4-0-0T. Metformin 1 gm 1-1-1BMI: 43, c/o weight gainHbA1c: 14.1FBS: 396PPBS: 275Complaints of hypos prompting him to eat sugars. Blames it on insulin.

Case 4 (Contd…)Treatment modifiedInj. Glargine 60 -0- 60T. Sitagliptin 100 mg 1-0-0T. Metformin 1 gm 1-0-1Finally after one monthFBS: 116PPBS: 132No hypo symptoms reported. Patient satisfied with therapy

Major Adverse Effects

Are All Gliptins Similar?

Gliptins: Comparison of safety

Sitagliptin: Well documented in Hepatic ImpairmentSitagliptin is primarily excreted unchanged in urineIn an open-label study, a single 100-mg oral dose of Sitagliptin was administered to 10 male or female patients with moderate hepatic insufficiency (Child-Pugh’s scores ranged from 7 to 9) and 10 healthy control subjects matched to each patient for race, gender, age (± 5 yrs) and body mass index (BMI kg/m2 ± 5%).Moderate hepatic insufficiency had no statistically significant effect on the Tmax, apparent terminal t1/2, fraction of the oral dose excreted into urine and renal clearance of sitagliptin. Sitagliptin was generally well tolerated by both patients and subjectsPooled safety analysis on 10,246 patients, no significant elevation of liver enzymes(SGOT/SGPT) was notedIJCP, 2010

Gliptins in Hepatic impairmentSitagliptin EMeASaxagliptin EMeAVildagliptin EMeA

Sitagliptin: Well documented in Renal ImpairmentSafety and efficacy of Sitagliptin in patients with type 2 diabetes and chronic renal insufficiencyIn a 54-week, randomized, double-blind, parallel-group study, patients with baseline glycosylated hemoglobin A1c (HbA1c) values of 6.5–10% were allocated (2:1) to Sitagliptin (for 54 weeks) or the sequence of placebo (for 12 weeks) followed by active treatment with Glipizide (for 42 weeks).Sitagliptin was generally well tolerated and provided effective glycemic control in patients with type 2 diabetes and moderate to severe renal insufficiency, including patients with ESRD on dialysis.

Possible benefit of Sitagliptin in protection of renal ischemia reperfusion induced renal damage in DM This study was designed to investigate the possible effect of Sitagliptin on renal damage induced by renal ischemia reperfusion (I/R) in diabetic rats.Sitagliptin treated rats demonstrated a decrease in DNA fragmentation and apoptosis and protection against renal I/R in diabetes. The results of present investigation established Sitagliptin treatment attenuated renal damage induced by renal I/R in diabetic rats.Vaghasiya J, et al, Regul Pept(2010), doi:10.1016/j.regpep.2010.08.007

Gliptins in Renal Impairment

Effect of DPP8/9 inhibitionPossible effect on T-LymphocytesPrescribing Info

Gliptins in Heart failure*No caution related to Sitagliptin/Saxagliptin in EMeA

IJCP, 2010Sitagliptin Cardiovascular Outcome Study (TECOS)Expected Completion: Dec 2014N=14,000Assess the impact of Sitagliptin vs usual care on CV-related death, non-fatal myocardial infarction, non-fatal stroke, or unstable angina requiring hospitalization)

Sitagliptin and Vildagliptin: Effect on FBG*DIABETES CARE, VOLUME 29, NUMBER 12, DECEMBER 2006**Diabetes, Obesity and Metabolism, 9, 2007, 733–745^Diabetes Research and Clinical Practice 76 (2007) 132–138^^Diabetes, Obesity and Metabolism, 10, 2008, 1047–1056

Future interests in Various gliptins

Take home messagesHypoglgeamia is a key factor in present scenarioDPP-4 inhibitors is a good option Sitagliptin do have added advantagesAdverse effects are lowEconomic burden is a problemBe aware of the Pancreatitis issue

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