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Saxagliptin is an oral DPP-4 inhibitor approved as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. A clinical trial studied 768 adult patients with type 2 diabetes who had inadequate glycemic control on the sulfonylurea glibenclamide alone. Patients were randomized to add-on therapy with saxagliptin 2.5 mg or 5 mg daily or placebo, or to up-titrate glibenclamide from 7.5 mg to 10 mg daily. The primary endpoint was change in A1C from baseline after 24 weeks of treatment. Saxagliptin provided statistically significant reductions in A1C

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Saxagliptin in clinical practice Mathew John, MD, DM, DNB Endocrinologist Providence Endocrine & Diabetes Specialty Centre www.endocrinologydiabetes.com
Agenda • Diabetes mellitus: current scenario • Unmet medical needs : why we need newer therapies ? • Drugs acting on incretin axis • Saxagliptin: overview efficacy trials safety trials • Rational positioning • Cardiovascular safety
World diabetes map 2025 http://www.oxan.com/worldnextweek/2007-11-08/Diabetesmedicaltimebomb.aspx
State of current glycemic control: NHANES Hoerger TJ . Is Glycemic Control Improving in U.S. Adults? Diabetes Care January 2008 vol. 31 no. 1 81-86
Nearly Half to 2/3rd of All Adult Patients With T2DM Remain Uncontrolled on Their Current Therapy Parameter DiabCare Asia1 DEDICOM2 Year of study 1998 2005 Total patients 2269 819 Mean age (yrs) 53 54 Mean HbA1c 8.9 NA % having HbA1c <7% 50 38 % tested for HbA1c 7.8 13 1. Raheja BS et al. JAPI 2001;49:717-22; 2.Nagpal J et al. Diabetes Care 2006; 29:2341-8
UKPDS results of Intensive therapy Risk reduction vs. conventional therapy
Unmet needs in diabetes therapeutics • Progressive nature of disease: beta cell failure, need to frequently modify therapy • Hypoglycemia risk: with sulphonylureas, insulin, combinations • Weight gain: sulphonylureas, insulin, pioglitazone • Cardiovascular disease
Normal Glucose Homeostasis: Role of Incretins1,2 In response to meals, incretin Fat Increased 1 hormones (GIP and GLP-1) are increasingly released from Glucose the small intestine Uptake Insulin Secretion DPP-4 Enzymes GI Tract β Indirect Glucose Incretin Effect Pancreas suppression Homeostasis α of glucagon Glucagon Secretion Pancreatic cells Incretins (GIP/GLP-1) 2 respond to high levels of incretins β Pancreatic beta cell Liver DPP-4 enzymes Decreased α Pancreatic alpha cell 3 break down incretins Glucose Production GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1; DPP-4=dipeptidyl peptidase-4. 1. Kim W et al. Pharmacol Rev. 2008;60:470-512. 2. Drucker DJ. Cell Metab. 2006;3:153-165.
T2DM: Role of Incretins1,2 In adults with T2DM, Fat Impaired 1 incretins are released, but the incretin-mediated Glucose effects are diminished Uptake DPP-4 Insulin Secretion Enzymes GI Tract β Less indirect Diminished suppression Hyperglycemia Pancreas Incretin Effect α of glucagon Glucagon Secretion Incretin action on Incretins (GIP/GLP-1) 2 pancreatic cells is reduced β Pancreatic beta cell Liver α Pancreatic alpha cell Increased Glucose Production 1. Kim W et al. Pharmacol Rev. 2008;60:470-512. 2. Drucker DJ. Cell Metab. 2006;3:153-165.
Saxagliptin DPP 4 inhibitor Potent, selective, reversible inhibitor 10 fold more potent that Sitagliptin and Vildagliptin Active metabolite : M2: 2 fold less potent
Relative Selectivity of Saxagliptin Selectivity for DPP-4 vs DPP-8/9* Saxagliptin DPP-4 selectivity Saxagliptin Active Metabolite Versus DPP-8 ~400 fold ~950 Versus DPP-9 ~75 fold ~160 * Calculated using Ki; the inhibitor concentration needed for 50% inhibition of the target enzyme; substrate-independent. DPP=dipeptidyl peptidase. Kirby MS et al. Poster presented at: 3rd International Conference on Dipeptidyl Peptidases and Related Proteins; April 23-25, 2008; Antwerp, Belgium.
Clinical Pharmacology: Pharmacokinetics Absorption • Median time to max. concentration (Tmax) following 5 mg once daily dose was 2 hrs for saxagliptin & 4 hrs for its active metabolite • Saxagliptin may be administered with or without food Distribution • In vitro protein binding of saxagliptin and its active metabolite in human serum is negligible • Changes in blood protein levels in various disease states (eg, renal or hepatic impairment) are not expected to alter the disposition of saxagliptin
Clinical Pharmacology: Pharmacokinetics Metabolism • Metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5) • Major metabolite of saxagliptin is also a DPP-4 inhibitor- one-half as potent as saxagliptin Excretion • Saxagliptin is eliminated by both renal & hepatic pathways • Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively • Following a single oral dose of Saxagliptin 5 mg to healthy subjects, mean plasma terminal half-life (t1/2) for – saxagliptin was 2.5 hrs – active metabolite 3.1 hs respectively
Saxagliptin Studies
Saxagliptin Has Been Proven in Well- Controlled Clinical Trials • All Phase 3 trials were multicenter, multinational, randomized, double- blind controlled studies • The primary efficacy endpoint for all studies was A1C change from baseline at 6 months Phase 3 (6) N=4148 Monotherapy(2) Initial Combo Add-On Combination Trials With MET (3) (N=766) (N=1306) Therapy Trials Entry A1C: 7.0%–10.0% Entry A1C: 8.0%–12.0% (N=2076) MET=metformin; SU=sulfonylurea; TZD=thiazolidinedione.
Saxagliptin Has Been Proven in Well- Controlled Clinical Trials Add-On Combination Therapy Trials (N=2076) Add-On to the SU Add-On to MET Add-On to a TZD (N=743) Glibenclamide (N=565) Entry A1C: 7.0%–10.0% (N=768) Entry A1C: 7.0%–10.5% Entry A1C: 7.5%–10.0%
Saxagliptin add on to Metformin 24 week data
In addition to diet and exercise Saxagliptin 5 mg Added to MET Provided Extra Help for Adult Patients Uncontrolled on MET Plus Placebo: A1C Results Percentage of Patients Achieving Change in A1C at 6 Months* A1C <7% at 6 Months Saxagliptin 5 mg + MET Placebo + MET 100.0 Percentage of Patients (%) (n=186) (n=175) Mean Change From Baseline (%) Mean baseline: 8.1 % Mean baseline: 8.1 % 0.2 80.0 0.0 60.0 +0.1% 44% -0.2 40.0 -0.4 20.0 17% -0.6 0.0 -0.8 Saxagliptin 5 mg + MET Placebo + MET –0.7% (n=186) (n=175) Mean baseline: 8.1 % Mean baseline: 8.1 % -1.0 P<0.0001 vs placebo + MET P<0.05 vs placebo + MET *Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy. DeFronzo RA The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone Diabetes Care 32:1649–1655, 2009
Saxagliptin 5 mg Added to MET Provided Significant Reductions in A1C at 6 Months 0.4 Mean Change From Baseline* (%) 0.2 Placebo + MET 0.0 -0.2 -0.4 -0.6 -0.8 Saxa 5 mg + MET -1.0 BL 4 6 8 12 16 20 24 24 LOCF Weeks *Includes patients with a baseline and week 24 value. Week 24 (LOCF) includes intent-to-treat population using last observation on study prior to pioglitazone rescue therapy for patients needing rescue. Mean change from baseline is adjusted for baseline value.
In addition to diet and exercise Saxagliptin 5 mg Added to MET Provided Statistically Significant Reductions in FPG and PPG Change in FPG at 6 Months* Change in 2-Hour PPG† at 6 Months* Saxagliptin 5 mg + MET Placebo + MET Saxagliptin 5 mg + MET Placebo + MET (n=187) (n=176) (n=155) (n=135) Mean baseline: 179 mg/dL Mean baseline: 175 mg/dL Mean baseline: 296 mg/dL Mean baseline: 295 mg/dL Mean Change From Baseline (mg/dL) Mean Change From Baseline (mg/dL) 10 10 0 0 +1 mg/dL -10 -10 -20 -20 –22 mg/dL –18 mg/dL -30 -30 -40 -40 -50 –23 mg/dL -50 Greater Reduction When -60 Saxagliptin 5 mg Added -60 –58 mg/dL P<0.05 vs placebo + MET -70 -70 P<0.05 vs placebo + MET *Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy. †As part of a 3-hour oral glucose tolerance test (OGTT). DeFronzo RA The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone Diabetes Care 32:1649–1655, 2009
Saxagliptin add on to Metformin 102 week data
HbA1c Mean Change From Baseline (LOCF) at Week 102 SAXA 5mg + MET PBO + MET Baseline HbA1c: 8.0 - 8.1% 0.4 Diabetes duration: 6.3 - 6.7 years 0.2 HbA1c (%) Mean ∆ From BL±SE BL 0.0 -0.2 -0.4 -0.6 BL 4 8 12 20 30 37 50 63 76 89 102 Weeks Ravichandran S, et al. Diabetologia 2009; 52(Suppl. 1):S60 [Abstract] & Oral Presentation at EASD 2009
HbA1c Mean Change From Baseline (LOCF) at Week 102 SAXA 5mg + MET PBO + MET FPG 120-min PPG HbA1c <7% SAXA (mg) SAXA (mg) SAXA (mg) Dose 5+MET PBO+MET Dose 5+MET PBO+MET Dose 5+MET PBO+MET n observed= 31 15 n observed= 46 24 n observed= 13 15 BL mean 179 175 12.0 10 50 9.0 -min Percentage of patients Achieving 0.0 6.0 40 30 Adjusted Mean Change in 120- Adjusted Mean Change in HbA1c <7% (95% CI) FPG (mg/dL) SE PPG (mg/dL) SE 3.0 3.0 ± ± ± ± ± -4 30 0.0 -20 -3.0 20 12 -6.0 -30 -9.0 10 -40 -12.0 -35 -15.0 -11 -50 0 SAXA: Saxagliptin; MET: Metformin; PBO: Placebo Ravichandran S, et al. Diabetologia 2009; 52(Suppl. 1):S60 [Abstract] & Oral Presentation at EASD 2009
Patients on Glibenclamide Saxagliptin add on vs. Glibenclamide uptitration
In addition to diet and exercise Saxagliptin 5 mg Added to a Submaximal Dose of GLIB Saxagliptin as Add-On Combination Therapy With GLY 768 adult patients with T2DM with inadequate glycemic control Number of Patients on a submaximal dose of the SU glibenclamide alone A1C Entry Criteria ≥7.5%–≤10% Duration 24 weeks Base Therapy Submaximal dose of Glib for 2 months or greater Single-blind, 4-week, diet and exercise lead-in period, and placed Lead-in Therapy on GlIB 7.5 mg once daily 4 arms: Saxagliptin (2.5 or 5 mg) + 7.5 mg GLIB, Treatment Arms* PBO + 10 mg GLIB Rescue Protocol MET rescue, added on to existing study medication *Patients who received placebo were eligible to have Glib up-titrated to a total daily dose of 15 mg. Up-titration of GLIB was not permitted in patients who received Saxagliptin 2.5 mg or 5 mg. Dose titration of Saxagliptin was not permitted during the study.
Saxagliptin: Add on to Sulphonylurea Add Saxagliptin 5 mg 768 adult patients On 7.5 mg of Glibenclamide Uptitrate Glibenclamide to 15 mg/day Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R. Saxagliptin Added to a Submaximal-Dose of Sulphonylurea Improves Glycaemic Control Compared With Uptitration of Sulphonylurea in Patients With Type 2 Diabetes: A Randomized Controlled Trial. Int J Clin Pract. 2009:63:1395-1406.
In addition to diet and exercise Saxagliptin 5 mg Added to a Submaximal Dose of GLIB: A1C Results Change in A1C at 6 Months* Percentage of Patients Achieving A1C <7% at 6 Months Saxagliptin 5 mg + Placebo + Up-Titrated 100.0 GLIB 7.5 mg (n=250) GLIB (n=264) P<0.05 vs placebo Mean baseline: 8.4% + up-titrated GLIB Percentage of Patients (%) Mean baseline: 8.5% 0.2 Mean Change From Baseline (%) 80.0 0.0 +0.1% 60.0 -0.2 40.0 -0.4 23% -0.6 20.0 –0.6% P<0.0001 vs placebo 9% + up-titrated GLY -0.8 0.0 Saxagliptin 5 mg + Placebo + Up-Titrated -1.0 92% of patients in the GLIB 7.5 mg (n=250) GLIB (n=264) placebo + SU group required up- Mean baseline: 8.5% Mean baseline: 8.4% titration to the maximum SU study dose of 15 mg *Intent-to-treat population using last observation on study prior to MET rescue therapy. Chacra AR . Int J Clin Pract. 2009:63:1395-1406
Saxagliptin 5 mg Added to a Submaximal Dose of GLIB: FPG and PPG Results Change in FPG at 6 Months* Change in 2-Hour PPG† at 6 Months* Saxagliptin 5 mg + Placebo + Up-Titrated Saxagliptin 5 mg + Placebo + Up-Titrated GLIB 7.5 mg (n=252) GLIB (n=265) GLIB 7.5 mg (n=202) GLIB (n=206) Mean baseline: 175 mg/dL Mean baseline: 174 mg/dL Mean baseline: 315 mg/dL Mean baseline: 323 mg/dL Mean Change From Baseline (mg/dL) Mean Change From Baseline (mg/dL) 10 10 0 0 +1 mg/dL +8 mg/dL -10 -10 –10 mg/dL -20 -20 -30 –10 mg/dL -30 Improvement When -40 Onglyza 5 mg Added -40 –34 mg/dL -50 -50 P<0.05 vs placebo P<0.05 vs placebo + up-titrated GLIB + up-titrated GLIB -60 -60 -70 -70 *Intent-to-treat population using last observation on study prior to MET rescue therapy. †As part of a 3-hour OGTT. Chacra AR . Int J Clin Pract. 2009:63:1395-1406
Saxagliptin Plus GLIB: Incidence of Hypoglycemia Incidence (%) of Hypoglycemia Add-on to the SU Glibenclamide study Saxagliptin 5 mg + Saxagliptin 2.5 mg + Placebo + GLIB 7.5 mg GLIB 7.5 mg Up-Titrated GLIB Reported 14.6% 13.3% 10.1% Hypoglycemia* Confirmed 0.8% 2.4% 0.7% Hypoglycemia† There was no significant differences between different groups in the reported and confirmed hypoglycemia *Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required. †Definedas symptoms of hypoglycemia accompanied by a fingerstick glucose value of ≤50 mg/dL.
Patients on Thiazolidinedione Saxagliptin add on Vs. Placebo
In addition to diet and exercise Saxagliptin 5 mg Provided Extra Help for Patients Struggling to Gain Glycemic Control on a TZD Saxagliptin as Add-On Combination Therapy With a TZD 565 adult patients with T2DM with inadequate glycemic control on Number of Patients TZD alone A1C Entry Criteria ≥7%–≤10.5% Duration 24 weeks Pioglitazone (30-45 mg once daily) or rosiglitazone (4 mg once Base Therapy daily or 8 mg either once daily or in two divided doses of 4 mg) for at least 12 weeks Single-blind, 2-week, diet and exercise placebo lead-in period, Lead-In Therapy during which patients received TZD at their pre-study dose for the duration of the study Treatment Arms* 3 arms: Saxagliptin (2.5 or 5 mg) + TZD, PBO + TZD Rescue Protocol MET added on to existing study medications *Dose titration of Onglyza or TZD was not permitted during the study.
Saxagliptin 5 mg Provided Statistically Significant A1C Reductions When Added to a TZD Percentage of Patients Achieving Change in A1C at 6 Months* A1C <7% at 6 Months Saxagliptin 5 mg + TZD Placebo + TZD 100.0 Percentage of Patients (%) (n=183) (n=180) Mean Change From Baseline (%) Mean baseline: 8.4% Mean baseline: 8.2% 0.2 80.0 0.0 60.0 -0.2 42% 40.0 -0.4 –0.3% 26% 20.0 -0.6 -0.8 0.0 Saxagliptin 5 mg + TZD Placebo + TZD P<0.0001 vs placebo + TZD (n=184) (n=180) -1.0 –0.9% Mean baseline: 8.4% Mean baseline: 8.2% P<0.05 vs placebo + TZD *Intent-to-treat population using last observation on study prior to MET rescue therapy.
Saxgliptin 5 mg Added to a TZD Provided Statistically Significant Reductions in FPG and PPG Change in FPG at 6 Months* Change in 2-Hour PPG† at 6 Months* Saxagliptin 5 mg + TZD Placebo + TZD Saxagliptin 5 mg + TZD Placebo + TZD (n=185) (n=181) (n=134) (n=127) Mean baseline: 160 mg/dL Mean baseline: 162 mg/dL Mean baseline: 303 mg/dL Mean baseline: 291 mg/dL 10 10 0 0 Mean Change From –3 mg/dL Mean Change From Baseline (mg/dL) Baseline (mg/dL) -10 -10 -20 -20 –17 mg/dL –15 mg/dL -30 -30 -40 –15 mg/dL -40 Greater Reduction When -50 -50 Onglyza 5 mg Added -60 -60 P<0.05 vs placebo + TZD P<0.05 vs placebo + TZD -70 -70 –65 mg/dL *Intent-to-treat population using last observation on study prior to MET rescue therapy. †As part of a 3-hour OGTT.
Saxagliptin Safety & Tolerability
35Version 1.3 Saxagliptin: Incidence of Adverse Events Overall Incidence of Adverse Events Was Similar to Placebo Pooled Analysis of Adverse Reactions Occurring in ≥5% of Patients and More Commonly Than Placebo In Monotherapy and Add-On Therapy Studies* Saxagliptin 5 mg Placebo (N=882) (N=799) Upper respiratory 7.7% 7.6% tract infection Urinary tract 6.8% 6.1% infection Headache 6.5% 5.9% *Prespecified pooled analysis of 2 monotherapy studies, the add-on to MET study, the add-on to the SU glibenclamide study, and the add-on to a TZD study; 24-week data regardless of glycemic rescue.
36Version 1.3 Saxagliptin: Discontinuation of Therapy Due to Adverse Events • Discontinuation of therapy due to adverse events occurred in 3.3% and 1.8% of patients receiving Saxagliptin and placebo, respectively Most Common Adverse Events Associated With Discontinuation of Therapy* Percent of Patients Saxagliptin Saxagliptin Comparator 5 mg 2.5 mg (N=799) (N=882) (N=882) Lymphopenia 0.5% 0.1% 0.0% Rash 0.3% 0.2% 0.3% Blood creatinine increase 0.0% 0.3% 0.0% Blood creatine phosphokinase 0.2% 0.1% 0.0% increase • There was a dose-related mean decrease in absolute lymphocyte count observed with Saxagliptin *Reported in at least 2 patients treated with Saxagliptin
37Version 1.3 Saxagliptin: Incidence of Hypoglycemia Incidence of Reported Hypoglycemia Across Phase 3 Clinical Trials Percent of Patients Saxagliptin Saxagliptin Comparator 5 mg 2.5 mg Add-On to MET 5.8% 7.8% 5.0% Initial Combo With MET 3.4% — 4.0% Add-On to the SU Glyburide 14.6% 13.3% 10.1% Add-On to a TZD 2.7% 4.1% 3.8% Pooled Monotherapy 5.6% 4.0% 4.1%
Cardiovascular safety Cardiovascular safety : MACE (Major Adverse CV Events) Ongoing CV trials : SAVOR-TIMI 53
Multiple Analytical Methods for Relative Risk1 • 41 of CV death/MI/ stroke (MACE), 40 CEC*-adjudicated CV events, and 61 Sponsor identified acute cardiovascular events assessed by multiple analytic methods showed similar results for relative risk • Onglyza was not associated with an increased risk of CV events in a pooled retrospective analysis of the Phase 2/3 clinical program * Clinical Events Committee 1Frederich R et al 2010 A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Post graduate Medicine 122 (3)
Incidence Rate Ratios1 • For investigator identified CV death, MI or stroke, the results within individual studies were consistent with the pooled analysis • Onglyza was not associated with an increased risk of CV events in a pooled retrospective analysis of the Phase 2/3/ clinical program 1FrederichR et al 2010 A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Post graduate Medicine 122 (3)
Kaplan Meier Analysis1 • This Kaplan Meier analysis of MACE and all cause mortality does not suggest increased risk for CV death, MI or stroke either early or late after initiation of saxagliptin treatment. 1Frederich R et al 2010 A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Post graduate Medicine 122 (3)
Cardiovascular risk factors (in addition to T2D) Saxagliptin controlled Phase 2b/3 pooled population Data on file. Not in public domain
Ongoing CV trials of Saxagliptin • Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus" trial (SAVOR-TIMI 53) • Multicenter, randomized, double-blind, placebo-controlled Phase 4 study, to evaluate treatment with Saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, in adult type 2 diabetes patients with cardiovascular risk factors. • The five-year study will follow approximately 12,000 patients with type 2 diabetes
Saxagliptin Hepatic Impairment Renal Impairment
45Version 1.3 Saxagliptin: Renal Impairment • Mild Impairment, creatinine clearance [CrCl] ≤50 mL/min: No dosage adjustment • Moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis (creatinine clearance [CrCl] ≤50 mL/min). Saxagliptin 2.5 mg is recommended. • Saxagliptin should be administered following hemodialysis. Saxagliptin has not been studied in patients undergoing peritoneal dialysis. • Assessment of renal function is recommended prior to initiation of Saxagliptin and periodically thereafter.
46Version 1.3 Saxagliptin: Hepatic Impairment • In subjects with hepatic impairment (Child-Pugh classes A, B, and C) • Mean Cmax and AUC of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls following administration of a single 10 mg dose of saxagliptin. • The corresponding Cmax and AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls. • These differences are not considered to be clinically meaningful. • No dosage adjustment is recommended for patients with hepatic impairment
Saxagliptin Dosing
Convenient Once-Daily Dosing Dosing Considerations for Saxagliptin • Standard dose : 5 Recommended Dose mg/day Recommended dose once or 5 mg once daily 2.5 mg once daily daily taken regardless of meals • Taken any time Moderate-to-severe renal impairment, 2.5 mg once daily or ESRD requiring of day, with or hemodialysis (CrCl ≤50 mL/min) without food Tablets Not Actual Size. Co-administration with strong CYP3A4/5 inhibitors* • 24-hour glycemic control *Such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin. ESRD= end-stage renal disease
FDA approval Saxagliptin is approved for Monotherapy in patients not controlled on diet / exercise Add on therapy to Metformin, SU or Thiazolidinedione
AACE 2010 guidelines HbA1c : 6.5-7.5 % HbA1c : 7.6-9 % HbA1c : > 9 % •Metformin Combination Combination therapy : 2 agents therapy : 3 agents •TZD •Metformin •Metformin •DPP-4 inhibitors •TZD •TZD •Alfa- glucosidase inhibitors •GLP 1 agonist •GLP 1 agonist •DPP-4 inhibitors •DPP-4 inhibitors •Glinides •Glinides •Sulphonylureas •Sulphonylureas Rodbard, H., Jellinger, P., et al (2009). Consensus Panel on Type 2 Diabetes Mellitus: An Algorithm for Glycemic Control. Endocrine Practice, 15(6), 540-559. •Insulin
Algorithm Tier 1 therapies Lifestyle + MF Lifestyle + MF +Basal Insulin +Intensive insulin At diagnosis Lifestyle + Metformin Lifestyle + MF + SU Step 1 Step2 Step 3 Lifestyle + MF Lifestyle + MF Tier 2 therapies + Pioglitazone + Pioglitazone++SU Lifestyle + MF Lifestyle + MF + Basal Insulin + GLP-1 agent Diabetes Care 32:1–11 Oct 2008 e pub
Where to position Saxagliptin Evidence based Tier 1 therapies Lifestyle + MF Lifestyle + MF +Basal Insulin +Intensive insulin At diagnosis Saxagliptin Lifestyle + Metformin Saxagliptin Lifestyle + MF + SU /Saxagliptin Step 1 Step2 Step 3 Lifestyle + MF Lifestyle + MF Tier 2 therapies + Pioglitazone + Pioglitazone+ SU Lifestyle + MF Lifestyle + MF + Basal Insulin/ Saxaglipin + Saxagliptin Diabetes Care 32:1–11 Oct 2008 e pub
Key messages • Saxagliptin is a new potent DPP 4 inhibitor • It is found to reduce all the key parameters of glycemic control : FBS, PPBS and HbA1c • It improves measures of beta cell function • It is weight neutral • It has a safety profile similar to placebo
Thank you
Disclaimer The material for these slides were derived from various sources including pictures and cartoons from the world wide web. I have tried my best to acknowledge all possible sources and references. However, if I have overlooked any particular reference, it is not done intentionally. Anyone reproducing materials from this presentations should acknowledge the author of the original work. Some of the slides are made by Aztra Zeneca/ Bristol Myers Squibb, the manufactures of Onglyza. However, all these data are currently in public domain, paid or otherwise.

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Saxaslideshare

  • 1.
    Saxagliptin in clinicalpractice Mathew John, MD, DM, DNB Endocrinologist Providence Endocrine & Diabetes Specialty Centre www.endocrinologydiabetes.com
  • 2.
    Agenda • Diabetes mellitus:current scenario • Unmet medical needs : why we need newer therapies ? • Drugs acting on incretin axis • Saxagliptin: overview efficacy trials safety trials • Rational positioning • Cardiovascular safety
  • 3.
    World diabetes map2025 http://www.oxan.com/worldnextweek/2007-11-08/Diabetesmedicaltimebomb.aspx
  • 4.
    State of currentglycemic control: NHANES Hoerger TJ . Is Glycemic Control Improving in U.S. Adults? Diabetes Care January 2008 vol. 31 no. 1 81-86
  • 5.
    Nearly Half to2/3rd of All Adult Patients With T2DM Remain Uncontrolled on Their Current Therapy Parameter DiabCare Asia1 DEDICOM2 Year of study 1998 2005 Total patients 2269 819 Mean age (yrs) 53 54 Mean HbA1c 8.9 NA % having HbA1c <7% 50 38 % tested for HbA1c 7.8 13 1. Raheja BS et al. JAPI 2001;49:717-22; 2.Nagpal J et al. Diabetes Care 2006; 29:2341-8
  • 6.
    UKPDS results ofIntensive therapy Risk reduction vs. conventional therapy
  • 7.
    Unmet needs indiabetes therapeutics • Progressive nature of disease: beta cell failure, need to frequently modify therapy • Hypoglycemia risk: with sulphonylureas, insulin, combinations • Weight gain: sulphonylureas, insulin, pioglitazone • Cardiovascular disease
  • 8.
    Normal Glucose Homeostasis:Role of Incretins1,2 In response to meals, incretin Fat Increased 1 hormones (GIP and GLP-1) are increasingly released from Glucose the small intestine Uptake Insulin Secretion DPP-4 Enzymes GI Tract β Indirect Glucose Incretin Effect Pancreas suppression Homeostasis α of glucagon Glucagon Secretion Pancreatic cells Incretins (GIP/GLP-1) 2 respond to high levels of incretins β Pancreatic beta cell Liver DPP-4 enzymes Decreased α Pancreatic alpha cell 3 break down incretins Glucose Production GIP=glucose-dependent insulinotropic peptide; GLP-1=glucagon-like peptide-1; DPP-4=dipeptidyl peptidase-4. 1. Kim W et al. Pharmacol Rev. 2008;60:470-512. 2. Drucker DJ. Cell Metab. 2006;3:153-165.
  • 9.
    T2DM: Role ofIncretins1,2 In adults with T2DM, Fat Impaired 1 incretins are released, but the incretin-mediated Glucose effects are diminished Uptake DPP-4 Insulin Secretion Enzymes GI Tract β Less indirect Diminished suppression Hyperglycemia Pancreas Incretin Effect α of glucagon Glucagon Secretion Incretin action on Incretins (GIP/GLP-1) 2 pancreatic cells is reduced β Pancreatic beta cell Liver α Pancreatic alpha cell Increased Glucose Production 1. Kim W et al. Pharmacol Rev. 2008;60:470-512. 2. Drucker DJ. Cell Metab. 2006;3:153-165.
  • 10.
    Saxagliptin DPP 4inhibitor Potent, selective, reversible inhibitor 10 fold more potent that Sitagliptin and Vildagliptin Active metabolite : M2: 2 fold less potent
  • 11.
    Relative Selectivity ofSaxagliptin Selectivity for DPP-4 vs DPP-8/9* Saxagliptin DPP-4 selectivity Saxagliptin Active Metabolite Versus DPP-8 ~400 fold ~950 Versus DPP-9 ~75 fold ~160 * Calculated using Ki; the inhibitor concentration needed for 50% inhibition of the target enzyme; substrate-independent. DPP=dipeptidyl peptidase. Kirby MS et al. Poster presented at: 3rd International Conference on Dipeptidyl Peptidases and Related Proteins; April 23-25, 2008; Antwerp, Belgium.
  • 12.
    Clinical Pharmacology: Pharmacokinetics Absorption • Median time to max. concentration (Tmax) following 5 mg once daily dose was 2 hrs for saxagliptin & 4 hrs for its active metabolite • Saxagliptin may be administered with or without food Distribution • In vitro protein binding of saxagliptin and its active metabolite in human serum is negligible • Changes in blood protein levels in various disease states (eg, renal or hepatic impairment) are not expected to alter the disposition of saxagliptin
  • 13.
    Clinical Pharmacology: Pharmacokinetics Metabolism • Metabolism of saxagliptin is primarily mediated by cytochrome P450 3A4/5 (CYP3A4/5) • Major metabolite of saxagliptin is also a DPP-4 inhibitor- one-half as potent as saxagliptin Excretion • Saxagliptin is eliminated by both renal & hepatic pathways • Following a single 50 mg dose of 14C-saxagliptin, 24%, 36%, and 75% of the dose was excreted in the urine as saxagliptin, its active metabolite, and total radioactivity, respectively • Following a single oral dose of Saxagliptin 5 mg to healthy subjects, mean plasma terminal half-life (t1/2) for – saxagliptin was 2.5 hrs – active metabolite 3.1 hs respectively
  • 14.
    Saxagliptin Studies
  • 15.
    Saxagliptin Has BeenProven in Well- Controlled Clinical Trials • All Phase 3 trials were multicenter, multinational, randomized, double- blind controlled studies • The primary efficacy endpoint for all studies was A1C change from baseline at 6 months Phase 3 (6) N=4148 Monotherapy(2) Initial Combo Add-On Combination Trials With MET (3) (N=766) (N=1306) Therapy Trials Entry A1C: 7.0%–10.0% Entry A1C: 8.0%–12.0% (N=2076) MET=metformin; SU=sulfonylurea; TZD=thiazolidinedione.
  • 16.
    Saxagliptin Has BeenProven in Well- Controlled Clinical Trials Add-On Combination Therapy Trials (N=2076) Add-On to the SU Add-On to MET Add-On to a TZD (N=743) Glibenclamide (N=565) Entry A1C: 7.0%–10.0% (N=768) Entry A1C: 7.0%–10.5% Entry A1C: 7.5%–10.0%
  • 17.
    Saxagliptin add onto Metformin 24 week data
  • 18.
    In addition todiet and exercise Saxagliptin 5 mg Added to MET Provided Extra Help for Adult Patients Uncontrolled on MET Plus Placebo: A1C Results Percentage of Patients Achieving Change in A1C at 6 Months* A1C <7% at 6 Months Saxagliptin 5 mg + MET Placebo + MET 100.0 Percentage of Patients (%) (n=186) (n=175) Mean Change From Baseline (%) Mean baseline: 8.1 % Mean baseline: 8.1 % 0.2 80.0 0.0 60.0 +0.1% 44% -0.2 40.0 -0.4 20.0 17% -0.6 0.0 -0.8 Saxagliptin 5 mg + MET Placebo + MET –0.7% (n=186) (n=175) Mean baseline: 8.1 % Mean baseline: 8.1 % -1.0 P<0.0001 vs placebo + MET P<0.05 vs placebo + MET *Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy. DeFronzo RA The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone Diabetes Care 32:1649–1655, 2009
  • 19.
    Saxagliptin 5 mgAdded to MET Provided Significant Reductions in A1C at 6 Months 0.4 Mean Change From Baseline* (%) 0.2 Placebo + MET 0.0 -0.2 -0.4 -0.6 -0.8 Saxa 5 mg + MET -1.0 BL 4 6 8 12 16 20 24 24 LOCF Weeks *Includes patients with a baseline and week 24 value. Week 24 (LOCF) includes intent-to-treat population using last observation on study prior to pioglitazone rescue therapy for patients needing rescue. Mean change from baseline is adjusted for baseline value.
  • 20.
    In addition todiet and exercise Saxagliptin 5 mg Added to MET Provided Statistically Significant Reductions in FPG and PPG Change in FPG at 6 Months* Change in 2-Hour PPG† at 6 Months* Saxagliptin 5 mg + MET Placebo + MET Saxagliptin 5 mg + MET Placebo + MET (n=187) (n=176) (n=155) (n=135) Mean baseline: 179 mg/dL Mean baseline: 175 mg/dL Mean baseline: 296 mg/dL Mean baseline: 295 mg/dL Mean Change From Baseline (mg/dL) Mean Change From Baseline (mg/dL) 10 10 0 0 +1 mg/dL -10 -10 -20 -20 –22 mg/dL –18 mg/dL -30 -30 -40 -40 -50 –23 mg/dL -50 Greater Reduction When -60 Saxagliptin 5 mg Added -60 –58 mg/dL P<0.05 vs placebo + MET -70 -70 P<0.05 vs placebo + MET *Intent-to-treat population using last observation on study prior to pioglitazone rescue therapy. †As part of a 3-hour oral glucose tolerance test (OGTT). DeFronzo RA The Efficacy and Safety of Saxagliptin When Added to Metformin Therapy in Patients With Inadequately Controlled Type 2 Diabetes With Metformin Alone Diabetes Care 32:1649–1655, 2009
  • 21.
    Saxagliptin add onto Metformin 102 week data
  • 22.
    HbA1c Mean ChangeFrom Baseline (LOCF) at Week 102 SAXA 5mg + MET PBO + MET Baseline HbA1c: 8.0 - 8.1% 0.4 Diabetes duration: 6.3 - 6.7 years 0.2 HbA1c (%) Mean ∆ From BL±SE BL 0.0 -0.2 -0.4 -0.6 BL 4 8 12 20 30 37 50 63 76 89 102 Weeks Ravichandran S, et al. Diabetologia 2009; 52(Suppl. 1):S60 [Abstract] & Oral Presentation at EASD 2009
  • 23.
    HbA1c Mean ChangeFrom Baseline (LOCF) at Week 102 SAXA 5mg + MET PBO + MET FPG 120-min PPG HbA1c <7% SAXA (mg) SAXA (mg) SAXA (mg) Dose 5+MET PBO+MET Dose 5+MET PBO+MET Dose 5+MET PBO+MET n observed= 31 15 n observed= 46 24 n observed= 13 15 BL mean 179 175 12.0 10 50 9.0 -min Percentage of patients Achieving 0.0 6.0 40 30 Adjusted Mean Change in 120- Adjusted Mean Change in HbA1c <7% (95% CI) FPG (mg/dL) SE PPG (mg/dL) SE 3.0 3.0 ± ± ± ± ± -4 30 0.0 -20 -3.0 20 12 -6.0 -30 -9.0 10 -40 -12.0 -35 -15.0 -11 -50 0 SAXA: Saxagliptin; MET: Metformin; PBO: Placebo Ravichandran S, et al. Diabetologia 2009; 52(Suppl. 1):S60 [Abstract] & Oral Presentation at EASD 2009
  • 24.
    Patients on Glibenclamide Saxagliptin add on vs. Glibenclamide uptitration
  • 25.
    In addition todiet and exercise Saxagliptin 5 mg Added to a Submaximal Dose of GLIB Saxagliptin as Add-On Combination Therapy With GLY 768 adult patients with T2DM with inadequate glycemic control Number of Patients on a submaximal dose of the SU glibenclamide alone A1C Entry Criteria ≥7.5%–≤10% Duration 24 weeks Base Therapy Submaximal dose of Glib for 2 months or greater Single-blind, 4-week, diet and exercise lead-in period, and placed Lead-in Therapy on GlIB 7.5 mg once daily 4 arms: Saxagliptin (2.5 or 5 mg) + 7.5 mg GLIB, Treatment Arms* PBO + 10 mg GLIB Rescue Protocol MET rescue, added on to existing study medication *Patients who received placebo were eligible to have Glib up-titrated to a total daily dose of 15 mg. Up-titration of GLIB was not permitted in patients who received Saxagliptin 2.5 mg or 5 mg. Dose titration of Saxagliptin was not permitted during the study.
  • 26.
    Saxagliptin: Add onto Sulphonylurea Add Saxagliptin 5 mg 768 adult patients On 7.5 mg of Glibenclamide Uptitrate Glibenclamide to 15 mg/day Chacra AR, Tan GH, Apanovitch A, Ravichandran S, List J, Chen R. Saxagliptin Added to a Submaximal-Dose of Sulphonylurea Improves Glycaemic Control Compared With Uptitration of Sulphonylurea in Patients With Type 2 Diabetes: A Randomized Controlled Trial. Int J Clin Pract. 2009:63:1395-1406.
  • 27.
    In addition todiet and exercise Saxagliptin 5 mg Added to a Submaximal Dose of GLIB: A1C Results Change in A1C at 6 Months* Percentage of Patients Achieving A1C <7% at 6 Months Saxagliptin 5 mg + Placebo + Up-Titrated 100.0 GLIB 7.5 mg (n=250) GLIB (n=264) P<0.05 vs placebo Mean baseline: 8.4% + up-titrated GLIB Percentage of Patients (%) Mean baseline: 8.5% 0.2 Mean Change From Baseline (%) 80.0 0.0 +0.1% 60.0 -0.2 40.0 -0.4 23% -0.6 20.0 –0.6% P<0.0001 vs placebo 9% + up-titrated GLY -0.8 0.0 Saxagliptin 5 mg + Placebo + Up-Titrated -1.0 92% of patients in the GLIB 7.5 mg (n=250) GLIB (n=264) placebo + SU group required up- Mean baseline: 8.5% Mean baseline: 8.4% titration to the maximum SU study dose of 15 mg *Intent-to-treat population using last observation on study prior to MET rescue therapy. Chacra AR . Int J Clin Pract. 2009:63:1395-1406
  • 28.
    Saxagliptin 5 mgAdded to a Submaximal Dose of GLIB: FPG and PPG Results Change in FPG at 6 Months* Change in 2-Hour PPG† at 6 Months* Saxagliptin 5 mg + Placebo + Up-Titrated Saxagliptin 5 mg + Placebo + Up-Titrated GLIB 7.5 mg (n=252) GLIB (n=265) GLIB 7.5 mg (n=202) GLIB (n=206) Mean baseline: 175 mg/dL Mean baseline: 174 mg/dL Mean baseline: 315 mg/dL Mean baseline: 323 mg/dL Mean Change From Baseline (mg/dL) Mean Change From Baseline (mg/dL) 10 10 0 0 +1 mg/dL +8 mg/dL -10 -10 –10 mg/dL -20 -20 -30 –10 mg/dL -30 Improvement When -40 Onglyza 5 mg Added -40 –34 mg/dL -50 -50 P<0.05 vs placebo P<0.05 vs placebo + up-titrated GLIB + up-titrated GLIB -60 -60 -70 -70 *Intent-to-treat population using last observation on study prior to MET rescue therapy. †As part of a 3-hour OGTT. Chacra AR . Int J Clin Pract. 2009:63:1395-1406
  • 29.
    Saxagliptin Plus GLIB:Incidence of Hypoglycemia Incidence (%) of Hypoglycemia Add-on to the SU Glibenclamide study Saxagliptin 5 mg + Saxagliptin 2.5 mg + Placebo + GLIB 7.5 mg GLIB 7.5 mg Up-Titrated GLIB Reported 14.6% 13.3% 10.1% Hypoglycemia* Confirmed 0.8% 2.4% 0.7% Hypoglycemia† There was no significant differences between different groups in the reported and confirmed hypoglycemia *Adverse reactions of hypoglycemia were based on all reports of hypoglycemia; a concurrent glucose measurement was not required. †Definedas symptoms of hypoglycemia accompanied by a fingerstick glucose value of ≤50 mg/dL.
  • 30.
    Patients on Thiazolidinedione Saxagliptin add on Vs. Placebo
  • 31.
    In addition todiet and exercise Saxagliptin 5 mg Provided Extra Help for Patients Struggling to Gain Glycemic Control on a TZD Saxagliptin as Add-On Combination Therapy With a TZD 565 adult patients with T2DM with inadequate glycemic control on Number of Patients TZD alone A1C Entry Criteria ≥7%–≤10.5% Duration 24 weeks Pioglitazone (30-45 mg once daily) or rosiglitazone (4 mg once Base Therapy daily or 8 mg either once daily or in two divided doses of 4 mg) for at least 12 weeks Single-blind, 2-week, diet and exercise placebo lead-in period, Lead-In Therapy during which patients received TZD at their pre-study dose for the duration of the study Treatment Arms* 3 arms: Saxagliptin (2.5 or 5 mg) + TZD, PBO + TZD Rescue Protocol MET added on to existing study medications *Dose titration of Onglyza or TZD was not permitted during the study.
  • 32.
    Saxagliptin 5 mgProvided Statistically Significant A1C Reductions When Added to a TZD Percentage of Patients Achieving Change in A1C at 6 Months* A1C <7% at 6 Months Saxagliptin 5 mg + TZD Placebo + TZD 100.0 Percentage of Patients (%) (n=183) (n=180) Mean Change From Baseline (%) Mean baseline: 8.4% Mean baseline: 8.2% 0.2 80.0 0.0 60.0 -0.2 42% 40.0 -0.4 –0.3% 26% 20.0 -0.6 -0.8 0.0 Saxagliptin 5 mg + TZD Placebo + TZD P<0.0001 vs placebo + TZD (n=184) (n=180) -1.0 –0.9% Mean baseline: 8.4% Mean baseline: 8.2% P<0.05 vs placebo + TZD *Intent-to-treat population using last observation on study prior to MET rescue therapy.
  • 33.
    Saxgliptin 5 mgAdded to a TZD Provided Statistically Significant Reductions in FPG and PPG Change in FPG at 6 Months* Change in 2-Hour PPG† at 6 Months* Saxagliptin 5 mg + TZD Placebo + TZD Saxagliptin 5 mg + TZD Placebo + TZD (n=185) (n=181) (n=134) (n=127) Mean baseline: 160 mg/dL Mean baseline: 162 mg/dL Mean baseline: 303 mg/dL Mean baseline: 291 mg/dL 10 10 0 0 Mean Change From –3 mg/dL Mean Change From Baseline (mg/dL) Baseline (mg/dL) -10 -10 -20 -20 –17 mg/dL –15 mg/dL -30 -30 -40 –15 mg/dL -40 Greater Reduction When -50 -50 Onglyza 5 mg Added -60 -60 P<0.05 vs placebo + TZD P<0.05 vs placebo + TZD -70 -70 –65 mg/dL *Intent-to-treat population using last observation on study prior to MET rescue therapy. †As part of a 3-hour OGTT.
  • 34.
  • 35.
    35Version 1.3 Saxagliptin: Incidence of Adverse Events Overall Incidence of Adverse Events Was Similar to Placebo Pooled Analysis of Adverse Reactions Occurring in ≥5% of Patients and More Commonly Than Placebo In Monotherapy and Add-On Therapy Studies* Saxagliptin 5 mg Placebo (N=882) (N=799) Upper respiratory 7.7% 7.6% tract infection Urinary tract 6.8% 6.1% infection Headache 6.5% 5.9% *Prespecified pooled analysis of 2 monotherapy studies, the add-on to MET study, the add-on to the SU glibenclamide study, and the add-on to a TZD study; 24-week data regardless of glycemic rescue.
  • 36.
    36Version 1.3 Saxagliptin: Discontinuation of Therapy Due to Adverse Events • Discontinuation of therapy due to adverse events occurred in 3.3% and 1.8% of patients receiving Saxagliptin and placebo, respectively Most Common Adverse Events Associated With Discontinuation of Therapy* Percent of Patients Saxagliptin Saxagliptin Comparator 5 mg 2.5 mg (N=799) (N=882) (N=882) Lymphopenia 0.5% 0.1% 0.0% Rash 0.3% 0.2% 0.3% Blood creatinine increase 0.0% 0.3% 0.0% Blood creatine phosphokinase 0.2% 0.1% 0.0% increase • There was a dose-related mean decrease in absolute lymphocyte count observed with Saxagliptin *Reported in at least 2 patients treated with Saxagliptin
  • 37.
    37Version 1.3 Saxagliptin: Incidenceof Hypoglycemia Incidence of Reported Hypoglycemia Across Phase 3 Clinical Trials Percent of Patients Saxagliptin Saxagliptin Comparator 5 mg 2.5 mg Add-On to MET 5.8% 7.8% 5.0% Initial Combo With MET 3.4% — 4.0% Add-On to the SU Glyburide 14.6% 13.3% 10.1% Add-On to a TZD 2.7% 4.1% 3.8% Pooled Monotherapy 5.6% 4.0% 4.1%
  • 38.
    Cardiovascular safety Cardiovascular safety: MACE (Major Adverse CV Events) Ongoing CV trials : SAVOR-TIMI 53
  • 39.
    Multiple Analytical Methodsfor Relative Risk1 • 41 of CV death/MI/ stroke (MACE), 40 CEC*-adjudicated CV events, and 61 Sponsor identified acute cardiovascular events assessed by multiple analytic methods showed similar results for relative risk • Onglyza was not associated with an increased risk of CV events in a pooled retrospective analysis of the Phase 2/3 clinical program * Clinical Events Committee 1Frederich R et al 2010 A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Post graduate Medicine 122 (3)
  • 40.
    Incidence Rate Ratios1 • For investigator identified CV death, MI or stroke, the results within individual studies were consistent with the pooled analysis • Onglyza was not associated with an increased risk of CV events in a pooled retrospective analysis of the Phase 2/3/ clinical program 1FrederichR et al 2010 A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Post graduate Medicine 122 (3)
  • 41.
    Kaplan Meier Analysis1 •This Kaplan Meier analysis of MACE and all cause mortality does not suggest increased risk for CV death, MI or stroke either early or late after initiation of saxagliptin treatment. 1Frederich R et al 2010 A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Post graduate Medicine 122 (3)
  • 42.
    Cardiovascular risk factors(in addition to T2D) Saxagliptin controlled Phase 2b/3 pooled population Data on file. Not in public domain
  • 43.
    Ongoing CV trialsof Saxagliptin • Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus" trial (SAVOR-TIMI 53) • Multicenter, randomized, double-blind, placebo-controlled Phase 4 study, to evaluate treatment with Saxagliptin, a dipeptidyl peptidase-4 (DPP4) inhibitor, in adult type 2 diabetes patients with cardiovascular risk factors. • The five-year study will follow approximately 12,000 patients with type 2 diabetes
  • 44.
  • 45.
    45Version 1.3 Saxagliptin: Renal Impairment • Mild Impairment, creatinine clearance [CrCl] ≤50 mL/min: No dosage adjustment • Moderate or severe renal impairment, or with end-stage renal disease (ESRD) requiring hemodialysis (creatinine clearance [CrCl] ≤50 mL/min). Saxagliptin 2.5 mg is recommended. • Saxagliptin should be administered following hemodialysis. Saxagliptin has not been studied in patients undergoing peritoneal dialysis. • Assessment of renal function is recommended prior to initiation of Saxagliptin and periodically thereafter.
  • 46.
    46Version 1.3 Saxagliptin:Hepatic Impairment • In subjects with hepatic impairment (Child-Pugh classes A, B, and C) • Mean Cmax and AUC of saxagliptin were up to 8% and 77% higher, respectively, compared to healthy matched controls following administration of a single 10 mg dose of saxagliptin. • The corresponding Cmax and AUC of the active metabolite were up to 59% and 33% lower, respectively, compared to healthy matched controls. • These differences are not considered to be clinically meaningful. • No dosage adjustment is recommended for patients with hepatic impairment
  • 47.
  • 48.
    Convenient Once-Daily Dosing Dosing Considerations for Saxagliptin • Standard dose : 5 Recommended Dose mg/day Recommended dose once or 5 mg once daily 2.5 mg once daily daily taken regardless of meals • Taken any time Moderate-to-severe renal impairment, 2.5 mg once daily or ESRD requiring of day, with or hemodialysis (CrCl ≤50 mL/min) without food Tablets Not Actual Size. Co-administration with strong CYP3A4/5 inhibitors* • 24-hour glycemic control *Such as atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, and telithromycin. ESRD= end-stage renal disease
  • 49.
    FDA approval Saxagliptin isapproved for Monotherapy in patients not controlled on diet / exercise Add on therapy to Metformin, SU or Thiazolidinedione
  • 50.
    AACE 2010 guidelines HbA1c : 6.5-7.5 % HbA1c : 7.6-9 % HbA1c : > 9 % •Metformin Combination Combination therapy : 2 agents therapy : 3 agents •TZD •Metformin •Metformin •DPP-4 inhibitors •TZD •TZD •Alfa- glucosidase inhibitors •GLP 1 agonist •GLP 1 agonist •DPP-4 inhibitors •DPP-4 inhibitors •Glinides •Glinides •Sulphonylureas •Sulphonylureas Rodbard, H., Jellinger, P., et al (2009). Consensus Panel on Type 2 Diabetes Mellitus: An Algorithm for Glycemic Control. Endocrine Practice, 15(6), 540-559. •Insulin
  • 51.
    Algorithm Tier 1 therapies Lifestyle + MF Lifestyle + MF +Basal Insulin +Intensive insulin At diagnosis Lifestyle + Metformin Lifestyle + MF + SU Step 1 Step2 Step 3 Lifestyle + MF Lifestyle + MF Tier 2 therapies + Pioglitazone + Pioglitazone++SU Lifestyle + MF Lifestyle + MF + Basal Insulin + GLP-1 agent Diabetes Care 32:1–11 Oct 2008 e pub
  • 52.
    Where to positionSaxagliptin Evidence based Tier 1 therapies Lifestyle + MF Lifestyle + MF +Basal Insulin +Intensive insulin At diagnosis Saxagliptin Lifestyle + Metformin Saxagliptin Lifestyle + MF + SU /Saxagliptin Step 1 Step2 Step 3 Lifestyle + MF Lifestyle + MF Tier 2 therapies + Pioglitazone + Pioglitazone+ SU Lifestyle + MF Lifestyle + MF + Basal Insulin/ Saxaglipin + Saxagliptin Diabetes Care 32:1–11 Oct 2008 e pub
  • 53.
    Key messages • Saxagliptinis a new potent DPP 4 inhibitor • It is found to reduce all the key parameters of glycemic control : FBS, PPBS and HbA1c • It improves measures of beta cell function • It is weight neutral • It has a safety profile similar to placebo
  • 54.
  • 55.
    Disclaimer The materialfor these slides were derived from various sources including pictures and cartoons from the world wide web. I have tried my best to acknowledge all possible sources and references. However, if I have overlooked any particular reference, it is not done intentionally. Anyone reproducing materials from this presentations should acknowledge the author of the original work. Some of the slides are made by Aztra Zeneca/ Bristol Myers Squibb, the manufactures of Onglyza. However, all these data are currently in public domain, paid or otherwise.