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Incretin Based Therapy in Diabetes Mellitus Type 2 JOSEPHINE CARLOS-RABOCA,M.D.,F.P.S.E.M. ENDOCRINOLOGY,DIABETES AND METABOLISM DIABETES CARE CENTER WEIGHT.

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Presentation on theme: "Incretin Based Therapy in Diabetes Mellitus Type 2 JOSEPHINE CARLOS-RABOCA,M.D.,F.P.S.E.M. ENDOCRINOLOGY,DIABETES AND METABOLISM DIABETES CARE CENTER WEIGHT."— Presentation transcript:

1 Incretin Based Therapy in Diabetes Mellitus Type 2 JOSEPHINE CARLOS-RABOCA,M.D.,F.P.S.E.M. ENDOCRINOLOGY,DIABETES AND METABOLISM DIABETES CARE CENTER WEIGHT WELLNESS CENTER MAKATI MEDICAL CENTER

2 Outline Review of Incretins and Diabetes Goals of Treatment for Diabetes Treatment Options Sitagliptin Studies(Case/Clinical trials) – Monotherapy Use – Combination Use – Cardiovascular Benefits

3 After food ingestion GLP-1 is secreted from the L-cells of the jejunum & ileum That in turn… Stimulates glucose-dependent insulin secretion Suppresses glucagon secretion Slows gastric emptying Leads to reduction of food intake Improves insulin sensitivity Longtime effects in animal models: Increase of β-cell mass and improved β-cell function Drucker. Curr Pharm Des Drukcer. Mol. Endocrinol GLP-1: effects in humans

4 GLP-1: Biological Activity LL Baggio and DJ Drucker. Gastroenterology 2007; 132: CVD Fasting hyperglycemia Postprandial hyperglycemia / hypertriglyceridemia Obesity Insulin Resistance Impaired insulin secretion Hyperglucagonemia  -cell mass 

5 GLP-1 Enhancenent GLP-1 Secretion is impaired in Type 2 Diabetes Natural GLP-1 has extremely short half-life Add GLP-1 analogues with longer half-life: exenatide liraglutide Block DPP-4, the enzyme that degrades GLP-1: sitagliptin vildgaliptin Injectables Oral agents DPP-4= Dipeptidyl Peptidase-4 ; GLP=Glucagpn like peptide-1 Drucker. Curr. Pharm. Des. 200; Drucker. Mol. Endocrinol. 2003

6 Incretin Mimetics and DPP-4 Inhibitors: Major Differences Gallwitz. European Endocrine Diseases. 2003

7 Type 2 Diabetes arises when a pancreatic islet cell dysfunction occurs alongside insulin resistance

8 Outline Incretins and Diabetes Goals of Treatment for Diabetes Treatment Options Role of incretins in diabetes treatment Sitagliptin Studies – Monotherapy Use – Combination Use

9 Goals of Therapy in Type 2 Diabetes To lower the incidence of microvascular disease To reduce the excess of cardiovascular disease To improve the quality of life To limit the burden of treatment

10 Treatment Guidelines for Type 2 Diabetes *Capillary glucose † May not be achievable with as manyt as 5 anytihypertensive drugs in some individuals; use higher targets where there is a risk of postural hypertension ‡With statin treatment for patients>40 y.o. or with evidence of cardiovascular disease §Consider use of fibrates to achieve thee goals once LDL-C is controlled

11 Outline Incretins and Diabetes Goals of Treatment for Diabetes Treatment Options Role of incretins in diabetes treatment Sitagliptin Studies – Monotherapy Use – Combination Use

12 Efficacy and tolerability of existing anti-diabetic agents Class Primary therapeutic effectLimitations Sulfonylureas  HbA 1c Hypoglycemia, weight gain Meglitinides  PPGHypoglycemia, weight gain Biguanides (metformin)  HbA 1c GI adverse effects, lactic acidosis (rare) PPARs  HbA 1c Weight gain, edema, anemia, potential for liver toxicity Alpha-glucosidase inhibitors  PPGGI adverse effects Insulin  HbA 1c Injectable route, hypoglycemia, weight gain Adapted from DeFronzo RA Ann Intern Med 1999;131:281–303; Williams G, Pickup JC, eds. Handbook of Diabetes. 3rd ed. Malden, MA: Blackwell Publishing, 2004; Holz GG, Chepurny OG Curr Med Chem 2003;10(22):2471–2483; Meneilly GS Diabetes Care 2003;26(10): 2835–2841; Ahrén B et al Diabetes Care 2002;25(5):869–875; Moller DE Nature 2001;414:821–828.

13 Sitagliptin - Overview DPP-4 inhibitor for the treatment of patients with type 2 diabetes Provides potent and highly selective inhibition of the DPP-4 enzyme Fully reversible and competitive inhibitor ADA 2006 Late Breaking Clinical Presentation (Stein).

14 Sitagliptin Is Potent and Highly Selective (>2500x) for the DPP-4 Enzyme EnzymeIC 50 (nM) DPP-418 DPP-848,000 DPP-9>100,000 DPP-2, DPP-7>100,000 FAP>100,000 PEP>100,000 APP>100,000 ADA 2006 Late Breaking Clinical Presentation (Stein).

15 Pharmacokinetics of Sitagliptin Supports Once-Daily Dosing With once-daily administration, trough (at 24 hrs) DPP-4 inhibition is ~80% – ≥80% inhibition provides full enhancement of active incretin levels No effect of food on pharmacokinetics Well absorbed following oral dosing Low protein binding Primarily renal excretion as parent drug – Approximately 80% of a dose recovered as intact drug in urine No clinically important drug-drug interactions – No meaningful P450 system inhibition or activation ADA 2006 Late Breaking Clinical Presentation (Stein).

16 Incretin based therapy in diabetes Incretin hormone secretion and actions are impaired in type 2 diabetes. Although β-cell responsiveness to GLP-1 is reduced, exogenous GLP-1 can still restore β-cell sensitivity to glucose and improve glucose-induced insulin secretion. A GLP-1 based therapy of type 2 diabetes may therefore be expected to – Reduce hyperglycaemia and HbA 1c levels – Improve β-cell function – Improve insulin sensitivity – Improve metabolism

17 Lifestyle + Metformin + Basal Insulin Lifestyle + Metformin + Sulfonylurea Lifestyle + Metformin + Intensive Insulin Lifestyle + Metformin + Pioglitazone No hypoglycemia Weight loss Nausea/Vomiting Lifestyle + Metformin + Basal Insulin Lifestyle + Metformin + GLP-1 agonist No hypoglycemia Weight loss Nausea/Vomiting STEP 1 STEP 2 STEP 3 Tier 1 : Well-validated core therapies Tier 2 : Less well-validated therapies At diagnosis: Lifestyle + Metformin Lifestyle + Metformin + Pioglitazone + Sulfonylurea Nathan, D et al. Diabetes Care 2009; 32(1): 1-11 ADA-EASD –Algorithm for Control of Type 2 Diabetes (2008)

18 Recent Clinical Studies of Sitagliptin Monotherapy use Combination use with metformin or a PPAR  agent Combination use with sulfonylurea with / without metformin With adjusted doses in patients with diabetes and renal insufficiency ADA 2006 Late Breaking Clinical Presentation (Stein).

19 26 R.M. 43 year old Filipino saw you because he wanted to know if he had diabetes because his parents are diabetic. He had no polyuria, polydipisia, no weight loss. He didn’t smoke but had no exercise. Past medical history was unremarkable. Physical Examination was normal Lab exams: FBS 116 2h post 75 gm,OGTT 283 HBa1c 7.6 % Creatinine 1.0 SGOT 71 SGPT 146 cholesterol 226 triglyceride 213 HDL 45 LDL 139 Hb 15.7 HCT 45 WBC Seg 51 Lympho 40 Mono 6 platelet Urine wbc 5-10/hpf rbc 0-1 protein trace sugar negative CASE # 1

20 26 What would be your initial treatment plan? a. Insulin b. Sitagliptin c. Exenatide d. TZD e. Sulfonylurea f. Metformin

21 Placebo (n=244) Sitagliptin 100 mg (n=229) 24-week Study Time (weeks) % (p<0.001) Japanese Study -1.05% (p<0.001) Placebo (n=75) Sitagliptin 100 mg (n=75) Time (weeks) A1C (%)  change vs placebo* 18-week Study Placebo (n=74) Sitagliptin 100 mg (n=168) Time (weeks) A1C (%) % (p<0.001) A1C (%) = Sitagliptin Consistently and Significantly Lowers A1C With Once-Daily Dosing in Monotherapy

22 Reduction in A1C (%) Baseline A1C (%) Mean (%) Reduction in A1C (%) <8%8–<9%≥9% <8%8–<9%≥9% Sitagliptin 100 mg Once-daily Provides Significant and Progressively Greater Reductions in A1C With Progressively Higher Baseline A1C Inclusion Criteria: 7%–10%+ Reductions are placebo-subtracted. Adapted from Raz I, et al. Protocol 023; Aschner P, et al. Protocol 021. Abstracts presented at ADA2006. ADA 2006 Late Breaking Clinical Presentation (Stein). 18-week Study week Study

23 Sitagliptin Once Daily Significantly Improves Both Fasting and Post-meal Glucose In Monotherapy * LS mean difference from placebo after 24 weeks. Aschner P, et al. Protocol 021. Abstract presented at American Diabetes Association; June 10, 2006; Washington, DC. ADA 2006 Late Breaking Clinical Presentation (Stein). Fasting Glucose  FPG* = –17.1 mg/dL (p<0.001) Weeks Fasting Glucose (mg/dL) Sitagliptin 100 mg (n=234) Post-meal Glucose Time (minutes) Plasma Glucose (mg/dL)  in 2-hr PPG* = –46.7 mg/dL (p<0.001) Placebo (N=204) Sitagliptin 100 mg (n=201) Baseline 24 Weeks Baseline 24 Weeks Placebo (n=247) 6

24 Sitagliptin Placebo Monotherapy Study Add-On to Metformin Study Add-On to TZD Study Percentage P< % 41% 18% 47% 23% 45% Sitagliptin Once Daily Significantly Increases Proportion of Patients Achieving Goal in Monotherapy or Combination Therapy Goal A1C <7% Aschner P, et al. Protocol 021. Rosenstock J, et al. Protocol 019. Karacik A, et al. Protocol 020. ADA ADA 2006 Late Breaking Clinical Presentation (Stein).

25 Sitagliptin Once-daily Lowers A1C Without Increasing the Incidence of Hypoglycemia or Leading to Weight Gain Neutral effect on body weight – In monotherapy studies, small decreases from baseline (~0.1 to 0.7 kg) with sitagliptin; slightly greater reductions with placebo (~0.7 to 1.1 kg) – In combination studies, weight changes with sitagliptin similar to placebo-treated patients Pooled Phase III Population Analysis: no statistically significant difference in incidence for either dose vs. placebo Hypoglycemia Weight Changes 0.9 Placebo 1.2 Sitagliptin 100 mg 0.9 Sitagliptin 200 mg Hypoglycemia Proportion of patients with (%)

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27 Safety laboratory mean changes Small rise in WBC – largely due to slight increase in absolute neutrophil count (ANC) – ~ 0.2 K/mm 3 maximum difference from placebo in WBC with baseline mean of 6.7 K/mm 3 – No increase in patients meeting PDLC (> 20% increase and > ULN) for WBC or ANC; no increase in bands/earlier WBC forms – No associated laboratory AEs of increased WBC Slight increase in uric acid ~ 0.2 mg/dL (baseline ~ 5.3 mg/dL) – No increase in gout AEs Decrease in alk phosphatase – ~ 4-5 IU/mL (baseline of ~ 55 IU/mL) – Small decrease ALT (-1 mIU/mL), small/variable decrease in bili – In Phase II studies – similar reduction in total AP with metformin (-6.4 IUI/mL) and glipizide (-2.4 IU/mL) comparator groups – Literature suggests decrease AP occurs with improved glycemic control

28 Combination Treatment

29 26 R. C. M 61 y/o consulted for diabetes mellitus of 8 years. Medications include glimepiride 2 mg BID, Metformin 100 mg BID. FPG 154 mg/dl His mother, brother and sister are diabetic. He does not smoke nor drink alcohol. His past medical history was unremarkable. Physical examination: Height cm weight 88.5 kg BP 140/80 BMI WC 38 inches. He had no retinopathy on funduscopy. The rest of the physical examination was normal. Lab work up: 2hour PPBS 240 Hba1c of 7.8%. uric acid 5.51 cholesterol 294 triglyceride 387 VLDL LDL 145 SGPT 36 Serum creatinine 1.22, urine microalbumin 64mg/dl; urine creatinine 118 mgdl ; UAC 54 ECG, sinus bradycardia incomplete RBBB, Treadmill stress test: Exaggerated BP response to exercise CASE # 2

30 26 Diagnosis: Diabetes Mellitus Type 2 Diabetic nephropathy, stage 2 Dyslipidemia Hypertension How will modify treatment to reach target goals for his diabetes? a. Insulin b. Sitagliptin 100 mg OD c. Sulfonylurea d. Pioglitazone

31 26 Other treatment? a. Fenofibrate b. Statin c. Aspirin d. ARB e. Vaccination

32 Summary: Mechanism of Action of the Co-administration of Sitagliptin Plus Metformin Co-administration of sitagliptin and metformin addresses the 3 core defects of type 2 diabetes in a complementary manner Sitagliptin and metformin have different but complementary mechanisms of action – Metformin increases total GLP-1 → likely by enhancing GLP-1 release – By inhibition of DPP-4, sitagliptin increases levels of active GLP-1 Co-administration of these drugs results in higher GLP-1 levels than when either drug is administered alone Co-administration of sitagliptin and metformin results in a more than additive effect on both pre- and post-prandial active GLP-1 concentrations 25

33 Sitagliptin Once Daily Significantly Lowers A1C When Added on to Metformin or Pioglitazone * Placebo Subtracted Difference in LS Means. Rosenstock J, et al. Protocol 019. Karasik A, et al. Protocol 020. Abstracts presented at ADA ADA 2006 Late Breaking Clinical Presentation (Stein). Add-on to Metformin  in A1C vs. Placebo* = –0.65% (p<0.001) Weeks A1C (%) Weeks Add-on to Pioglitazone  in A1C vs. Placebo* = –0.70% (p<0.001) A1C (%) PlaceboSitagliptin 100 mg

34 Co-administration of Sitagliptin and Metformin in Healthy Adults Increased Active GLP-1 Greater Than Either Agent Alone Values represent geometric mean±SE. Placebo Metformin 1000 mg Sitagliptin 100 mg Co-administration of sitagliptin 100 mg plus metformin 1000 mg Mean AUC ratio Sita + Met: 4.12 Mean AUC ratios Sita: 1.95 Met: 1.76 – – Active GLP-1 Concentrations, pM MealMorning Dose Day 2 Time (hours pre/post meal) N=16 healthy subjects. AUC=area under the curve 24

35 HbA 1c With Sitagliptin or Glipizide as Add-on Combination With Metformin: Comparable Efficacy a Specifically glipizide ≤ 20 mg/day; b Sitagliptin 100 mg/day with metformin (≥1500 mg/day). Per-protocol population; LSM=least squares mean. SE=standard error. 27 Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.

36 Greater Reductions in HbA 1c Associated With Higher Baseline HbA 1c – 52-Week Post Hoc Analysis n=117 Baseline HbA 1c Category Mean Change From Baseline in HbA 1c, % <7%≥7 to <8%≥8 to <9%  9% − 0.1 − 0.6 −1.1 −1.8 − 0.3 −0.5 −1.1 −1.7 −2.0 −1.8 −1.6 −1.4 −1.2 −1.0 −0.8 −0.6 −0.4 − Sitagliptin b plus metformin Sulfonylurea a plus metformin n=33n=21 n=82 n=179n=167 n=112 a Specifically glipizide ≤20 mg/day. b Sitagliptin 100 mg/day with metformin (≥1500 mg/day); Per-protocol population. Add-on sitagliptin with metformin vs sulfonylurea with metformin study. 28 Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.

37 Sitagliptin With Metformin Provided Weight Reduction (vs Weight Gain) and a Much Lower Incidence of Hypoglycaemia a Specifically glipizide ≤20 mg/day; b Sitagliptin (100 mg/day) with metformin (≥1500 mg/day); c All-patients-as-treated population. Least squares mean between-group difference at week 52 (95% CI): change in body weight = –2.5 kg [–3.1, –2.0] (P<0.001); Least squares mean change from baseline at week 52: glipizide: +1.1 kg; sitagliptin: –1.5 kg (P<0.001). Add-on sitagliptin with metformin vs sulfonylurea with metformin study.  between groups = –2.5 kg Least squares mean change over time c Body Weight, kg ± SE Sulfonylurea a plus metformin (n=416) Sitagliptin b plus metformin (n=389) −3 −2 − Weeks Hypoglycaemia c P< % 5% Week 52 Patients With ≥1 Episode, % P<0.001 Sulfonylurea a plus metformin (n=584) Sitagliptin b plus metformin (n=588) 29 Adapted from Nauck MA, Meininger G, Sheng D, et al, for the Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab. 2007;9:194–205 with permission from Blackwell Publishing Ltd., Boston, MA.

38 Summary: Sitagliptin or Glipizide as Add-on Combination With Metformin Efficacy profile – Comparable efficacy in lowering HbA 1c – Both provided greater HbA 1c reductions in patients with the highest baseline HbA 1c Safety profile – Both were generally well tolerated – Adverse event profiles (ie, serious and GI-related adverse events, those leading to discontinuation) were similar, with the exception of hypoglycaemia Significantly lower incidence of hypoglycaemic episodes associated with sitagliptin with metformin – Body weight significantly decreased for sitagliptin with metformin, but increased for glipizide with metformin Nauck MA et al. Diabetes Obes Metab. 2007;9:194–

39 Summary: Initial Combination Therapy With Sitagliptin Plus Metformin Through 54 Weeks Efficacy profile – Marked reductions in HbA 1c for up to 54 weeks – Continued and substantial reductions in FPG and 2-hour PPG concentrations – Improved measures of β-cell function (HOMA-β; proinsulin-to-insulin ratio) – Provided greater HbA 1c reductions in patients with the highest baseline HbA 1c Safety profile –Generally well tolerated –Discontinuation due to adverse events was low across treatment groups –Adverse event profile similar to that observed with metformin monotherapy, including gastrointestinal adverse events –Weight loss similar to that observed with metformin monotherapy –Low incidences of hypoglycaemia Goldstein BJ et al. Diabetes Care. 2007;30:1979–1987; Williams-Herman D et al. Poster presentation at ADA 67th Annual Scientific Sessions in Chicago, Illinois, USA, 22–26 June Late Breaker (04-LB). 38

40 Sitagliptin and metformin have complementary mechanisms of action that address all 3 core defects of type 2 diabetes – Improves HbA 1c, fasting plasma glucose and post-prandial glucose As initial therapy, compared with metformin monotherapy, co-administration of sitagliptin with metformin provides improved efficacy without increased incidence of weight gain or hypoglycaemia – Provides an additive effect on the reduction of HbA 1c – Improves the markers of β-cell function – Has similar adverse event profile to metformin monotherapy Combination of therapy of sitagliptin as an add-on to sulfonylurea or as an add-on to sulfonylurea plus metformin resulted in a reduction in HbA 1c and was generally well-tolerated Nauck MA et al. Diabetes Obes Metab. 2007;9:194–205;; Goldstein BJ et al. Diabetes Care. 2007;30:1979–1987; Hermansen K et al. Diabetes Obes Metab. 2007;9:733– Summary: A Case for Earlier Use of Combination Therapy in the Management of Type 2 Diabetes

41 Clinical data overview of combination therapy of sitagliptin and sulfonylurea (as add-on to sulfonylurea alone or sulfonylurea plus metformin) 26

42 Summary: Sitagliptin Add-on to Glimepiride With or Without Metformin Study Efficacy profile – Provided sustained reduction in HbA 1c for 24 weeks Safety profile – Was generally well tolerated – No differences were observed in the incidence of clinical adverse events, serious adverse events, or adverse events leading to treatment discontinuation between groups – Provided modest increase in mean body weight in the overall cohort Weight gain observed when added to glimepiride alone Small numerical increase when added to the combination of glimepiride and metformin – As expected, the incidence of hypoglycaemia increased when glimepiride, a sulfonylurea, was co-administered with sitagliptin Hermansen K et al. Diabetes Obes Metab. 2007;9:733–

43 DPP-4 Inhibition by Sitagliptin Improves the Myocardial Response to Dobutamine Stress and Mitigates Stunning in a Pilot Study of Patients with Coronary Artery Disease Read PA et al, Circ Cardiovasc Imaging published online Jan 14, 2010;

44 Echocardiographic Analysis Regional wall LV motion (septal, lateral, anterior, inferior, anteroseptal and posterior ) Global LV function – mitral annular systolic velocity – 6 sites Peak systolic tissue velocity (Vs) Strain and strain rate A diameter of >50% stenosis on CA was considered hemodynamically significant

45 Global LV function assessed by LV ejection fraction (mean ± SEM) at baseline, peal stress and 30 minute recovery. P A Read et al. Circ Cardiovasc Imaging 2010; DOI: /CIRCIMAGING ± 7.9% 72.6 ± 7.2%

46 Conclusions In patients with CAD, metabolic manipulation with DPP4-inhibition to prevent degradation of GLP-1 can protect the heart from ischemic LV dysfunction during dobutamine stress and mitigate post- ischemic stunning. Global and regional wall LV performance was greater following sitaglipitin at peak stress and at 30 minutes into recovery compared to control.

47 Conclusions The rise in plasma insulin was also reduced by sitagliptin which suggests that the beneficial effect on the heart was due to GLP-1 and not to insulin. At peak stress, sitagliptin improved both global function assessed by ejection fraction and mitral annular Vs, and regional wall function assessed by Vs, strain and strain rate. This was primarily driven by increasing the performance of the ischemic segments.

48 Conclusions In the recovery period, there was evidence of post- ischemic stunning in the control scans with reduced global and regional wall function compared to baseline. However, sitagliptin protected the heart from ischemia and mitigated this effect.

49 Conclusions The inhibition of DPP-4 augmented plasma levels of GLP-1 (7-36) which improved global and regional wall LV function during dobutamine stress and mitigated post-ischemic stunning in the recovery period. This was predominantly driven by a cardioprotective effect on ischemic segments and was independent of insulin.

50 Conclusion Incretin Based therapy in diabetes can be used as monotherapy or in combination therapy with other hypoglycemic agents Safe, effective, provides long term glucose control Benefits beyond glucose control weight neutral or weight loss probable CV benefits and beta cell mass enhancement

51 Thank you


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