F. Hosseinpanah Obesity Research Center - PowerPoint Presentation

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F. HosseinpanahObesity Research CenterResearch Institute for Endocrine sciencesShahid Beheshti University of Medical SciencesNovember 23, 2014

Incretin

-based therapies

Part

II

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Expectations for New Agents and/or New Strategies

Modify

disease progression and halting the decline in



-

cell function – better long-term control

Reducing

cardiovascular morbidity and mortality

Lowering A1C to targets as close to normal as possible without unacceptable

hypoglycemia

in selected populations

Lowering A1C with no weight gain or lowering A1C with weight loss (ideally)

No unexpected side effects in the long term (

eg

rosiglitazone)

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Limitations of Older Agents for T2DMLimitation

Agent

Hypoglycemia

Secretagogues, insulin

Weight gain

Secretagogues, glitazones, insulin

Edema

Glitazones, insulinGI side effectsMetformin, alpha-glucosidase inhibitorsLactic acidosis (rare)MetforminSafety issues in elderly, renal-impaired, or CHF patientsGlitazones, metformin, sulfonylureasPoor response ratesAll oral medicationsLack of durable effectAll oral monotherapy except glitazones

Abbreviations: CHF: Congestive heart failure; GI: gastrointestinal.

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What are incretins?Hormones produced by the gastrointestinal tract in response to incoming nutrients, and have important actions that contribute to glucose homeostasis.Two hormones: - Gastric inhibitory polypeptide (GIP) . - Glucagon-like peptide-1 (GLP-1). Drugs 2014; 74(2): 223-242

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ROLE OF INCRETIN IN GLUCOSE HOMEOSTASIS

IN-CRET-IN

IN

testine

se

CRET

ion INsulin Definition: gut derived factors that increase glucose stimulated insulin secretionTwo hormones: (1) glucagon-like peptide-1 (GLP-1) (2) glucose-dependent insulinotropic polypeptide (GIP)Diabetologia 1985; 28: 5645.

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Role of

Incretins

in Glucose

Homeostatis

DPP-4=

dipeptidyl

peptidase–4

GIP=glucose-dependent insulinotropic peptideGLP-1=glucagon-like peptide–1Beta cellsAlpha cells

Inactive

GLP-1

Blood

Glucose

GI tract

Release of gut hormones –

Incretins

Ingestion of food

Glucose

uptake by

muscles

Glucose

production

by liver

Inactive

GIP

DPP-4

enzyme

Glucose dependent glucagon from alpha cells

(GLP-1)

Glucose-dependent insulin from beta cells

(GLP-1, GIP)

Active

GLP-1 & GIP

Pancreas

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↑ Insulin secretion to maintain glucose homeostasis↓ Glucagon secretion↓ Postprandial glycemia

↓

Gastric emptying

↑ Satiety due to delayed gastric emptying ↓ Food ingestion due to effects on brain

↑ Β cell number and

↑

Β cell mass (animal studies)↑ Β cell proliferation and ↑ islet neogenesis↓ Apoptosis. J Clin Pathol. 2008; 61: 401-409.Circulating GLP-1 Has Many Beneficial Effects

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DPP-4 Inhibitors MOA

Incretin

effects

Augments glucose-dependent

insulin secretion

Inhibits glucagon secretion

and hepatic glucose production

Improves hyperglycemiaMealInactive GLP-1ActiveGIP

DPP-4

Intestinal

GIP

release

Intestinal

GLP-1

release

DPP-4

DPP-4

inhibitor

Inactive

GIP

DPP-4

inhibitor

Active

GLP-1

Selective inhibition of DPP-4 increases plasma GLP-1

levels, resulting in reduction in

glycemia

Drugs 2014; 74(2): 223-242

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Inhibition of DPP-IV:Increases Active Portal GLP-1 and GIPDPP-IV inhibitors exhibit both short term and long term actions of GLP-1Augment glucose induced insulin secretion

Inhibit glucagon secretion

Slow gastric emptying

Increase insulin biosynthesisPromote beta cell differentiation

T

½=1-2mins

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Noninsulin Therapies for Hyperglycemia in Type 2 Diabetes (7)ClassDPP-4 inhibitors (incretin enhancers)

Compound

Sitagliptin

VildagliptinSaxagliptin

Linagliptin

Mechanism

Inhibits

DPP-4 activity, prolongs survival of endogenously released incretin hormonesAction(s)Active GLP-1 concentration Active GIP concentration Insulin secretion Glucagon secretion AdvantagesNo hypoglycemiaWeight “neutrality”DisadvantagesOccasional reports of urticaria/angioedemaCases of pancreatitis observedLong-term safety unknownCostHigh

Diabetes Care

2012; 35(

suppl

1): S23.

Adapted with permission from Silvio

Inzucchi

, Yale University

.

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ADA/EASD Consensus statement 2012

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DPP-4 Inhibitors in the AACE/ACE Diabetes Algorithm For Glycemic Control1A guiding principle of the current algorithm is “the recognition of the importance of avoiding hypoglycemia.”The AACE/ACE diabetes algorithm favors the use of DPP-4 inhibitors and GLP-1 agonists as dual therapy with metformin over sulfonylureas, in patients with HbA1c levels 6.5%-9.0%, based on efficacy and overall safety profiles.

Sulfonylureas have been associated with greater risks of hypoglycemia and weight gain.

In combination with metformin, DPP-4 inhibitors are a preferred oral option in dual therapy for patients with HbA

1c levels between 6.5% and 9.0%.

AACE=American Association of Clinical Endocrinologists; ACE=American College of Endocrinology;

DPP-4=

dipeptidyl

peptidase-4; GLP-1=glucagonlike peptide-1.Endocr Pract. 2009; 15(6): 540–559.

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Efficacy: Add-on Sitagliptin

LSM

 =

least-squares mean change

1

Diabetes Care

2006; 29: 2638-2643 |

2 Clin Ther 2006; 28: 1556-1568.–0.65% (P<0.001)–0.70% (P<0.001)12

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Efficacy: HbA1c Reductions at Week 1041

2-Year Per-Protocol Population

(Patients Inadequately Controlled on Metformin)

Difference in LS Mean HbA

1c

= –0.03

(95% CI: –0.13, 0.07)

LS Mean (95% CI) Change in HbA1c From Baseline, %–0.7–0.5–0.30Glipizide + metformin (n=256)

Sitagliptin

+ metformin (n=248)

Mean baseline HbA

1c

,%

7.30

7.31

LS=least-squares; SD=standard deviation.

Int

J

Clin

Pract

. 2010

; 64(5): 562–576

.

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Sitagliptin vs SU(Glipizide): Weight Change and Incidence of Hypoglycemia1

Patients With

at Least 1 Episode, %

APaT

Population

(Patients Inadequately Controlled on Metformin)

Sitagliptin + metformin

Glipizide + metformin

Between-groups difference = –28.8%

(95% CI: –33.0, –24.5)

n=588

n=584

APaT

=all-patients-as-treated; CI=confidence interval;

LS=least-squares

Int

J

Clin

Pract

. 2010

; 64(5): 562–576

.

LS Mean (±95% CI) Body Weight Change From Baseline, kg

Between-groups difference = –2.3 kg

(95% CI: –3.0, –1.6) Hypoglycemia over 104 weeksBody weight at week 104n=253n=261

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Very well toleratedImprove physiologyExpensiveSo far, no serious adverse effects with long term use.No increased risk of pancreatic caner.

DDP-4 inhibitors – Bottom Line

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Properties of Dipeptidyl Peptidase–4 (DPP-4) Inhibitors

Pharmacotherapy of Diabetes

2007: 111-142.

Oral administration

GLP-1/GLP-1 receptor agonist concentration elevated 3–6 hours after meals when secretion from endogenous sources is stimulated

GLP-1 concentration close to physiological concentration (~ x 2–3)

Action through GLP-1 receptors and possibly GIP receptors

GLP-1 action probably through nerves more than circulationA1C reduction −0.6% to 0.9%Weight change ±0 kg-Cell mass effects probable in animals, no human data 

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Conclusion:Benefits and Advantages of SitagliptinEfficacy: Lower HbA1c; ~0.6 %–0.9% from baselineLow risk of hypoglycemiaWeight neutral (do not promote weight gain)Once-daily, oral therapy

Very

well

tolerated Drugs 2014; 74(2): 223-242.

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SitagliptinOnce a dayTablet, orallyDosage and Adminstration:Sitaglipitin 100 mg daily50 mg if Cr 1.7-3.0 for men and 1.5-2.5 for women

25 mg in ESRD

1.

Sitagliptin: FDA label 2013; Reference ID: 3391688.

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27 reports of 19 studies including 7136 patients randomised to a DPP-4 inhibitor and 6745 patients randomised to another hypoglycaemic drug were eligible for the systematic review and meta-analysis.BMJ 2012;344:e1369 doi: 10.1136/bmj.e1369 (Published 12 March 2012)

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Results Compared with metformin as monotherapy, DPP-4 inhibitors were associated with a smaller decline in HbA1c (weighted mean difference 0.20, 95% CI 0.08 to 0.32) and in body weight (1.5, 0.9 to 2.11)

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Results As a second line treatment, DPP-4 inhibitors were inferior to GLP-1 agonists (0.49, 0.31 to 0.67) Similar to pioglitazone (0.09, −0.07 to 0.24) in reducing HbA1c No advantage over sulfonylureas in the attainment of the HbA1c goal (risk ratio in favour of sulfonylureas 1.06, 0.98 to 1.14).

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Results DPP-4 inhibitors had a favourable weight profile compared with sulfonylureas (weighted mean difference −1.92, −2.34 to −1.49) or pioglitazone (−2.96, −4.13 to −1.78), but not compared with GLP-1 agonists (1.56, 0.94 to 2.18)

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Results Only a minimal number of hypoglycaemias were observed in any treatment arm in trials comparing a DPP-4 inhibitor with metformin as monotherapy or with pioglitazone or a GLP-1 agonist as second line treatment.

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Results Incidence of nausea, diarrhoea, and vomiting was higher in patients receiving metformin or a GLP-1 agonist than in those receiving a DPP-4 inhibitor. Risk for nasopharyngitis, upper respiratory tract infection, or urinary tract infection did not differ between DPP-4 inhibitors and any of the active comparators

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Key messageIn patients with type 2 diabetes who do not achieve the glycaemic targets with metformin alone, DPP-4 inhibitors can lower HbA1c, in a similar way to sulfonylureas or pioglitazone, with neutral effects on body weight.

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Wang T, Gou Z, Wang F, Ma M, Zhai S-d (2014) Comparison of GLP-1 Analogues versus Sitagliptin in the Management of Type 2 Diabetes: Systematic Review and Meta-Analysis of Head-to-Head Studies. PLoS ONE 9(8): e103798. doi:10.1371/journal.pone.0103798

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Meta-analysis of change in HbA1C (%)

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Meta-analysis of change in Fasting Plasma Glucose (mmol/L) in

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Meta-analysis of change in body weight (kg)

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Key messagesThe result of this meta-analysis demonstrates that compared to sitagliptin, GLP-1 analogues are more effective for glycemic control and weight loss, but have similar efficacy in reducing blood pressure and lipid parametersHowever, GLP-1 analogues are associated with a higher incidence of gastrointestinal adverse events and a similar incidence of hypoglycemia compared to sitagliptin

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Thank You