Incretin Hormones as Targets in the Management of Type 2 Diabetes

Dr C Rajeswaran Consultant Physician, Diabetes & Endocrinology Mid Yorkshire NHS Trust

Lessons from UKPDS: better control means fewer complications

EVERY 1% reduction in HbA 1c REDUCED RISK* Deaths from diabetes Heart attacks 1% UKPDS 35. BMJ 2000;321:405ñ12 Microvascular complications Peripheral vascular disorders *p<0.0001

UKPDS: progressive decline in glycaemic control irrespective of treatment regime 9 cross-sectional, median values Conventional 8 Intensive 7 6.2% upper limit of normal range 6 0 0 3 6 9 Years from randomisation UKPDS 33. Lancet 1998; 352: 837 –853.

12 15

Stepwise Management of Type 2 Diabetes

Insulin ± oral agents Oral 3- triple therapy Oral 2- combination Oral monotherapy Diet & exercise

Oral Anti-Diabetes Agents

Insulin Secretion

Sulphonylureas Insulin secretagogues (rapid) Incretin-mimetics DPP4 - inhibitors

Glucose Absorption

Alpha-glucosidase inhibitors

Insulin Action

Thiazolidinediones (Glitazones) Metformin

Appetite supressants**

Orlistat Sibutramine

Long-Acting Insulin Secretagogues

• Tolerability issues(1-3) – Increased risk of hypoglycaemia – The UKPDS noted 4.8kg weight gain over a three year period 1. UKPDS 13 BMJ 1995; 310: 83-8 2. UKPDS 28: Diabetes Care; 21:87-92 3. Adverse Drug React Toxicol. Rev 2002; 21 (4): 205-17

Thiazolidinediones

Enhance insulin action without directly stimulating insulin secretion

‘Insulin action enhancers’

Insulin Thiazolidinediones Insulin receptor Metabolic effects PPAR



CELL MEMBRANE Adipocyte differentiation Gene regulation NUCLEUS CYTOPLASM

Effect of rosiglitazone on the risk of MI and death from cardiovascular cause Nissen & Wolski

New England Journal Medicine 2007,356: 2457 - 2471

Defects in Type 2 Diabetes (plus incr. hepatic glucose output)

Normal Islet Function: Glucose Regulation

Postprandial Glucagon Is Inappropriately Elevated in Type 2 Diabetes Type 2 Diabetes* Nondiabetic Subjects † Meal 360 Defects in Diabetes Glucose (mg/%) 300 Hyperglycaemia 240 110 80 Insulin ‡ (µU/mL) 120 60 0 Glucagon (µg/mL) 140 120 100 Deficient Insulin Release Glucagon Not Suppressed (Postprandially) -60 0 60 120 Time (min) 180 240 Mean ± SEM;*N = 14; † N = 12; ‡ mean insulin values N = 5.

Adapted from Muller WA, et al . N Engl J Med. 1970;283:109-115.

Copyright © 1970 Massachusetts Medical Society . All rights reserved. Translated with permission 2005.

The Incretins

• Gut-derived hormones, secreted in response to nutrient ingestion that potentiate insulin secretion from pancreatic beta-cells • Unique from other insulinotropic agents in that stimulation of insulin secretion is glucose-dependent. Incretins only work when glucose levels are above basal levels • Two predominant incretins  glucagon-like peptide-1 (GLP-1)  glucose-dependent insulinotropic peptide (GIP), also known as gastric inhibitory peptide

GLP-1 Effects in Humans: Understanding the Glucoregulatory Role of Incretins GLP-1 secreted upon the ingestion of food Promotes satiety and reduces appetite Beta cells: Enhances glucose dependent insulin secretion Alpha cells: ↓ Postprandial glucagon secretion Liver: ↓ Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying Adapted from Flint A, et al . J Clin Invest. 1998;101:515-520.; Adapted from Larsson H, et al . Acta Physiol Scand. 1997;160:413-422.; Adapted from Nauck MA, et al . Diabetologia. 1996;39:1546-1553.; Adapted from Drucker DJ . Diabetes. 1998;47:159-169.

The Incretin Effect Is Reduced in Patients With Type 2 Diabetes Intravenous Glucose Oral Glucose Control Subjects Patients With Type 2 Diabetes 80 80 60 60 40 40 20

* * * * * * *

0 0 30 60 90 120 150 180 Time (min) 20 0 0

*

30

*

*P ≤.05 compared with respective value after oral load. Nauck MA, et al . Diabetologia. 1986;29:46-52. Reprinted with permission from Springer Verlag © 1986 .

*

60 90 120 150 180 Time (min)

Summary

• The incretin hormones GLP-1 and GIP are essential components of normal glucose control • GLP-1 exhibits several glucoregulatory activities that may be favourable for improving glycaemic control • Rapid inactivation by DPP-IV limits the therapeutic utility of GLP-1 • Agents that mimic the actions of GLP-1 and are resistant to DPP-IV degradation (incretin mimetics) or prolong the activities of endogenous GLP-1 (DPP-IV inhibitors) are of high clinical interest

Gila Monster (

Heloderma suspectum

)

Exenatide: Effects on Glycaemic Control in Combination With Current Oral Therapies

0.4

0.2

0.0

-0.2

-0.4

-0.6

-0.8

-1.0

-1.2

*

Placebo

*

5 μg BID † 10 μg BID † † Ex + Met Ex + SU † Ex + Met + SU *P < 0.001 vs placebo † P < 0.0001 vs placebo DeFronzo RA et al. Diabetes Care 2005;28:1092-1100. Buse JB et al. Diabetes Care 2004;27:2628-2635. Kendall DM et al. Diabetes Care 2005;28:1083-1091.

Hypoglycaemia with Exenatide

Placebo 5 μg BID 10 μg BID 40 30 20 10 0 Ex + Met Ex + SU Ex + Met + SU DeFronzo RA et al. Diabetes Care 2005;28:1092-1100. Buse JB et al. Diabetes Care 2004;27:2628-2635. Kendall DM et al. Diabetes Care 2005;28:1083-1091.

.00

-0.5

Exenatide: Change in Body Weight

Placebo 5 μg BID 10 μg BID -1.0

-1.5

-2.0

* * * *

-2.5

-3.0

Ex + Met

*

Ex + SU Ex + Met + SU *P < 0.05 vs placebo DeFronzo RA et al. Diabetes Care 2005;28:1092-1100. Buse JB et al. Diabetes Care 2004;27:2628-2635. Kendall DM et al. Diabetes Care 2005;28:1083-1091.

Nausea with Exenatide

Placebo 5 μg BID 10 μg BID 40 30 20 10 0 0-4 >4-8 >8-12 >12-16 >16-20 Treatment weeks >20-24 >24-28 >28 Kendall DM et al. Diabetes Care 2005;28:1083-1091.

Degradation of Incretins by DPP-4

Therapies in Development

DPP-IV Inhibitors: Rationale

Mixed meal Intestinal GLP-1 release GLP-1 (7-36) active DPP-IV DPP-IV inhibitor

DPP-IV=dipeptidyl peptidase IV Adapted from Drucker DJ

Expert Opin Invest Drugs

2003;12(1):87 –100; Ahrén B

Curr Diab Rep

2003;3:365 –372.

GLP-1 (9-36) inactive

Body weight (kg)

Gliptin add-on to metformin: weight neutral

Gliptin 100 mg daily + metformin (n=143) Placebo + metformin (n=130) +0.2 kg * −1.0 kg Time (weeks of treatment)

*p<0.05 vs Gliptin.

Primary ITT population.

Data on file, Novartis Pharmaceuticals, LAF237A2303.

Body weight (kg)

Gliptin: no weight gain

Add-on treatment to metformin (~1.9 g mean daily) −1.8 kg difference Time (weeks) Gliptin 50 mg bid + metformin Glimepiride up to 6 mg qd + metformin

Per protocol population. Data on file, Novartis Pharmaceuticals, LAF237A2308 52-week interim analysis.

Gliptin add-on to insulin: fewer hypoglycaemic events 200 160 120 80 40 0 Add-on treatment to insulin No. of events ** 185 No. of severe events † Gliptin + insulin Placebo + insulin 10 8 113 6 * 6 4 2 0 0

† Severe defined as grade 2 or suspected grade 2 hypoglycaemia.

*

p<0.05; **p<0.001 between groups.

Fonseca V, et al.

Diabetologia

2007; 50: 1148-1155.

What is the Hepatic Safety Profile of Gliptin? Liver Enzymes Clinical Findings and Monitoring

•Incidence of ALT or AST >3x ULN (%) a • Imbalance in liver enzyme levels seen with Gliptin 100 mg QD regimen*

1.0

0.86

• Hepatic enzyme elevations across the clinical studies were spread over time with no pattern of time to onset

0.8

0.6

• Most cases were asymptomatic and many resolved or improved while on treatment

0.4

0.2

0.32

0.21

0.34

0.18

0.0

PBO N=1241 Vilda 50 mg qd N=1404 Vilda 50 mg bid N=4406 Vilda 100 mg od N=1274 All comp, inc PBO N=4428

•From pooled mono and add-on studies up to week 24

(includes IA from GALIANT only)

a Persistent enzyme elevations: classified as present on at least 2 consecutive measurements or at the final on-treatment visit. AST=aspartate aminotransferase; ALT=alanine aminotransferase; bid=twice daily; comp=comparators; LFT=liver function test; PBO=placebo; qd=once daily; ULN=upper limit of normal

DPP-4 Inhibitors

• Effective as mono- and combination therapy • Daily oral dosing • Low risk of hypoglycaemia • Weight neutral • Well tolerated • Theoretical possibility that they could preserve and even reverse progressive loss of insulin secretory capacity

•

NICE recommendations

•

DPP-4 inhibitors

•

Consider adding a DPP-4 inhibitor instead of a sulfonylurea as second line therapy to first-line metformin when control of blood glucose remains or becomes inadequate (HbA1c ≥ 6.5%, or other higher level agreed with the individual) if:

•

• Significant risk of hypoglycaemia or its consequences (for example, older people and people in certain jobs [for example, those working at heights or with heavy machinery] or people in certain social circumstances [for example, those living alone]), or

•

• Person does not tolerate a sulfonylurea or a sulfonylurea is contraindicated.

• •

Consider adding a Gliptin as second-line therapy to first-line sulfonylurea monotherapy when control of blood glucose remains or becomes inadequate (HbA1c ≥ 6.5%, or other higher level agreed with the individual) if:

•

• the person does not tolerate metformin, or metformin is contraindicated.

•

Consider adding gliptin as third-line therapy to first-line metformin and a second-line sulfonylurea when control of blood glucose remains or becomes inadequate (HbA1c ≥ 7.5% or other

•

Only continue Gliptin if the person has had a beneficial metabolic response (a reduction of at least 0.5 percentage points in HbA1c in 6 months).

•

A DPP-4 inhibitor may be preferable to a thiazolidinedione (pioglitazone, rosiglitazone) if:

•

• further weight gain would cause or exacerbate significant problems associated with a high body weight, or

•

• a thiazolidinedione (pioglitazone, rosiglitazone) is contraindicated, or

•

• the person has previously had a poor response to, or did not tolerate, a thiazolidinedione (pioglitazone, rosiglitazone).

•

There may be some people for whom either a Gliptin or a thiazolidinedione (pioglitazone, rosiglitazone) may be suitable and, in this case, the choice of treatment should be based on patient preference.