‘Emerging Insulin-Independent Approaches for the Management of Type 2 Diabetes’

Chair:

Clifford J. Bailey, PhDProfessor of Clinical Science Head of Diabetes Research Life and Health Sciences Aston University Birmingham, United Kingdom

Bernard Charbonnel, MDProfessor of Endocrinology and Metabolic Diseases Head of Internal Medicine,Endocrinology and DiabetesUniversity of NantesNantes, France

Ele Ferrannini, MDProfessor of Internal Medicine, Chief, Metabolism Unit National Research Council Institute of Clinical Physiology University of Pisa Pisa, Italy

Michael Nauck, MD, PhD Professor of Internal Medicine Head, Specialist Clinic for Diabetes and Metabolic DiseasesDiabetes CentreBad Lauterberg, Germany

• The role of the kidney in the physiological regulation of glucose homeostasis has come into focus.

• Latest development efforts for novel antidiabetic therapies have concentrated on insulin-independent mechanisms like the sodium-glucose co-transporter 2 (SGLT2) inhibitors.

• The emerging profile of the most advanced compounds in this novel class points towards likely clinical benefits but also potential risks and issues to be addressed.

• We will attempt to formulate where these novel drugs may fit into future treatment algorithms and which patients may benefit the most.

Introduction

Development and Progression of Type 2 Diabetes: Multiple Intervention Targets

Image courtesy of Clifford Bailey, PhD

IGT = Impaired Glucose Tolerance Normal

HyperglycaemiaFasting glucose

Glucose tolerance

Insulin action

Insulin secretion

Abnormal glucose tolerance

β-cell failure

Insulin resistance

β-cell compensation

IGT T2DM Blood glucose

InsulinGlucagon

Type 2 Diabetes: Current Therapy Options

InsulinResistance

β-CellDysfunction

CarbohydrateDigestion

Loss ofβ-Cell Mass

Treatments for Obesity

MetforminTZDs

Insulinα-glucosidase

inhibitors

Diet, Exercise Treat lipids + BP

Orlistat,

Pramlintide BromocriptineColesevelam

α-CellDysfunction

SulphonylureasMeglitinides

GLP-1 agonistsDPP4 inhibitors

Image courtesy of Clifford Bailey, PhD

Available Medications Used to Get the HbA1c Target (in 2011)

1. Metformin

2. Sulfonylureas/Glinides

3. TZDs (Pioglitazone)

4. α-glucosidase-inhibitors

5. DPP4-inhibitors

6. GLP1-agonists

7. Insulins

8. Coming-up : SGLT2-inhibitors

Courtesy of Bernard Charbonnel, MD

injections

Oral agents

Standard Therapies Metformin

Diagnosis

Metformin (if tolerated) is widely accepted as the 1st-line drug for type 2 diabetes

• An insulin-sensitizer fits with the early physiopathological features of the disease• Decreases HbA1c by >1%• Absence of weight gain and hypoglycaemia• Possible cardiovascular protective effect• Possible protective effect against cancer• Safe : low level of serious side effects • Inexpensive

Lifestyle changes + Metformin for everybody

Depends on a sufficient residual insulin secretion

Courtesy of Bernard Charbonnel, MD

Standard Therapies Sulfonylureas and Glinides

The generally recommended 2nd line drug (for cost-effectiveness reasons)

• Inexpensive• Rapid response• Poor durability• Risk of hypoglycemia• Weight gain• Perhaps excess risk for cancers• No evidence of a CV benefit

Depends on a sufficient residual insulin secretion

Courtesy of Bernard Charbonnel, MD

Standard Therapies TZDs (Pioglitazone)

A good 2nd or 3rd line option in selected patients with: •marked insulin resistance •and high cardio-vascular risk, especially:–Post-MI (if no heart failure)–Post-stroke–Chronic kidney disease

• The most powerful on the long-term : good durability

• No hypos• A likely CV benefit in high CV risk

patients• But various adverse effects

In whom the benefits are likely to exceed the risks

Depends on a sufficient residual insulin secretion

Courtesy of Bernard Charbonnel, MD

DPP-4 inhibitors•Sitagliptin

•Vildagliptin

•Saxagliptin

•Linagliptin

In development•Alogliptin*

* Licensed in Japan

Incretin-based Therapies

GLP-1 receptor agonists•Exenatide

•Liraglutide

Courtesy of Clifford Bailey, PhD

Glucotoxicity

• High glucose levels are toxic for two main pathogenetic defects of type 2 diabetes

– Beta-cell function– Insulin action in peripheral tissues

• High chronic hyperglycaemia damages vascular tissues resulting in

– Microvascular complications– Macroangiopathy of diabetes

The Kidney •Produces glucose

•Uses glucose

•Filters glucose

•Reabsorbs glucose

Kidney and Glucose Homeostasis

Courtesy of Clifford Bailey, PhD

S1 & S2 segment SGLT2

(> 90% glucose reabsorbed)

S1 & S2 segment proximal renal tubule S3 segment

proximal renal tubule

S3 segment SGLT1 (remaining 10% glucose

reabsorbed)

Glucose

SGLT2

Glucose

Na+

K+K+

Na+

Na+

Glucose

Epithelium lining proximal

tubule

LumenBlood

Glucose GLUT2

Lumen Blood

SGLT1

Glucose

2Na+

K+ K+

Na+

Na+

Glucose

Epithelium lining proximal

tubule

Glucose GLUT1

Location of Sodium Glucose Transporters in the Kidney

Adapted from Bailey CJ, Day C. Br J Diabetes Vasc Dis. 2010;10:193-199.

Sodium-Glucose Co-transporter-2 Inhibitors

Courtesy of Clifford Bailey, PhD.

Diet

Blood glucose

Normally no glucosuria

SGLT-1

SGLT-2 - in proximal tubules reabsorbs most of filtered glucoseSGLT-1 - also in proximal tubules, normally reabsorbs remaining filtered glucose

SGLT2 inhibitors Increase renal glucose

elimination

Normally all filtered glucose

reabsorbed

SGLT-2 SGLT-1

HbA1c (%) mean change from baseline

N = 546

Dapagliflozin Added to Metformin Mean Change in HbA1c (%) and Body Weight (kg)

From Bailey et al. Lancet. 2010;375:2223-33.Week 24 (LOCF) change from baseline

(n = 137)(n = 137)

(n = 137)(n = 135)

Weeks

Body weight (kg) mean change from baseline

Weeks

Dapagliflozin Monotherapy & Canagliflozin Add-on to Metformin

12 week from baseline Body Weight (%)

Dapagliflozin Canagliflozin

From List et al. Diabetes Care. 2009;32:650-657. Rosenstock et al. Diabetes. 2010;59(suppl 1):77-OR Abstract.

HbA1c (%)

Mea

n ch

ange

from

bas

elin

e

Body weight (kg)

Mea

n ch

ange

from

bas

elin

e

N = 75 N = 65 N = 64 N = 70

Dapagliflozin – Sustained Effects on HbA1c and Body WeightSubjects with T2D with Inadequate Glycaemic Control on Metformin

Woo et al. Data presented at: World Diabetes Congress; Dubai, UAE; December 4, 2011.

Limitations of SGLT2 Inhibitor Therapy

• Increased risk of genito-urinary infections – Slight excess of UTIs but amenable to treatment, no

recurrence– Increase in genital infections, particularly in women or

those with history of genital infections• Risk of dehydration

– Some dehydration in patients with very high glucose levels ( osmotic diuresis)

– Very few cases of dehydration reported

Additional Benefit - Blood Pressure Reduction

• Well documented, consistent reduction of systolic blood pressure in clinical trials

• Probably triggered by osmotic diuresis

• Clinical value – Reduction in use/dose of anti-hypertensives ?– Cardiovascular risk reduction ?

Increased Risk for Cancer ?

• Bladder Cancer– 9 occurrences of bladder cancer in 5478 dapagliflozin recipients

(0.16%) versus 1 in 3156 (0.03%) for control– Of the 10 bladder cancer cases, 6 were associated with haematuria at

baseline and 5 of the cases were identified within the first year– Ascertainment bias ?

• Breast Cancer– 9 breast cancer cases in 2223 (0.4%) dapagliflozin recipients versus 1

in 1053 (0.1%) for control– All breast cancer cases were identified in the first year of treatment

• No overall imbalance in malignant tumours• No carcinogenic or genotoxic activity in preclinical studies

SGLT2-inhibitors : For which Patients? At What Stage of the Disease?

No in monotherapy

Yes: in dual therapy in some obese or hypertensive patients, mainly when DPP4-inhibitors fail

Yes: in triple oral therapy (when you want to avoid injections)

Type 2 Diabetes: the Usual Step-by-step Approach

Lifestyle changes

One oral agent

Two oral agents

Injections

Diabetes progression

Step 1

Step 2

Step 3

Courtesy of Bernard Charbonnel, MD

Yes: on the top of insulin when large doses of insulin fail

Type 2 Diabetes Treatment intensification : 3rd LineWhen Oral Dual Therapies Are Not Enough

HbA1c > 7-7.5 %

Metformin + Sulfonylurea/DPP4

Insulin

Injections

GLP1-agonists

Generally recommended

Dual oral

Courtesy of Clifford Bailey, PhD

Especially in obese and/or hypertensive patients, in whom insulin may not be the best option: risk of hypos, need for high doses…

An alternative to injections

Rather than adding Pioglitazone

Metformin + SUs/DPP4 + SGLT2-inhibitor

Triple oral therapy

1st step for everybody

When Basal Insulin Is Not Enough

Start with basal insulin

TitrationIf HbA1c 7.5%*, despite titration

Intensify insulin

Add SGLT2-inhibitor

*or an individualized target

The usual option

A very promising option

• Weight gain• Hypos• Large doses of insulin often needed

• Weight loss• A reduced risk of hypos• Reduced doses of insulin

Courtesy of Bernard Charbonnel, MD

Intensification of insulin therapy usually consists of additional prandial injections

Further Considerations - Diabetic Patient Groups for SGLT2 Inhibitor Treatment

Caution in •Elderly patients at risk of dehydration•Diabetic women with history of infections•Compromised renal function

– Eg, stage 3 or 4 of chronic kidney disease

Potential in type 1 diabetes ?•Reduce dose of insulin•Reduce frequency of hypoglycaemia

• Type 2 diabetes is progressive and difficult to control

• Tight glycaemic control is essential to reduce the burden of complications

• Insulin-dependent therapies address beta-cell failure and insulin resistance, but are limited by disease progression

• Insulin-independent therapies - such as SGLT2 inhibition - enable glucose-lowering and weight loss without increased propensity for hypoglycaemia

General Take-Home Messages