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

• Chair
• Clifford J. Bailey, PhD
• Professor of Clinical Science
• Head of Diabetes Research
• Life and Health Sciences
• Aston University
• Birmingham, United Kingdom
• Bernard Charbonnel, MD
• Professor of Endocrinology and Metabolic Diseases
  
• Head of Internal Medicine,
• Endocrinology and Diabetes
• University of Nantes
• Nantes, France

• Ele Ferrannini, MD
• Professor 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 Diseases
• Diabetes Centre
• Bad Lauterberg, Germany

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Introduction

• 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.

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Development and Progression of Type 2 Diabetes
Multiple Intervention Targets
IGT Impaired Glucose Tolerance
Image courtesy of Clifford Bailey, PhD
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Type 2 Diabetes Current Therapy Options
Insulin Resistance
ß-Cell Dysfunction
Diet, Exercise Treat lipids BP
Metformin TZDs
Sulphonylureas Meglitinides GLP-1 agonists DPP4
inhibitors
Pramlintide Bromocriptine Colesevelam
Hyperglycaemia
a-Cell Dysfunction
a-glucosidase inhibitors
Orlistat,
Insulin
Treatments for Obesity
Loss of ß-Cell Mass
Carbohydrate Digestion
Image courtesy of Clifford Bailey, PhD
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Available Medications Used to Get the HbA1c
Target (in 2011)

1. Metformin
2. Sulfonylureas/Glinides
3. TZDs (Pioglitazone)
4. a-glucosidase-inhibitors
5. DPP4-inhibitors
6. GLP1-agonists
7. Insulins
8. Coming-up SGLT2-inhibitors

Oral agents
injections
Courtesy of Bernard Charbonnel, MD
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Standard Therapies Metformin
Depends on a sufficient residual insulin secretion
Lifestyle changes Metformin for everybody
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 gt1
• Absence of weight gain and hypoglycaemia
• Possible cardiovascular protective effect
• Possible protective effect against cancer
• Safe low level of serious side effects
• Inexpensive

Courtesy of Bernard Charbonnel, MD
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Standard Therapies Sulfonylureas and Glinides

• 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
The generally recommended 2nd line drug (for
cost-effectiveness reasons)
Courtesy of Bernard Charbonnel, MD
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Standard Therapies TZDs (Pioglitazone)

• The most powerful on the long-term good
  durability
• No hypos
• A likely CV benefit in high CV risk patients
• But various adverse effects

Depends on a sufficient residual insulin secretion

• 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

In whom the benefits are likely to exceed the
risks
Courtesy of Bernard Charbonnel, MD
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Incretin-based Therapies

• DPP-4 inhibitors
• Sitagliptin
• Vildagliptin
• Saxagliptin
• Linagliptin
• In development
• Alogliptin

• GLP-1 receptor agonists
• Exenatide
• Liraglutide

Licensed in Japan
Courtesy of Clifford Bailey, PhD
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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

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Kidney and Glucose Homeostasis

• The Kidney
• Produces glucose
• Uses glucose
• Filters glucose
• Reabsorbs glucose

Courtesy of Clifford Bailey, PhD
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Location of Sodium Glucose Transporters in the
Kidney
S1 S2 segment SGLT2 (gt 90 glucose reabsorbed)
S3 segment SGLT1 (remaining 10 glucose
reabsorbed)
S1 S2 segment proximal renal tubule
S3 segment proximal renal tubule
Adapted from Bailey CJ, Day C. Br J Diabetes
Vasc Dis. 201010193-199.
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Sodium-Glucose Co-transporter-2 Inhibitors

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

Normally all filtered glucose reabsorbed
Diet
SGLT-1
Blood glucose
SGLT-2 SGLT-1
SGLT2 inhibitors Increase renal glucose
elimination
Normally no glucosuria
Courtesy of Clifford Bailey, PhD .
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Dapagliflozin Added to Metformin Mean Change in
HbA1c () and Body Weight (kg)
(n 137)
(n 137)
N 546
(n 137)
(n 135)
Weeks
Weeks
Body weight (kg) mean change from baseline
HbA1c () mean change from baseline
Week 24 (LOCF) change from baseline
From Bailey et al. Lancet. 20103752223-33.
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Dapagliflozin Monotherapy Canagliflozin Add-on
to Metformin
12 week ? from baseline Body Weight ()
Dapagliflozin
Canagliflozin
From List et al. Diabetes Care. 200932650-657.
Rosenstock et al. Diabetes. 201059(suppl
1)77-OR Abstract.
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Dapagliflozin Sustained Effects on HbA1c and
Body Weight Subjects with T2D with Inadequate
Glycaemic Control on Metformin
HbA1c ()
Body weight (kg)
Mean change from baseline
Mean change from baseline
N 75
N 65
N 64
N 70
Woo et al. Data presented at World Diabetes
Congress Dubai, UAE December 4, 2011.
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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

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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 ?

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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

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SGLT2-inhibitors For which Patients? At What
Stage of the Disease?
Type 2 Diabetes the Usual Step-by-step Approach
Yes on the top of insulin when large doses of
insulin fail
Injections
Step 3
Yes in triple oral therapy (when you want to
avoid injections)
Lifestyle changes
Two oral agents
Yes in dual therapy in some obese or
hypertensive patients, mainly when
DPP4-inhibitors fail
Step 2
One oral agent
Step 1
No in monotherapy
Diabetes progression
Courtesy of Bernard Charbonnel, MD
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Type 2 Diabetes Treatment intensification 3rd
LineWhen Oral Dual Therapies Are Not Enough
Dual oral
Metformin Sulfonylurea/DPP4
HbA1c gt 7-7.5
An alternative to injections
Injections
Triple oral therapy
Insulin
GLP1-agonists
Metformin SUs/DPP4 SGLT2-inhibitor
Generally recommended
Rather than adding Pioglitazone
Especially in obese and/or hypertensive patients,
in whom insulin may not be the best option risk
of hypos, need for high doses
Courtesy of Clifford Bailey, PhD
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When Basal Insulin Is Not Enough
Start with basal insulin
1st step for everybody
Titration
If HbA1c ? 7.5, despite titration
or an individualized target
Intensify insulin
Add SGLT2-inhibitor
The usual option
A very promising option
Intensification of insulin therapy usually
consists of additional prandial injections

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

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

Courtesy of Bernard Charbonnel, MD
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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

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General Take-Home Messages

• 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