‘Emerging Insulin-Independent Approaches for the
Management of Type 2 Diabetes’
Chair:
Clifford J. Bailey, PhD
Ele Ferrannini, MD
Professor of Clinical Science
Head of Diabetes Research
Life and Health Sciences
Aston University
Birmingham, United Kingdom
Professor of Internal Medicine,
Chief, Metabolism Unit
National Research Council Institute of
Clinical Physiology
University of Pisa
Pisa, Italy
Bernard Charbonnel, MD
Professor of Endocrinology and
Metabolic Diseases
Head of Internal Medicine,
Endocrinology and Diabetes
University of Nantes
Nantes, France
Michael Nauck, MD, PhD
Professor of Internal Medicine
Head, Specialist Clinic for
Diabetes and Metabolic Diseases
Diabetes Centre
Bad Lauterberg, Germany
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.
Development and Progression of Type 2 Diabetes:
Multiple Intervention Targets
Fasting
glucose
Glucose
tolerance
Hyperglycaemia
Abnormal glucose
tolerance
Glucagon
Insulin
resistance
Insulin
action
Insulin
secretion
Insulin
β-cell
compensation
Normal
IGT = Impaired Glucose Tolerance
Image courtesy of Clifford Bailey, PhD
β-cell
failure
IGT
T2DM
Blood
glucose
Type 2 Diabetes: Current Therapy Options
Insulin
Resistance
Diet, Exercise
Treat lipids + BP
Metformin
TZDs
β-Cell
Dysfunction
Sulphonylureas
Meglitinides
GLP-1 agonists
DPP4 inhibitors
Pramlintide
Bromocriptine
Colesevelam
α-Cell
Dysfunction
α-glucosidase
inhibitors
Carbohydrate
Digestion
Image courtesy of Clifford Bailey, PhD
Insulin
Loss of
β-Cell Mass
Orlistat,
Treatments for
Obesity
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
injections
8. Coming-up : SGLT2-inhibitors
Courtesy of Bernard Charbonnel, MD
Oral agents
Standard Therapies
Metformin
Diagnosis
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 >1%
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
Standard Therapies
Sulfonylureas and Glinides
•
•
•
•
•
•
•
Depends on a sufficient residual insulin secretion
Inexpensive
Rapid response
Poor durability
Risk of hypoglycemia
Weight gain
Perhaps excess risk for cancers
No evidence of a CV benefit
The generally recommended 2nd line drug
(for cost-effectiveness reasons)
Courtesy of Bernard Charbonnel, MD
Standard Therapies
TZDs (Pioglitazone)
• The most powerful on the longterm : 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
Incretin-based Therapies
DPP-4 inhibitors
GLP-1 receptor agonists
• Sitagliptin
• Exenatide
• Vildagliptin
• Liraglutide
• Saxagliptin
• Linagliptin
In development
• Alogliptin*
* Licensed in Japan
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
Kidney and Glucose Homeostasis
The Kidney
• Produces glucose
• Uses glucose
• Filters glucose
• Reabsorbs glucose
Courtesy of Clifford Bailey, PhD
Location of Sodium Glucose Transporters in the
Kidney
Glucose
S1 & S2 segment SGLT2
S3 segment SGLT1
(> 90% glucose reabsorbed)
(remaining 10% glucose
reabsorbed)
Glucose
Glucose
Glucose
Glucose
GLUT2
Na+
SGLT2
Na+
Lumen
Glucose
Na+
Glucose
GLUT1
Na+
SGLT1
K+
Epithelium
lining proximal
tubule
K+
2Na+
K+
Blood
S1 & S2 segment
proximal renal tubule
Adapted from Bailey CJ, Day C. Br J Diabetes Vasc Dis. 2010;10:193-199.
Na+
Lumen
Epithelium
lining proximal
tubule
K+
Blood
S3 segment
proximal renal tubule
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
Courtesy of Clifford Bailey, PhD
Normally no glucosuria
Dapagliflozin Added to Metformin
Mean Change in HbA1c (%) and Body Weight (kg)
(n = 137)
N = 546
(n = 137)
(n = 137)
(n = 135)
Weeks
Weeks
HbA1c (%)
Body weight (kg)
mean change from baseline
mean change from baseline
Week 24 (LOCF) change from baseline
From Bailey et al. Lancet. 2010;375:2223-33.
Dapagliflozin Monotherapy &
Canagliflozin Add-on to Metformin
12 week  from baseline Body Weight (%)
Dapagliflozin
From List et al. Diabetes Care. 2009;32:650-657.
Rosenstock et al. Diabetes. 2010;59(suppl 1):77-OR Abstract.
Canagliflozin
Dapagliflozin –
Sustained Effects on HbA1c and Body Weight
Subjects with T2D with Inadequate Glycaemic Control on Metformin
Body weight (kg)
Mean change from baseline
Mean change from baseline
HbA1c (%)
N = 75
N = 65
N = 64
N = 70
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?
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)
Two oral
agents
Lifestyle changes
Step 2
Yes: in dual therapy in some
obese or hypertensive patients,
mainly when DPP4-inhibitors fail
One oral agent
Step 1
Diabetes progression
Courtesy of Bernard Charbonnel, MD
No in monotherapy
Type 2 Diabetes Treatment intensification : 3rd Line
When Oral Dual Therapies Are Not Enough
Dual oral
Metformin +
Sulfonylurea/DPP4
HbA1c > 7-7.5 %
Triple oral therapy
Metformin + SUs/DPP4
+ SGLT2-inhibitor
An
alternative
to
injections
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
Injections
Insulin
GLP1-agonists
Generally recommended
When Basal Insulin Is Not Enough
1st step for
everybody
Start with basal insulin
Titration
If HbA1c  7.5%*, despite titration
*or an individualized target
Add SGLT2inhibitor
A very promising option
• Weight loss
• A reduced risk of hypos
• Reduced doses of insulin
Courtesy of Bernard Charbonnel, MD
Intensify
insulin
The usual option
Intensification of insulin therapy usually
consists of additional prandial injections
• Weight gain
• Hypos
• Large doses of insulin often needed
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
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