updates in management of Diabetes mellitus

Updates of T2DM
Management
Alaa Wafa . MD
Associate Professor of Internal Medicine
PGDIP DM Cardiff University UK
Diabetes & Endocrine Unit.
Mansoura University
2014

Addressing The
Pathogenesis of Poorly
Controlled T2DM

Pathogenesis of T2DM.........Few Years
Ago
Insulin
resistance
Genetic
susceptibility,
obesity, Western
lifestyle
Type 2 diabetes
IR
b-cell
dysfunction
b
Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl. 3):3–13.
Insulin resistance and b-cell dysfunction was core defects of type
2 diabetes

Adapted from Type 2 Diabetes BASICS. International Diabetes Center; 2000.
β-cell function declines while insulin sensitivity
remains stable over course of T2DM
Diagnosis
Insulin
Glucose
Prediabetes
(IFG/IGT)
NGT Diabetes
Decreasing
β-cell function
Inadequate
β-cell function
Postprandial glucose
Fasting glucose
Insulin resistance
Insulin secretion

But It Is Now Clear That
 T2DM is a metabolic disorder characterized by
hyperglycemia, which arises from :
I. Insufficient pancreatic insulin secretion.
II. Insulin resistance in peripheral tissues.
III. Inadequate suppression of glucagon
production.
Spellman • Pathophysiology of Type 2 Diabetes: Targeting Islet Cell Dysfunction JAOA • Supplement 2 • Vol 110 • No 3 • March 2010

Action of glucagon
Low blood glucose promotes
glucagon release from
a-cells of pancreasGlycogen
Glucos
e
Glucagon stimulates
breakdown of glycogen
Raises blood glucose

Glycolysis
 Glycogenolysis
HGP: Hepatic Glucose Production.
Adapted from McMurry J, et al. Fundamentals of General, Organic, and Biological Chemistry. 4th ed. Upper Saddle River, NJ:Prentice Hall; 2006. Jiang
G and Zhang BB. Am J Physiol Endocrinol Metab 2003;284: E671-E678.
Glucagon Stimulation of Hepatocytes Leads
to Increased Hepatic Glucose Production
 HGP
Glucose
Glucagon
-
+
 Glycogenesis
 Gluconeogenesis
-
+


Glucagon is Important to Maintain
Adequate FPG Levels Between Meals
Adapted from Unger RH. Diabetes 1983;32:575-583.
α-Cell
Blood glucose
4 g/h
6 g/h
Glucagon
10 g/h
+
Glucose production = Glucose utilization

NGT=normal glucose tolerance; T2DM=type 2 diabetes mellitus.
Adapted from Kelley D, et al. Metabolism. 1994; 43: 1549–1557.
α-Cell Sensitivity to Glucose is Reduced in T2DM
Time (min)
–30 –15 0 30 60 90 120 150 180 210 240 270 300
Meal
2
6
10
14
18
EndogenousGlucose
(µmol/min/kg)
NGT (n=12)
T2DM (n=18)
Suppression of endogenous glucose production is impaired in T2DM

NGT = Normal Glucose Tolerance, IGT = Impaired Glucose Tolerance, T2DM= Type 2 Diabetes Mellitus
Insulin
resistance
Insulin
X
Reduced Glucose
uptake
More Insulin
needed to
compensate
More work for
b-cells
Unhealthy
lifestyle and
environment
al factors
Healthy
Pancreas
=
Normal
Glucose
Tolerance
(NGT)
Normal
pancreatic islet
function
Sufficient
Insulin
Appropriate
Glucagon
Unhealthy
Pancreas
=
Impaired GT
which likely
progresses to
Type 2 DM
Pancreatic islet
dysfunction
Insufficient
Insulin
Excess
Glucagon
Pancreatic Islet Function Determines Onset
of IGT and T2DM in an Insulin-Resistant
Setting

+
-
-
peripheral
glucose
uptake
hepatic
glucose
production
pancreatic
insulin
secretion
pancreatic
glucagon
secretion
Main Pathophysiological Defects in T2DM
gut
carbohydrate
delivery &
absorption
incretin
effect
HYPERGLYCEMIA
?
Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011

Current Oral Therapies do not Cover All
Disease Aspect
Pancreatic Islet Dysfunction
Inadequate
glucagon
suppression
(a-cell
dysfunction)
Progressive
decline of β-cell
function
Insufficient
Insulin secretion
(β-cell
dysfunction)
Sulfonylureas
Glinides
TZDs
Metformin
TZDs
No currently available therapy addresses a-cell function
(glucagon) and chronic b-cell function
Ins. Resistance
(Impaired insulin action)
TZD= Thiazolidinedione; T2DM= Type 2 Diabetes Mellitus
Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003;3(suppl 1):S24–S40

Weight of red arrows reflects the degree to which DPP-4 inhibitors influence the disease mechanisms.
DPP-4=dipeptidyl peptidase-4; TZD=thiazolidinedione.
Adapted from DeFronzo RA. Br J Diabetes Vasc Dis. 2003; 3(suppl 1): S24–S40.
Sulfonylureas
Glinides
TZDsMetformin
DPP-4 inhibitors
Pancreatic islet dysfunction
Inadequate
glucagon
suppression
(a-cell
dysfunction)
Progressive
decline of β-cell
function
Insufficient
insulin
secretion
(β-cell
dysfunction)
Insulin resistance
(impaired insulin action)
DPP-4 inhibitors influence both insulin
resistance and pancreatic islet dysfunction

Glycemic Recommendations for
Nonpregnant Adults with Diabetes
A1C <7.0%*
Preprandial capillary
plasma glucose
70–130 mg/dL*
(3.9–7.2 mmol/L)
Peak postprandial
capillary plasma glucose†
<180 mg/dL*
(<10.0 mmol/L)
*Individualize goals based on these values.
†Postprandial glucose measurements should be made 1–2 h after the beginning of the meal, generally
peak levels in patients with diabetes.
ADA. V. Diabetes Care. Diabetes Care 2013;36(suppl 1):S21; Table 9.

The General Goal is
<7% in most patients to
reduce the incidence of
microvascular disease
For selected individual patients, if this can be achieved
without significant hypoglycemia or other adverse
effects of treatment. Appropriate patients might include
those with short duration of diabetes, long life
expectancy, and no significant CVD.
<6.5%
For patients with a history of severe hypoglycemia,
limited life expectancy, advanced microvascular or
macrovascular complications, extensive comorbid
conditions, and those with long-standing diabetes in
whom the general goal is difficult to achieved
<8.0%
ADA 2013 Individualized Glycemic Goal

Guidelines for Glycemic, BP, & Lipid Control
American Diabetes Assoc. Goals
HbA1C < 7.0% (individualization)
Preprandial
glucose 70-130 mg/dL (3.9-7.2 mmol/l)
Postprandial
glucose < 180 mg/dL
Blood pressure < 130/80 mmHg
Lipids
LDL: < 100 mg/dL (2.59 mmol/l)
< 70 mg/dL (1.81 mmol/l) (with overt
CVD)
HDL: > 40 mg/dL (1.04 mmol/l)
> 50 mg/dL (1.30 mmol/l)
TG: < 150 mg/dL (1.69 mmol/l)ADA. Diabetes Care. 2012;35:S11-63
HDL = high-density lipoprotein; LDL = low-density
lipoprotein; PG = plasma glucose; TG = triglycerides.

Adapted from Riddle MC. Endocrinol Metab Clin North Am. 2005;34:77–98.
Diet and Exercise
Oral Monotherapy
Standard Approach to the Management
of T2DM: Treatment Intensification
Oral Combination +
+
Oral + Injectable
Incretin Mimetics
Oral + Insulin + +
Insulin

This algorithm also stratifies choice of
therapies based on initial A1c.
Garber AJ, et al. Endocr Pract. 2013;19(2):327-36.

Fig. 2. T2DM Antihyperglycemic Therapy: General Recommendations
Diabetes Care 2012;35:1364–1379
Diabetologia 2012;55:1577–1596

Initial drug
monotherapy
Efficacy (! HbA1c)
Hypoglycemia
Weight
Side effects
Costs
Healthy eating, weight control, increased physical activity
Metformin
high
low risk
neutral/loss
GI / lactic acidosis
low
If needed to reach individualized HbA1c target after ~3 months, proceed to 2-drug combination
(order not meant to denote any specific preference):
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Efficacy (! HbA1c)
Hypoglycemia
Weight
Major side effect(s)
Costs
high
low risk
gain
edema, HF,fx’s‡
high
Thiazolidine-
dione
intermediate
low risk
neutral
rare‡
high
DPP-4
Inhibitor
highest
high risk
gain
hypoglycemia‡
variable
Insulin (usually
basal)
Two drug
combinations*
Sulfonylurea†
+
Thiazolidine-
dione
+
DPP-4
Inhibitor
+
GLP-1 receptor
agonist
+
Insulin (usually
basal)
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
SU†
DPP-4-i
GLP-1-RA
Insulin§
SU† SU†
TZD TZD
TZD
DPP-4-i
Insulin§ Insulin§
If combination therapy that includes basal insulin has failed to achieve HbA1c target after 3-6 months,
proceed to a more complex insulin strategy, usually in combination with 1-2 non-insulin agents:
Insulin#
(multiple daily doses)
Three drug
combinations
More complex
insulin strategies
or
or
or
or
or
or
or
or
or
or
or
or GLP-1-RA
high
low risk
loss
GI‡
high
GLP-1 receptor
agonist
Sulfonylurea†
high
moderate risk
gain
hypoglycemia‡
low
T2DM Antihyperglycemic Therapy: General Recommendations
Diabetes Care, Diabetologia. 19 April 201
[Epub ahead of print]

Initial drug
monotherapy
Efficacy (! HbA1c)
Hypoglycemia
Weight
Side effects
Costs
Metformin
high
low risk
neutral/loss
low
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Efficacy (! HbA1c)
Hypoglycemia
Weight
Costs
high
low risk
gain
edema, HF,fx’s‡
high
Thiazolidine-
dione
intermediate
low risk
neutral
rare‡
high
DPP-4
Inhibitor
highest
high risk
gain
hypoglycemia‡
variable
Insulin (usually
basal)
Two drug
combinations*
Sulfonylurea†
+
Thiazolidine-
dione
+
DPP-4
Inhibitor
+
GLP-1 receptor
agonist
+
Insulin (usually
basal)
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
SU†
DPP-4-i
GLP-1-RA
Insulin§
SU† SU†
TZD TZD
TZD
DPP-4-i
Insulin§ Insulin§
Insulin#
Three drug
combinations
More complex
insulin strategies
or
or
or
or
or
or
or
or
or
or
or
or GLP-1-RA
high
low risk
loss
GI‡
high
GLP-1 receptor
agonist
Sulfonylurea†
high
moderate risk
gain
hypoglycemia‡
low
Diabetes Care, Diabetologia.
19 April 2012 [Epub ahead of print]

Non-pharmacological Management of
T2DM (Lifestyle interventions)
– Diet
• Decrease fat content and total calories
• Decrease saturated fat
• Decrease salt for hypertension
• Individualized diet
• Weight reduction in obese patients
– Exercise
• Increase energy expenditure with moderate-intensity
exercise
• Reduce cardiovascular risk factors
– Smoking cessation
Adapted from American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S15-S35.

Pharmacologic Targets of Current Drugs
Used in the Treatment of T2DM
26
a-glucosidase
inhibitors
Delay intestinal carbohydrate
absorption
Thiazolidinedione
Decrease lipolysis in adipose
tissue, increase glucose
uptake in skeletal muscle and
decrease glucose production
in liver
Sulfonylureas
Increase insulin secretion
from pancreatic b-cells
GLP-1 analogs
Improve pancreatic islet glucose sensing,
slow gastric emptying, improve satiety
DDP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1; T2DM=type 2 diabetes mellitus.
Adapted from Cheng AY, Fantus IG. CMAJ. 2005; 172: 213–226. Ahrén B, Foley JE. Int J Clin Pract. 2008; 62: 8–14.
Glinides
Increase insulin secretion
from pancreatic b-cells
DPP-4 inhibitors
Prolong GLP-1 action leading to improved
pancreatic islet glucose sensing, increase
glucose uptake

Why should metformin be initiated concurrently
with lifestyle intervention at diagnosis?
• For most individuals with Type 2 Diabetes, lifestyle
interventions fail to achieve or maintain the metabolic
goals either because of:
 Failure to lose weight
 Weight regain
 Progressive disease
 A combination of factors
28Adapted from Nathan DM, et al. Diabetes Care 2009;32:193-203.

Attributes of Metformin
29
How it works
• Decreases hepatic glucose output
• Increase glucose uptake from peripheral tissue and
liver
• Lowers fasting glycaemia
Efficacy • High
Adverse events
• GI side effects ( reduced by initiating treatment at a low
dose and gradually titrating )
• Lactic acidosis (extremely rare)
• Contraindications CKD and Heart failure
Advantages
• Extensive experience
• No weight gain
• No hypoglycemia
• Likely ↓ CVD events (UKPDS)
• Low cost

Gastrointestinal Adverse Events are
Common During Treatment with Metformin
Glucophage, Glucophage XR [prescribing information]. Princeton, NJ: Bristol-Myers Squibb Company; 2004.
8.3
25.5
Nausea/vomiting
11.7
53.2
Diarrhea
5.5
12.1
Flatulence
0
10
20
30
40
50
60
Proportionofpatients(%)
Placebo
Metformin

Drugs in this class
• Chlorpropamide
• Tolbutamide
(No longer recommended)
• Glipizide Glucotrol
• Gliclazide Diamicron
• Glibenclamide (glyburide)
Daonil
• Glimepiride (Amaryl )
Sulfonylureas were the first widely used oral anti-hyperglycaemic
medications. Many types of these pills have been marketed but not all
remain available.

SUs - Class overview
• SUs are the oldest class of OAD (first launched in ~1960’s)
reduce blood glucose levels primarily by acting on pancreatic
beta cells to stimulate pancreatic insulin secretion. This in
turn reduces hepatic glucose production and stimulates
glucose uptake by peripheral tissues, such as muscle.
• Sulfonylureas require the presence of functioning beta cells
that are capable of secreting insulin, and their action is not
dependent on glucose levels.
• Sulphonylureas bind to the sulphonlyurea receptors on the
surface of the pancreatic β cell which results in closure of the
potassium channel in the β cell. This results in opening of
voltage-dependent calcium channel ultimately resulting in the
exocytosis of insulin from the vesicles.

Pancreatic b cell
Sulphonylureas do not work in glucose-dependent
manner increasing risk of hypoglycemia
Adapted from: Cheng AYY, et al CMAJ. 2005; 172: 213–216.
* Levy AR et al. Health and Quality of Life Outcomes 2008, 6:73
• Increased secretion of insulin independently of glucose level
• Increased risk of hypoglycemia
• Chronic effect: weight gain due to defensive eating*
SU
K+
X
Release of insulin
Pancreas Insulin

How it works
• Stimulation of Insulin Secretion from Panc. B cell
• Accordingly, decrease hepatic Glucose release
Efficacy • High
Adverse events
• Hypoglycemia
• Wight gain
• B Cell Exhaustion
Advantages
• Extensive experience
•  Microvascular risk (related to glucose control)
• Low cost
Attributes of Sulphonylureas

Risk of hypoglycemia with different
sulfonylureas
*<50 mg/dL.
Tayek J. Diabetes Obes Metab. 2008; 10: 1128–1130.
0
5
10
15
20
25
30
Gliclazide
0.85
Glipizide
8.70
Glimepiride
0.86
Tolbutamide
3.50
Chlorpropamide
16.00
Glyburide
16.00
Severe hypoglycemia*
n/1000 person years =
RelativeRisk(%)

Meglitinides
 Meglitinides, stimulate insulin secretion in response to food,
and are designed to reduce postprandial hyperglycemia
without sustained insulin elevation (which might cause
hypoglycemia). There for it may be associated with less
hypoglycemia
 The meglitinides bind to (ATP)-dependent potassium
channels, which causes depolarization of the pancreatic
beta cells and opening of calcium channels.
 This allows calcium to enter the beta cells, stimulating
insulin secretion, which subsequently lowers blood glucose
levels.
 As with sulfonylureas, meglitinides require the presence of
functioning beta cells for their activity
Wallace TM, Matthews DR. The drug treatment of type 2 diabetes. In: Pickup JC, Williams G, eds. Textbook of Diabetes.
3rd ed. Malden, Mass: Blackwell Science Ltd; 2003: 45.6-45.12.
Nateglinide (Starlix) Repaglinide (NovoNorm)

How it works
• An agent that inhibits an intestinal enzyme, resulting
in reduced absorption of starches and sugars.
Efficacy • Modest
Adverse events • Gastrointestinal upset (Flatulence )
Advantages
• No Body weight gain
• No hypoglycemia
• ↓Post-prandial glucose
Attributes of Alpha Glucosidase Inhibitors

TZDs - Class overview
• TZDs have been on the market for over a decade and are
positioned as an early-stage treatment option for T2DM;
Availability of class wide SPCs with metformin strengthens
this position (Avandamet)
• The TZD drug class has been linked to a number of serious
adverse effects :
 Rosiglitazone was withdrawn in august 2010 after the publication of a
meta analysis that linked the drug to increasing the risk of MI in 2007
 Pioglitazone:
 Warning from FDA, Reconsideration from EMA due to increasing
risk of bladder cancer
 Fatal or non fatal liver failure (Strict liver test monitoring for enzyme
elevation with follow up each 3 months since pio is extensively
metabolized (around 79%) in the liver via CYT P 450)

TZDs-Cardiovascular risk
• TZDs have a black-box warning for risk of exacerbating
congestive heart failure
• TZDs can cause fluid retention which may
exacerbate or lead to heart failure
• TZDs are not recommended in patients with symptomatic
heart failure.
• Additionally, initiation of TZDs in patients with established
NYHA Class III or IV heart failure is contraindicated

Rosiglitazone enhances GLUT-4 production and
insulin-stimulated translocation in adipocytes
Glucose uptake
Rosiglitazone
Young PW, et al. Diabetes 1995; 44:1087–1092.
Increases
translocation
of GLUT-4 to
cell surface
Increases
synthesis of
GLUT-4-containing
vesicles
GLUT-4 transporter
on cell membraneInsulin

How it works
• Insulin sensitizers ,They increase peripheral Insulin
action on Skeletal Muscle
• Decrease hepatic Glucose production
Efficacy • High
Disadvantage
• Edema ,
• Weight Gain,
• Increases risk of CHF,
• Bone fracture,
• Increased risk of bladder cancer.
• High cost
Advantages
• No hypoglycemia
• Durability
• ↓TGs,↑HDL-C
Attributes of TZDs

Edema is Common During Treatment with
TZDs (Pioglitazone)
Actos [prescribing information]. Indianapolis, IN: Eli Lilly and Company, 2004.
4.8
7.2
6
15.3
1.2
2.1 2.5
7
0
2
4
6
8
10
12
14
16
18
Monotherapy Combination
with SU
Combination
with
metformin
Combination
with insulin
Pioglitazone
Placebo or combination

Use of TZDs is Associated with Increased
Incidence of Congestive Heart Failure
NumberofCHFEvents
P=0.01
CHF=congestive heart failure; TZDs=thiazolidinediones.
Adapted from DREAM Trial Investigators, et al. Lancet. 2006; 368: 1096–1105.
P <0.0001
14
2
0
5
10
15
20
11
8
0
5
10
15
Rosiglitazone
Placebo
PatientswithHF(%)
Placebo
Pioglitazone ≤45 mg daily
DREAM Study PROactive Study

DPP-4 inhibitors & GLP-1 Agonists

IV=intravenous
Adapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986; 63: 492–498.
Oral Glucose Tolerance Test and Matched IV Infusion
PlasmaGlucose(mg/dL)
0
50
100
150
200
–30 0 30 60 90 120 150 180 210
Time (Min)
PlasmaInsulin(pmol/L)
0
100
200
300
400
–30 0 30 60 90 120 150 180 210
Time (Min)
Proof of a Gastrointestinal ‘Incretin Effect’:
Different Responses to Oral vs IV Glucose
Oral IV
50 g Glucose
N=6

• Incretin Hormones are hormones produced in
GI tract in response to nutrients which in turn
stimulates insulin secretion
• Predominant Hormones are:
GLP-1 and GIP
GLP-1: Glucagon-like peptide-1
GIP: Glucose-dependent insulinotropic peptide
Incretin Hormones

Incretins, in Type 2 diabetes
In patients with Type 2 diabetes, the incretin effect is either
greatly impaired or absent, and it is assumed that this could
contribute to the inability of these patients to adjust their
insulin secretion to their needs
Diabetologia (2004) 47:357–366

Pharmacologic Approaches to
Enhancing GLP-1 Action in Diabetes
Drucker. Curr Pharm Des. 2001; Drucker. Mol Endocrinol. 2003
GLP-1 secretion is impaired in Type 2 diabetes
Natural GLP-1 has extremely short half-life
Add GLP-1 analogues
with longer half-life:
• exenatide
• liraglutide
Injectables
Block DPP-4, the
enzyme that degrades
GLP-1:
• Vildagliptin
• sitagliptin
Oral agents
DPP-4=dipeptidyl peptidase 4

Attributes of GLP-1 analogues
How it works
• Activates GLP-1 receptor
• ↑Insulin, ↓glucagon
• ↓ gastric emptying
• ↑satiety
Efficacy • High
Disadvantage
• GI
• ?↑ Pancreatitis
• Injectable
• High cost
Advantages
• Weight loss
• Low risk of hypoglycemia but relatively higher than
DPP-4 inhibitors
• ? ↑Beta cell mass
• ? CV protection

Attributes of DPP-4 inhibitors
How it works
• Inhibits DPP-4
• Increases GLP-1, GIP
Efficacy • Moderate to High (Glucose Dependent Manner)
Disadvantage
• ? Pancreatitis
• High cost
Advantages
• No hypoglycemia
• Well tolerated

New Approaches to Harnessing Incretins
for Improved Glucose Control
Two Approaches to Prolonging Incretin Activity
DPP-4 Inhibitors Incretin Mimetics
• Significant HbA1c reduction
• Weight neutral
• Oral administration
• Almost no GI side effects
• Very low rate of hypoglycemia
• Drug overdose not toxic
• Significant HbA1c reduction
• Weight loss
• Injection
• Higher rate in GI side effects
• Higher rate of hypoglycemia
• Drug overdose problematic
GI = Gastrointestinal

Gastrointestinal Adverse Events are Common
During Treatment with GLP-1 Analog (exenatide)
Byetta [prescribing information]. San Diego, CA: Amylin Pharmaceuticals Inc; 2005.
18
4
6
44
13 13
0
5
10
15
20
25
30
35
40
45
50
Nausea Vomiting Diarrhoea
Placebo (n=483)
exenatide (n=963)

Inhibition of DPP-4 increases active GLP-1
GLP-1
inactive
(>80% of pool)
Active
GLP-1
Meal
DPP-4
Intestinal
GLP-1
release
GLP-1 t½=1–2 min
DPP-4
inhibitor
DPP-4=dipeptidyl peptidase-4; GLP-1=glucagon-like peptide-1.
Adapted from Rothenberg P, et al. Diabetes. 2000; 49 (Suppl 1): A39. Abstract 160-OR.
Adapted from Deacon CF, et al. Diabetes. 1995; 44: 1126–1131.

Different Considerations Of
T2DM Management

ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS
• Age
• Weight
• Sex / racial / ethnic / genetic differences
• Comorbidities
- Coronary artery disease
- Heart Failure
- Chronic kidney disease
- Liver dysfunction
- Hypoglycemia
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of prin

• Age: Older adults
- Reduced life expectancy
- Higher CVD burden
- Reduced GFR
- At risk for adverse events from polypharmacy
- More likely to be compromised from hypoglycemia
Less ambitious targets
HbA1c <7.5–8.0% if tighter
targets not easily achieved
Focus on drug safety
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of
print]

• Weight
- Majority of T2DM patients overweight / obese
- Intensive lifestyle program
- Metformin
- GLP-1 receptor agonists
- ? Bariatric surgery
- Consider LADA in lean patients

Initial drug
monotherapy
Efficacy (! HbA1c)
Hypoglycemia
Weight
Side effects
Costs
Metformin
high
low risk
neutral/loss
low
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Efficacy (! HbA1c)
Hypoglycemia
Weight
Costs
high
low risk
gain
edema, HF,fx’s‡
high
Thiazolidine-
dione
intermediate
low risk
neutral
rare‡
high
DPP-4
Inhibitor
highest
high risk
gain
hypoglycemia‡
variable
Insulin (usually
basal)
Two drug
combinations*
Sulfonylurea†
+
Thiazolidine-
dione
+
DPP-4
Inhibitor
+
GLP-1 receptor
agonist
+
Insulin (usually
basal)
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
SU†
DPP-4-i
GLP-1-RA
Insulin§
SU† SU†
TZD TZD
TZD
DPP-4-i
Insulin§ Insulin§
Insulin#
Three drug
combinations
More complex
insulin strategies
or
or
or
or
or
or
or
or
or
or
or
or GLP-1-RA
high
low risk
loss
GI‡
high
GLP-1 receptor
agonist
Sulfonylurea†
high
moderate risk
gain
hypoglycemia‡
low
T2DM Anti-hyperglycemic Therapy: General Recommendations
Diabetes Care, Diabetologia. 19 April
2012 [Epub ahead of print]

Initial drug
monotherapy
Efficacy (! HbA1c)
Hypoglycemia
Weight
Side effects
Costs
Metformin
high
low risk
neutral/loss
low
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Efficacy (! HbA1c)
Hypoglycemia
Weight
Costs
high
low risk
gain
edema, HF,fx’s‡
high
Thiazolidine-
dione
intermediate
low risk
neutral
rare‡
high
DPP-4
Inhibitor
highest
high risk
gain
hypoglycemia‡
variable
Insulin (usually
basal)
Two drug
combinations*
Sulfonylurea†
+
Thiazolidine-
dione
+
DPP-4
Inhibitor
+
GLP-1 receptor
agonist
+
Insulin (usually
basal)
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
SU†
DPP-4-i
GLP-1-RA
Insulin§
SU† SU†
TZD TZD
TZD
DPP-4-i
Insulin§ Insulin§
Insulin#
Three drug
combinations
More complex
insulin strategies
or
or
or
or
or
or
or
or
or
or
or
or GLP-1-RA
high
low risk
loss
GI‡
high
GLP-1 receptor
agonist
Sulfonylurea†
high
moderate risk
gain
hypoglycemia‡
low
Adapted Recommendations: When Goal is to Avoid Weight Gain
Diabetes Care, Diabetologia. 19 April
2012 [Epub ahead of print]

• Sex/ethnic/racial/genetic differences
- Little is known
- MODY & other monogenic forms of diabetes
- Latinos: more insulin resistance
- East Asians: more beta cell dysfunction
- Gender may drive concerns about adverse effects
(e.g., bone loss from TZDs)

• Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Metformin: CVD benefit
(UKPDS)
 Avoid hypoglycemia
 ? SUs & ischemic
preconditioning
 ? Pioglitazone &  CVD events
 ? Effects of incretin-based
therapies

• Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Metformin: May use unless
condition is unstable or severe
 Avoid TZDs
 ? Effects of incretin-based
therapies

• Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Increased risk of hypoglycemia
 Metformin & lactic acidosis
 US: stop @SCr ≥ 1.5 (1.4
women)
 UK:  dose @GFR <45 &
stop @GFR <30
 Caution with SUs (esp. glyburide)
 DPP-4-i’s – dose adjust for most
 Avoid exenatide if GFR <30

• Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Most drugs not tested in
advanced liver disease
 Pioglitazone may help steatosis
 Insulin best option if disease
severe

• Comorbidities
- Coronary Disease
- Heart Failure
- Renal disease
- Liver dysfunction
- Hypoglycemia
 Emerging concerns regarding
association with increased
mortality
 Proper drug selection in the
hypoglycemia prone

Initial drug
monotherapy
Efficacy (! HbA1c)
Hypoglycemia
Weight
Side effects
Costs
Metformin
high
low risk
neutral/loss
low
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Efficacy (! HbA1c)
Hypoglycemia
Weight
Costs
high
low risk
gain
edema, HF,fx’s‡
high
Thiazolidine-
dione
intermediate
low risk
neutral
rare‡
high
DPP-4
Inhibitor
highest
high risk
gain
hypoglycemia‡
variable
Insulin (usually
basal)
Two drug
combinations*
Sulfonylurea†
+
Thiazolidine-
dione
+
DPP-4
Inhibitor
+
GLP-1 receptor
agonist
+
Insulin (usually
basal)
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
SU†
DPP-4-i
GLP-1-RA
Insulin§
SU† SU†
TZD TZD
TZD
DPP-4-i
Insulin§ Insulin§
Insulin#
Three drug
combinations
More complex
insulin strategies
or
or
or
or
or
or
or
or
or
or
or
or GLP-1-RA
high
low risk
loss
GI‡
high
GLP-1 receptor
agonist
Sulfonylurea†
high
moderate risk
gain
hypoglycemia‡
low
T2DM Anti-hyperglycemic Therapy: General Recommendations

Initial drug
monotherapy
Efficacy (! HbA1c)
Hypoglycemia
Weight
Side effects
Costs
Metformin
high
low risk
neutral/loss
low
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Efficacy (! HbA1c)
Hypoglycemia
Weight
Costs
high
low risk
gain
edema, HF,fx’s‡
high
Thiazolidine-
dione
intermediate
low risk
neutral
rare‡
high
DPP-4
Inhibitor
highest
high risk
gain
hypoglycemia‡
variable
Insulin (usually
basal)
Two drug
combinations*
Sulfonylurea†
+
Thiazolidine-
dione
+
DPP-4
Inhibitor
+
GLP-1 receptor
agonist
+
Insulin (usually
basal)
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
SU†
DPP-4-i
GLP-1-RA
Insulin§
SU† SU†
TZD TZD
TZD
DPP-4-i
Insulin§ Insulin§
Insulin#
Three drug
combinations
More complex
insulin strategies
or
or
or
or
or
or
or
or
or
or
or
or GLP-1-RA
high
low risk
loss
GI‡
high
GLP-1 receptor
agonist
Sulfonylurea†
high
moderate risk
gain
hypoglycemia‡
low
Adapted Recommendations: When Goal is to Avoid Hypoglycemia

Initial drug
monotherapy
Efficacy (! HbA1c)
Hypoglycemia
Weight
Side effects
Costs
Metformin
high
low risk
neutral/loss
low
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Efficacy (! HbA1c)
Hypoglycemia
Weight
Costs
high
low risk
gain
edema, HF,fx’s‡
high
Thiazolidine-
dione
intermediate
low risk
neutral
rare‡
high
DPP-4
Inhibitor
highest
high risk
gain
hypoglycemia‡
variable
Insulin (usually
basal)
Two drug
combinations*
Sulfonylurea†
+
Thiazolidine-
dione
+
DPP-4
Inhibitor
+
GLP-1 receptor
agonist
+
Insulin (usually
basal)
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
Metformin
+
TZD
DPP-4-i
GLP-1-RA
Insulin§
SU†
DPP-4-i
GLP-1-RA
Insulin§
SU† SU†
TZD TZD
TZD
DPP-4-i
Insulin§ Insulin§
Insulin#
Three drug
combinations
More complex
insulin strategies
or
or
or
or
or
or
or
or
or
or
or
or GLP-1-RA
high
low risk
loss
GI‡
high
GLP-1 receptor
agonist
Sulfonylurea†
high
moderate risk
gain
hypoglycemia‡
low
Adapted Recommendations: When Goal is to Minimize Costs

Amylin Analogs
• Amylin is a peptide normally secreted by beta cells at the
same time as insulin.
• It has been observed that in patients with type 1 diabetes,
amylin is almost absent and, in advanced type 2 diabetes,
levels are reduced.
• Mechanism of action
– Activates amylin receptor
–  glucagon
–  gastric emptying
–  satiety
• The drug is injected subcutaneously before meals.
A consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the
European Association for the Study of Diabetes. Diabetes Care. 2006;29:1963-1972
[Text_Diab_Chp 73] Bailey CJ. New approaches to the pharmacotherapy of diabetes. In: Pickup JC, Williams G, eds. Textbook of Diabetes. 3rd
ed. Malden, Mass: Blackwell Science Ltd; 2003:73.1-73.18.

SGLT2 Inhibitors
• One emerging novel therapeutic class of antidiabetic drugs is
sodium glucose cotransporter 2 (SGLT2) inhibitors. SGLT2
accounts for 90% of the glucose reabsorption in the kidney.
• The SGLT2 inhibitors increase urinary excretion of glucose
and lower plasma glucose levels in an insulin-independent
manner.

The human kidney is involved in the
regulation of glucose homeostasis via :
Release of glucose
into the circulation via
gluconeogenesis1
Glucose reabsorption
into the circulation
from glomerular
filtrate to conserve
glucose carbon1
Glucose utilization
from the circulation to
satisfy its energy
needs1
About 40% to 50% of
the insulin reaching
the circulation is
metabolized by the
kidney , A process that
is obviously
compromised in
patients with renal
failure2
1Gerich JE. Diabet Med. 2010 Feb;27(2):136-42; 2 Russo E, et al. Diabetes Metab Syndr Obes. 2013; 6: 161–170.

Majority of glucose is
reabsorbed by SGLT2
(90%)
Glucose
filtration
Proximal tubule
Remaining glucose
is reabsorbed by
SGLT1 (10%)
Minimal to no
glucose
excretion
Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-18; Lee YJ et al. Kidney Int Suppl. 2007;106:S27-35; Hummel CS et al. Am J Physiol
Cell Physiol. 2011;300:C14-21
SGLT, sodium-glucose co-transporter
Normal renal glucose handling
About 180
g/day glucose
is filtered. All
of the filtered
glucose is re-
absorbed

SGLT-1 vs. SGLT-2
SGLT-1 SGLT-2
Glucose
reabsorption
10% of glucose
reabsorption
90% of glucose
reabsorption
Substrate Glucose, Galactose Glucose only
Tissue distribution Intestine (mostly),
Kidney (to a lesser
extent)
Kidney (mostly)
Glucose release into
the circulation by
GLUT1 GLUT2
Gerich JE. Diabet Med. 2010 Feb;27(2):136-42.

Inhibition of SGLT-2
Glucose
filtration
Proximal tubule
Inhibition of SGLT-1
Glucose
excretion
(Glucosuria)
Wright EM. Am J Physiol Renal Physiol. 2001;280:F10-18; Lee YJ et al. Kidney Int Suppl. 2007;106:S27-35; Hummel CS et al. Am J Physiol
Cell Physiol. 2011;300:C14-21
SGLT, sodium-glucose co-transporter
MOA of SGLT inhibitors

Compound Company Stages of development
Forxiga®
/Farxiga®
(dapagliflozin) AZ
US: Approved Jan 2014, Launched Feb 2014
EU: Approved Nov 2012, Launched Nov 2012
JP: Approved Mar 2014
Invokana®
(canagliflozin)
Johnson & Johnson/Mitsubishi
Tanabe
US: Launched in March 2013
EU: Roll-out continues (launched in UK)
JP: Awaiting approval by Q2/Q3 2014
Jardiance®
(empagliflozin) Boehringer Ingelheim/Eli Lilly
US: File rejected (Mar 2014) due to BI’s
manufacturing site issues
EU: Received positive CHMP opinion in Mar 2014
JP: Filed
Suglat®
(ipragliflozin) Astellas/Merck
USA & EU: Discontinued development
JP: Approved Jan 2014, Launch expected
(Apr/May 2014)
Tofogliflozin (branded as Debelza®
from Kowa, and Apleway®
from
Sanofi)
Kowa Pharmaceuticals/Sanofi
US: No development since 2008
EU: No development since 2008
Lusefi®
(luseogliflozin) Taisho Pharmaceutical/ Novartis
US: No development
EU: No development
Ertugliflozin (PF-04971729) Pfizer/Merck Global: Phase III Clinical Trial
Currently available SGLT2 inhibitors:
Stages of development

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