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Updates of T2DM Management
Alaa Wafa . MDAssociate Professor of Internal Medicine
PGDIP DM Cardiff University UKDiabetes & Endocrine Unit.
Mansoura University2014
Addressing The Pathogenesis of Poorly
Controlled T2DM
Pathogenesis of T2DM.........Few Years Ago
Insulinresistance
Genetic susceptibility,
obesity, Western lifestyle
Type 2 diabetes
IR b-celldysfunctionb
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
Decreasingβ-cell function
Inadequateβ-cell function
Postprandial glucoseFasting glucose
Insulin resistanceInsulin 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 pancreas Glycogen
GlucoseGlucagon stimulatesbreakdown 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
Endo
geno
us G
luco
se(µ
mol
/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
SufficientInsulin
Appropriate Glucagon
Unhealthy Pancreas
=Impaired GT
which likely progresses to
Type 2 DM
Pancreatic islet dysfunction
InsufficientInsulin
Excess Glucagon
Pancreatic Islet Function Determines Onset of IGT and T2DM in an Insulin-Resistant
Setting
+
-
-
peripheralglucose uptake
hepatic glucose production
pancreatic insulinsecretion
pancreatic glucagonsecretion
Main Pathophysiological Defects in T2DM
gutcarbohydratedelivery &absorption
incretineffect
HYPERGLYCEMIA?
Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 2011
Current Oral Therapies do not Cover All Disease Aspect
Pancreatic Islet Dysfunction
Inadequate glucagonsuppression(a-cell dysfunction)
Progressivedecline of β-cell function
Insufficient Insulin secretion (β-celldysfunction)
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 MellitusAdapted 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)
Progressivedecline 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 forNonpregnant 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:S11-63HDL = high-density lipoprotein; LDL = low-density lipoprotein; PG = plasma glucose; TG = triglycerides.
Lifestyle Changes
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 + InjectableIncretin 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 RecommendationsDiabetes Care 2012;35:1364–1379
Diabetologia 2012;55:1577–1596
T2DM Antihyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
T2DM Antihyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
T2DM Antihyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
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 cessationAdapted from American Diabetes Association. Diabetes Care. 2004;27(suppl 1):S15-S35.
Pharmacological Management
Pharmacologic Targets of Current Drugs Used in the Treatment of T2DM
26
a-glucosidase inhibitorsDelay intestinal carbohydrate absorption
ThiazolidinedioneDecrease lipolysis in adipose tissue, increase glucose uptake in skeletal muscle and decrease glucose production in liverSulfonylureas
Increase insulin secretion from pancreatic b-cells
GLP-1 analogsImprove pancreatic islet glucose sensing, slow gastric emptying, improve satiety
BiguanidesIncrease glucose uptakeand decreases hepatic glucose production
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.
GlinidesIncrease insulin secretion from pancreatic b-cells
DPP-4 inhibitorsProlong 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
Prop
ortio
n of
pat
ient
s (%
)
Placebo
Metformin
Drugs in this class
First generation• Chlorpropamide• Tolbutamide
(No longer recommended)
Second generation• 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
Gliclazide0.85
Glipizide8.70
Glimepiride0.86
Tolbutamide3.50
Chlorpropamide16.00
Glyburide16.00
Severe hypoglycemia*n/1000 person years =
Rel
ativ
e R
isk
(%)
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)
Acarbose
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
(Glitiazones)TZDs
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 translocationof GLUT-4 to cell surface
Increases synthesis ofGLUT-4-containing vesicles
GLUT-4 transporteron 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
7.26
15.3
1.22.1 2.5
7
0
2
4
6
8
10
12
14
16
18
Monotherapy Combinationwith SU
Combinationwith
metformin
Combinationwith insulin
Prop
ortio
n of
pat
ient
s (%
)
PioglitazonePlacebo or combination
Use of TZDs is Associated with Increased Incidence of Congestive Heart Failure
Num
ber o
f CH
F Ev
ents
P=0.01
CHF=congestive heart failure; TZDs=thiazolidinediones.Adapted from DREAM Trial Investigators, et al. Lancet. 2006; 368: 1096–1105.
P <0.000114
2
0
5
10
15
20
11
8
0
5
10
15
RosiglitazonePlacebo
Patie
nts
with
HF
(%)
Placebo Pioglitazone ≤45 mg daily
DREAM Study PROactive Study
DPP-4 inhibitors & GLP-1 Agonists
IV=intravenousAdapted from Nauck MA, et al. J Clin Endocrinol Metab. 1986; 63: 492–498.
Oral Glucose Tolerance Test and Matched IV Infusion
Plas
ma
Glu
cose
(mg/
dL)
0
50
100
150
200
–30 0 30 60 90 120 150 180 210Time (Min)
Plas
ma
Insu
lin (p
mol
/L)
0
100
200
300
400
–30 0 30 60 90 120 150 180 210Time (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 inGI tract in response to nutrients which in turn stimulates insulin secretion
• Predominant Hormones are: GLP-1 and GIP
GLP-1: Glucagon-like peptide-1GIP: 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
05
101520253035404550
Nausea Vomiting Diarrhoea
Prop
ortio
n of
pat
ient
s (%
)
Placebo (n=483)exenatide (n=963)
Inhibition of DPP-4 increases active GLP-1
GLP-1inactive
(>80% of pool)
ActiveGLP-1
Meal
DPP-4
IntestinalGLP-1 release
GLP-1 t½=1–2 min
DPP-4inhibitor
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 print]
4. OTHER CONSIDERATIONS•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 targetsHbA1c <7.5–8.0% if tighter
targets not easily achievedFocus on drug safety
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS•Weight
-Majority of T2DM patients overweight / obese-Intensive lifestyle program-Metformin-GLP-1 receptor agonists-? Bariatric surgery-Consider LADA in lean patients
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
T2DM Anti-hyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Adapted Recommendations: When Goal is to Avoid Weight GainDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
4. OTHER CONSIDERATIONS•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)
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS•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
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS•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
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS•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
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS•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
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
4. OTHER CONSIDERATIONS•Comorbidities
-Coronary Disease-Heart Failure-Renal disease-Liver dysfunction-Hypoglycemia
Emerging concerns regarding association with increased mortality
Proper drug selection in the hypoglycemia prone
Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
ADA-EASD Position Statement: Management of Hyperglycemia in T2DM
T2DM Anti-hyperglycemic Therapy: General RecommendationsDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Adapted Recommendations: When Goal is to Avoid HypoglycemiaDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Adapted Recommendations: When Goal is to Minimize CostsDiabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
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-1Glucose
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) AZUS: Approved Jan 2014, Launched Feb 2014EU: Approved Nov 2012, Launched Nov 2012JP: Approved Mar 2014
Invokana® (canagliflozin) Johnson & Johnson/MitsubishiTanabe
US: Launched in March 2013EU: 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 issuesEU: Received positive CHMP opinion in Mar 2014JP: Filed
Suglat® (ipragliflozin) Astellas/MerckUSA & EU: Discontinued developmentJP: Approved Jan 2014, Launch expected (Apr/May 2014)
Tofogliflozin (branded as Debelza® from Kowa, and Apleway® from Sanofi)
Kowa Pharmaceuticals/SanofiUS: No development since 2008EU: No development since 2008JP: Approved Mar 2014
Lusefi® (luseogliflozin) Taisho Pharmaceutical/ NovartisUS: No developmentEU: No developmentJP: Approved Mar 2014
Ertugliflozin (PF-04971729) Pfizer/Merck Global: Phase III Clinical Trial
Currently available SGLT2 inhibitors: Stages of development
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