updates in management of Diabetes mellitus

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]



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


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



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



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)



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





Metformin: May use unless condition is unstable or

severe Avoid TZDs ? Effects of incretin-based therapies





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





Most drugs not tested in advanced liver disease

Pioglitazone may help steatosis

Insulin best option if disease severe





Emerging concerns regarding association with increased mortality

Proper drug selection in the hypoglycemia prone



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

Health & Medicine

updates in management of Diabetes mellitus