Glucose Regulation in Diabetes - ptce.s3.amazonaws.com€¦ · Type 2 Diabetes Mellitus: Targeted Pharmacotherapy Curtis Triplitt, PharmD, CDE ... OMINOUS OCTET Increased Lipolysis

Achieving Glucose Balance in

Type 2 Diabetes Mellitus:

Targeted Pharmacotherapy

Curtis Triplitt, PharmD, CDE

Texas Diabetes Institute

Assistant Professor, Medicine/Diabetes

University of Texas Health Science Center

at San Antonio

2

Faculty InformationPresenter




University of Texas Health Science Center at San Antonio

San Antonio, TX

Moderator

Elena Beyzarov, PharmD

Director, Scientific Affairs

Pharmacy Times Office of Continuing Professional Education

This activity is supported by an educational grant from

Bristol-Myers Squibb and AstraZeneca LP.

3

DisclosuresCurtis Triplitt, PharmD, CDE, has disclosed the following commercial financial relationships:

Consultant/Advisory Board: Roche, Takeda Pharmaceuticals

Speakers’ Bureau: Amylin, Eli Lilly, Pfizer

Pharmacy Times Office of Continuing Professional Education

Planning Staff—Judy V. Lum, MPA; Elena Beyzarov, PharmD; Jennifer Barrio; and Donna

W. Fausak— have no financial relationships with commercial interests to disclose related to

this activity.

The American Journal of Managed Care

Planning Staff—Jeff D. Prescott, PharmD, RPh; Kara Guarini, MS; Ida Delmendo; and

Christina Doong— have no financial relationships with commercial interests to disclose

related to this activity.

The contents of this webinar may include information regarding the use of products that may

be inconsistent with or outside the approved labeling for these products in the United States.

Pharmacists should note that the use of these products outside current approved labeling is

considered experimental and are advised to consult prescribing information for these

products.

4

Educational Objectives

After completion of this activity, participants should be

better able to:

•Describe the mechanisms of action of currently available

pharmacologic options for the management of type 2 diabetes

mellitus

•Address the pharmacologic target and outcome associated with

each medication

•Review emerging antidiabetic agents, their role in diabetes

management, and how they will address defects in glucose

regulation

5

Pharmacy Accreditation

Pharmacy Times Office of Continuing

Professional Education is accredited by the

Accreditation Council for Pharmacy Education

(ACPE) as a provider of continuing pharmacy

education. This activity is approved for 1 contact

hour (0.1 CEU) under the ACPE universal activity

number 0290-0000-11-061-H01-P. This activity is

available for CE credit through January 25, 2014.

Type of Activity: Knowledge

Achieving Glucose Balance in

Type 2 Diabetes Mellitus:





University of Texas Health Science Center

at San Antonio

IncreasedHGP

Hyperglycemia

ETIOLOGY OF T2DM

DEFN75-3/99 Decreased GlucoseUptake

Impaired InsulinSecretion Increased Lipolysis

HYPERGLYCEMIA

DecreasedIncretin Effect

Decreased InsulinSecretion

Increased

HGP

Islet–a cell

IncreasedGlucagonSecretion

OMINOUS OCTET

IncreasedLipolysis

Increased

Glucose

Reabsorption

NeurotransmitterDysfunction

Decreased

Glucose Uptake

7Reprinted with permission from DeFronzo RA. Diabetes.

2009;58:773-795.

Management of Diabetes• Nonpharmacologic Therapy

• Pharmacologic Therapy– Sulfonylureas: many

– Biguanides: metformin

– Thiazolidinediones: pioglitazone, rosiglitazone

– Meglitinides (insulin secretagogues): repaglinide, nateglinide

– a-glucosidase inhibitors: acarbose, miglitol

– Insulins

– Incretin Therapy

• Mimetics (GLP-1 agonists): exenatide, liraglutide

• DPP-4 inhibitors: sitagliptin, saxagliptin, linagliptin

– Bile acid sequestrants: colesevelam

– Dopamine agonists: bromocriptine

– Amylinomimetics: pramlintide8

Antihyperglycemic Agents:

Pharmacologic ActionDrug Class Mechanism of action

Sulfonylureas/meglitinides Increase insulin release via pancreatic β-cell stimulation

Biguanides Reduce hepatic glucose output, increase insulin sensitivity

Thiazolidinediones Increase sensitivity of muscle, fat, and liver to insulin

Alpha-glucosidase inhibitors Reduce rate of polysaccharide digestion in proximal small intestine,

primarily lowering postprandial glucose levels

Glucagon-like peptide-1 receptor agonists bind to GLP-1 receptor on pancreatic beta-cells to augment glucose-mediated

insulin secretion

dipeptidyl peptidase-4 inhibitors Prolong effects of GLP-1 and GIP, increasing glucose-mediated insulin secretion

and suppressing glucagon secretion

Amylin agonists Mimic beta-cell hormone amylin, which known to inhibit postprandial glucagon

secretion, slow rate of gastric emptying

Bile acid sequestrants Delay/alter absorption of glucose from intestines

dopamine-2 receptor agonists

Enhance suppression of hepatic glucose production, lowering postmeal plasma

glucose levels

Sulfonylureas and Meglitinides

• Mechanism of Action

– Increase insulin release via pancreatic β-cell

stimulation

– Insulin helps to decrease hepatic glucose

production (decreases fasting blood glucose)

– May increase muscle glucose uptake slightly

through decrease in ―glucotoxicity‖

• Sulfonylureas

– Long half-life, long duration of action

• Meglitinides

– Short half-life, short duration of action 10

-50

0

50

100

150

200

250

300

Time (hours)

DF

rom

Ba

se

lin

e in

In

su

lin

AU

C0–

12

h(p

mo

l/L

)

10 1260 31 2 4 5 7 8 9 11

P < 0.05 GLY & NAT vs. placebo.P < 0.05 GLY vs. NAT.

Adapted from Hollander PA, et al. Diabetes Care. 2001;24:983-988.

Nateglinide Stimulates Early

Insulin

to Mimic Normal Physiology

NAT 120 mg (n = 51)

GLY 10 mg (n = 50)

Placebo (n = 51)

GLY

Placebo

NAT

Pancreatic β Cell

Glucose-Stimulated Secretion of Insulin

AC

+GLP-1

GIP

+

AC = adenylyl cyclase; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; GK = glucokinase; GLUT2 = glucose transporter; SUR = sulfonylurea receptor; TCA = tricarboxylic acid (Krebs cycle).

Hinke SA, et al. J Physiol. 2004;558:369-380.

Henquin JC. Diabetes. 2000;49:1751-1760.

Henquin JC. Diabetes. 2004;53(suppl 3):S48-S58.

K+Potassium

channel

SUR

cAMP

ATP

Amplifying

GLUT2Glucose

ATP

Pyruvate

GK

TCA

Cycle*

Glucose

Insulin

[Ca2+]

Triggering

Calcium

channel

Tan (n = 297)PERISCOPE (n = 181)

Hanefeld (n = 250)

Chicago (n = 230)UKPDS (n = 1573)

ADOPT (n = 1441)

Sulfonylureas

Change in A

IC (

%)

Glyburide

Glyburide

-2

-1

0

0 1 2 3 4 5 6 10

Glimepiride

Glyburide

Gliclazide

Glyburide

Thiazolidinediones

-2

-1

0

Change in A

IC (

%)

0 1 2 3 4 5 6

Durability of Glycemic Control:

Assessed by Serial A1C

PIO

Pioglitazone (PIO) Rosiglitazone

PIO

PIO

Adapted from DeFronzo RA. Diabetes. 2009;58:773-795.

13

Time (years)Time (years)

Insulin Resistance

Etiology of β -Cell Failure in T2DM

Genetics

(TCF7L2

protein)

Age

β-CellFailure

Lipotoxicity

Free Fatty Acids

Glucose

Toxicity

Amyloid (IAPP)Deposition

Incretin

Effect

14

Lipotoxicity

● Elevated plasma free fatty acids (FFAs)

● Increased tissue fat content

● Altered fat storage

● ―Sick‖ fat cell

15

Thiazolidinediones and Preservation

of β-Cell Function

● Direct effect on the β-cell (PPARg)

● Amelioration of insulin resistance

● Reduction in plasma FFAs (lipotoxicity)

● Mobilization of toxic lipid metabolites

(FACoA, DAG, ceramides) out of the β-cell

(lipotoxicity)

● Reversal of glucotoxicity

16

17

Effect of Pioglitazone in Patients

With Nonalcoholic Steatohepatitis

(NASH)

Subjects: 55 T2DM/IGT with biopsy-proven NASH

Age = 55 y, BMI = 32.1, % Body Fat = 35

FPG = 117 mg/dl, AIC = 6.2%

ALT = 53 U/L, AST = 39 U/L

Measurements:

Study Design: Randomized, placebo-controlled, double blind

Diet (-500 cal) + Placebo vs Diet + Pioglitazone

Placebo run-in (4 wks) PIO, 45 mg/d x 24 wks

Liver biopsy

Liver function tests, liver fat (MRS)

OGTT, adipocytokines

Before/after 24 weeksBelfort R, et al. N Engl J Med. 2006;355:2297-2307.

18

Steatosis

Inflammation

0

0.5

1

1.5

2

Before After

Pioglitazone

Before After

Placebo

*

¶

P = .008

Ballooning Necrosis

0

0.5

1

1.5

2

Before After

Pioglitazone

Before After

Placebo

**

P = .019

Fibrosis

P =.003

0

0.5

1

1.5

2

*

Before AfterPioglitazone

Before AfterPlacebo

0

0.5

1

1.5

2

Before AfterPioglitazone

Before AfterPlacebo

†

P = .08

Effect of Pioglitazone on Liver Histology

19

Reprinted with

permission from Belfort

R, et al. N Engl J Med.

2006;355:2297-2307.

Mea

n sco

re

Mea

n sco

re

Mea

n sco

re

Mea

n sco

re

Patient with 2 grade steatosis and inflammation-necrosis improvement

Effect of Pioglitazone on Liver

Steatosis in NASHPretreatment biopsy After treatment

biopsy

100x, H&E stain Belfort R, et al. N Engl J Med. 2006;355:2297-2307.

Glitazones: Documented Issues

• Fluid retention

– Edema, congestive heart failure (CHF) risk

• CHF

– Black box warning for use in NYHA class III and IV

• Signs and symptoms: short of breath, dyspnea on exertion,

peripheral edema, sleeping on more pillows than normal

• Fracture risk: osteocyte, osteoclast, osteoblast effect

– Do not use in documented osteoporosis, consider risk/benefit in post-

menopausal women

Rosiglitazone: ischemic events, restricted use

Pioglitazone: bladder carcinoma, 3 extra cases in 10,000 patient/year

exposure

Actos [package insert]. East Hanover, NJ: Takeda Pharmaceuticals America, Inc; 2011.

Avandia [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011.

IncreasedHGP

Hyperglycemia

ETIOLOGY OF T2DM



HYPERGLYCEMIA



Increased

HGP

Islet–a cell


OMINOUS OCTET

IncreasedLipolysis

Increased

Glucose

Reabsorption


Decreased Glucose

Uptake


2009;58:773-795.

Liver and Kidney

• Liver: Major source of net endogenous glucose

production

– Kidney: potentially responsible for 10% to 15% of fasting

glucose production

• Accomplished by gluconeogenesis and

glycogenolysis when glucose levels are low

• Glycogen synthesis when glucose levels are high

• Can oxidize glucose for energy and convert to fat;

may be incorporated into VLDL for transport. 23

Regulation of Hepatic Glucose

Production

DECREASE INCREASE

0

Parasympathetic

system

Hyperglycemia

Insulin

FFA

Cortisol

Glucagon

Epinephrine

Growth Hormone

Sympathetic system

24

In general, monotherapy, most

commonly involving metformin or

sulfonylureas, may not have durable

effects in advancing hyperglycemia

Kaplan-Meier Plot of Secondary Failure of Metformin

Monotherapy (n =1051) by Categories of Duration

of Diabetes at Metformin Initiation

0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60

0-3 Months

12.2% year

24-35 Months

18.4% year

>36 Months

21.9% year

12-23 Months

21.4% year

4-11 Months

17.7% year

Months on Metformin

Pro

po

rtio

n N

ot

Ex

pe

rie

nc

ing

Se

co

nd

ary

Fa

ilu

re

Reprinted with permission from JB Brown, et al.

Diabetes Care. 2010;33:501-506.

0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60

<7%

12.3% year

>9.0%

19.4% year

8-8.9%

19.2% year

7-7.9%

17.8% year

Months on Metformin

Pro

po

rtio

n N

ot

Ex

pe

rie

nc

ing

Se

co

nd

ary

Fa

ilu

re

Kaplan-Meier Plot of Secondary Failure of Metformin

Monotherapy (n = 1051) by Categories of A1C at

Metformin Initiation

Reprinted with permission from JB Brown, et al.

Diabetes Care. 2010;33:501-506.

0

4

8

12

25-44 (n=1000) 45-59 (n=1586) > 60 (n=648)

Lifestyle Metformin Placebo

Diabetes Incidence Rates by Age

Age (years)Knowler WC, et al; for the Diabetes Prevention Program Research Group. N Engl J Med. 2002;346:393-403.

Cases/1

00 p

ers

on

-yr

28

0

4

8

12

16

22 - < 30 30 - < 35 > 35

Ca

se

s/1

00

pe

rso

n-y

r Lifestyle Metformin Placebo

Diabetes Incidence Rates by BMI

Body Mass Index (kg/m2)Knowler WC, et al; for the Diabetes Prevention

Program Research Group. N Engl J Med. 2002;346:393-403.

Time (min) From Start of Mixed Meal

Mixed Meal (With ~85 g Dextrose)

0 120 240 360 480

-0.6

-0.4

-0.2

0

0.2

0.4

0.6G

ram

s o

f G

luco

se

Flu

x/m

in

-30

Calculated from data in Pehling G, et al. J Clin Invest. 1984;74:985-991.

Insulin-mediated

glucose uptake

Balance of insulin

stimulation and glucagon

suppression

Regulated by hormones:

amylin, CCK, GLP-1, GIP

Meal-derived glucose

Hepatic glucose production

Total glucose uptake

Multihormonal Regulation of Glucose

Appearance and Disappearance

30

Contribution of Basal Glucagon Levels to the Maintenance of Basal Hepatic Glucose Production (HGP) in Type 2 Diabetic Subjects

Baron AD, et al. Diabetes. 1987;36:274-283.

0

50

100

150

200

250

Pla

sm

a G

luca

go

n (p

g/m

l)Basal H

GP

(m

g/m

2X

min

)

0

40

80

120

160

BASAL BASAL

CON DIAB DIAB-Somatostatin

P <.001

58%

CON DIAB DIAB-Somatostatin

P <.001

44%

Time After Sustacal Meal, min

0

5

10

15

20

-30 0 30 60 90 120 150 180

Pla

sm

a A

mylin

, p

mo

l/L

Meal

T1DM (n = 190)

Insulin-using T2DM (n = 27)

Without diabetes (n = 27)

Amylin Is Cosecreted With Insulin

and Deficient in Diabetes

Pla

sm

a In

su

lin,

pm

ol/L

30

25

20

15

10

5

Time, 24 h

600

400

200

0

Meal Meal Meal

Amylin

Insulin

Pla

sm

a A

mylin

, pm

ol/L

Healthy male adults (n = 6)

7 AM Midnight5 PM12 Noon

Central satiety, decreases glucagon, slows gastric emptying

Reprinted with permission from Kruger DF, et al. Diabetes Educ. 1999;25:389-397.

32

33

Effect of Pramlintide on Postprandial Glucagon

Type 1 Diabetes2

Time, h

Placebo

Pramlintide

Infusion of 25 µg/h pramlintide or placebo

-20

0

10

20

30

-10

InsulinMeal

0 2 3 4 51

Type 2 Diabetes, Late Stage1

Time, h

Pla

sm

a G

luca

go

n, p

g/m

L

InsulinMeal

60

40

30

50

Infusion of 100 µg/h pramlintide or placebo

0 1 2 3 4

DP

lasm

a G

luca

go

n, p

g/m

LT2DM: AUC1–4 h: P = .005.

T1DM: AUC1–5 h: P <.001.

1. Adapted with permission from Fineman M, et al. Horm Metab Res. 2002;34:504-508.

2. Adapted with permission from Fineman M, et al. Metabolism. 2002;51:636-641.

N = 12 N = 9

Open-Label Extension

Baseline A1C = 8.3%

Time Course of Effect of Exenatide on A1C

Time (weeks)

D A

1C

(%

)

0 20 40 60 80 156

-2.0

-1.0

0

0.5

Placebo-Controlled

Trials

Exenatide-

10 g bid

Placebo

Exenatide

10 g bid

Data on file. Amylin Pharmaceuticals; DeFronzo et al.

Diabetes Care.2005;28:1092-1100.

34

Thyroid: No Signal With Liraglutide

Out to 104 Weeks

Center for Drug Evaluation and Research. Application Number: 22-341. NDA for Victoza (Liraglutide [rDNA]) Injection. Novo Nordisk, Inc.

Adapted from Ahren B, et al. J Clin Endocrinol Metab.2004;89:2078-2084.

Effect of Vildagliptin on Plasma Glucose and Hormone

Levels in Diet-Treated Patients With T2DM

Time (min)

00 60 120

125

275

Glucose

Insulin

Vildagliptin

(n = 18)

Placebo

(n = 19)

Vildagliptin

Placebo

pm

ol/L

mg

/dL

60

80

100

120

0 60 120

GLP-1

Glucagon

0

10

20

Placebo

pm

ol/L

pg

/mL

Vildagliptin

Placebo

Vildagliptin

175

225

100

200

300

Physiologic

Pharmacologic levels

DPP-4

inhibitor

Incretin Mimetics

Pla

sm

a G

LP

-1 o

r G

LP

-1 R

“Activity”

Satiety

Weight Loss

Gastric Emptying Delay

Injectable

No Satiety Effect

Weight Neutral

No Gastric Emptying

Delay

Oral Medication

DPP-4 Inhibitors vs Incretin Mimetics

37

IncreasedHGP

Hyperglycemia

ETIOLOGY OF T2DM



HYPERGLYCEMIA



Increased

HGP

Islet–a cell


OMINOUS OCTET

IncreasedLipolysis

Increased

Glucose

Reabsorption


Decreased Glucose

Uptake


2009;58:773-795.

SGLT1

SGLT 2

Renal Handling of Glucose

(180 L/day) (900 mg/L) = 162 g/day

10%

90%

Glucose

NOGLUCOSE

S1

S3

39Adapted from Basile J. Postgrad Med. 2011;123(4):38-45.

Effect of Dapagliflozin in

Metformin-Treated T2DM Patients

Bailey CJ, et al. Lancet. 2010;375:2223-2233.

Age = 54 y BMI = 31.5 kg/m2

Metformin-treated

Diabetes duration = 6.1 years

A1C = 8.0% FPG = 163 mg/dL

Subjects:

Randomized, placebo-controlled (n = 546)

Placebo vs dapagliflozin 2.5, 5, 10 mg/day

24 weeks

Study Design:

A1CPrimary End Point:

Change in body weight, lipids, blood pressure

Hypoglycemia

Adverse events

Secondary End Points:

40

C

ha

ng

e in

A1

C (

%)

Pla

ceb

o

-0.3

DA

PA

2.5

mg

-0.67-0.70

-0.84

DA

PA

5 m

g

DA

PA

10 m

g

-1.0

-0.8

-0.6

-0.4

-0.2

0

Effect of Dapagliflozin on A1C and Body

Weight in Metformin-Treated T2DM Patients

Ch

an

ge

in

BW

(k

g)

Pla

ceb

o

-0.9

DA

PA

2.5

mg

DA

PA

5 m

g

DA

PA

10 m

g

-3

-2

-1

0

-2.2

-3.0-2.9

Bailey CJ, et al. Lancet. 2010;375:2223-2233. 41

Effect of Dapagliflozin on Serum Lipids

In Metformin-Treated T2DM Patients

0

1

2

3

4

5

Inc

rem

en

t in

HD

L C

ho

l (%

)

0.4 DA

PA

2.5

mg

1.8

3.3

4.4

DA

PA

5 m

g

DA

PA

10 m

g

Placebo-6

-4

-2

0

22.1

DA

PA

2.5

mg

DA

PA

5 m

g

DA

PA

10 m

g

-2.4

-6.2 -6.2

Placebo

Ch

an

ge

in

Tri

gly

ce

rid

e (

%)

Bailey CJ, et al. Lancet. 2010;375:2223-2233.42

-5

-4

-3

-2

-1

0

Effect of Dapagliflozin on Blood Pressure

in Metformin-Treated T2DM Patients

Bailey CJ, et al. Lancet. 2010;375:2223-2233.

D

Sys

tolic

BP

D

Dia

sto

lic

BP

-5

-4

-3

-2

-1

0Placebo

-0.2

Placebo

-0.1

DA

PA

2.5

mg

-2.1

-4.3

-5.1

DA

PA

5 m

g

DA

PA

10 m

g

DA

PA

2.5

mg

DA

PA

5 m

g

DA

PA

10 m

g

43

Safety Considerations

● Urinary tract infection

● Intravascular volume depletion (osmotic diuresis)

● Electrolyte imbalance (Na+, K+, Ca++, PO43-)

● Nephrotoxicity (AGEs)

● Nocturia

● Drug-drug interactions

44

Unanswered Questions

About SGLT2 Inhibition

Weight May wane over time loss

Safety and The long-term safety of this class

tolerability remains to be proven

Risk of genitourinary infections may limit

use in some patients

Cancer risk must be negative

Renal Efficacy wanes as eGFR declines

impairment

45

Pathophysiologic Basis of Treatment

Adapted from Inzucchi SE. JAMA. 2002;287:360-372.

Incretin mimetics

Pramlintide

Nutrient absorption

Carbohydrate absorption

INCRETIN DEFICIENCY

HIGH GLUCAGON

Incretin mimetics

DPP-4 inhibitors

Pramlintide

TZDs

Increase glucoseuptake

TZDs

Decreaselipolysis

Adipose tissue

Increase lipolysis

TZDs

Increasefree fatty

acids

Pancreatic β cells

Decrease insulin

secretion

Sulfonylureasand

nonsulfonylureasecretagogues

Increase insulinsecretion

HYPERGLYCEMIA

α-Glucosidaseinhibitors

Delay intestinalcarbohydrate

absorption

Liver

Increase glucoseproductionSkeletal muscle

Decreaseglucose uptake INSULIN RESISTANCE

Glucotoxicity

LipotoxicityLipotoxicity

DEFECTIVE INSULIN SECRETION

Biguanides

Decreasehepatic glucose

production

Colesevelam

Bromocriptine

Factors That Influence Selection of Glucose-

Lowering Therapy

• Well Established

– Mechanism of Action

– Contraindications

• Think about

comorbidities!

– Side Effects

– Efficacy

– Long-term safety

– Ease of use

– Cost

• Less Well Established

―Non-glycemic effects‖

– Cardiovascular Outcomes

• Positive or negative?

– Weight Effects

– Lipid Effects

– Blood Pressure

– β-cell effects

• Positive or negative?

Nathan DM, et al. Diabetes Care. 2006;29:1963-1972.

ADA Treatment Algorithm

For Type 2 Diabetes

Reprinted with permission from Nathan DM, et al. Diabetes

Care. 2009;32:193-203.

Tier 1: Well-Validated Core

Therapies

Tier 2: Less Well-Validated

Therapies

At diagnosis:

Lifestyle

Intervention

+ Metformin

Lifestyle + Metformin+

Basal Insulin


Sulfonylurea*


Intensive Insulin


Pioglitazone

• No hypoglycemia

• Edema/CHF

• bone loss


GLP-1 Agonist†

• No hypoglycemia• Weight loss• Nausea/vomiting


Pioglitazone+

Sulfonylurea*


Basal Insulin*Excludes glyburide or chlorpropamide.†Insufficient clinical use to be confident regarding safety.

Step 1 Step 2 Step 3

48

AACE/ACE Algorithm for Glycemic Control

Reprinted with permission from Rodbard HW, et al. Endocr Pract. 2009;15(6):540-559. Erratum in 2009;15(7):768-770.

Reuse (print or electronic) of this material requires a license from the copyright holder.

*May not be appropriate for all patients.

**For patients with diabetes and A1C <6.5%, Rx may be considered.

***If A1C goal not achieved safely.1DPP-4 if ↑ PPG and ↑ FPG or GLP-1 if ↑↑ PPG.2TZD if metabolic syndrome and/or nonacoholic fatty liver disease

(NAFLD).3AGI if ↑ PPG .4Glinide if ↑ PPG.or SU if ↑ FPG. 5Low-dose secretagogue recommended.6 a) Disontinue insulin secretagogue with multidose insulin.

b) Can use pramlintide with prandial insulin.7Decrease secretagogue by 50% when added to GLP-1 or DPP-4.8If A1C <8.5%, combination Rx with agents that cause hypoglycemia

should be used with caution.9If A1C >8.5%, in patients on dual therapy, insulin should be

considered.

49

Antihyperglycemic Agents:

A1C Lowering Effects

Drug Class Decrease in A1C (%)

Sulfonylureas 1.0 - 2.0

Meglitinides 0.5 - 1.5

Biguanides 1.0 - 2.0

Insulin 1.5 - 3.5

Thiazolidinediones 0.5 - 1.4

Alpha-glucosidase inhibitors 0.5 - 0.8

Glucagon-like peptide-1 receptor

agonists

0.5 - 1.0

dipeptidyl peptidase-4 inhibitors 0.5 - 1.0

Amylin agonists 0.5 - 1.0

Summary• Multiple drugs are likely necessary to address the underlying

abnormalities

– Brain: amylinomimetics, GLP-1 agonist, dopamine agonist

– Fat: thiazolidinediones (TZDs)

– Liver and muscle: Metformin and TZDs but HGP can be reduced

by ―mass action‖ through increased insulin

– Glucagon: GLP-1 agonist, DPP-4 inhibitors, amylinomimetics

– Insulin: Insulin, sulfonylureas, meglitinides, DPP-4 inhibitors, and

GLP-1 agonists

– Incretins: GLP-1 agonists and DPP-4 inhibitors,

alpha glucosidase inhibitors?, bile acid sequestrants?

– Renal glucose absorption: SGLT2 inhibitors (several being

developed)51


Summary

(1) Will require multiple drugs in combination to

correct multiple pathophysiologic defects

(2) Should be based upon known pathogenic

abnormalities, and NOT simply on the reduction in

A1C

(3) Must be started early in the natural history of

T2DM, if progressive β-cell failure is to be

prevented

52

53

Thank You!

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Glucose Regulation in Diabetes - ptce.s3.amazonaws.com€¦ · Type 2 Diabetes Mellitus: Targeted Pharmacotherapy Curtis Triplitt, PharmD, CDE ... OMINOUS OCTET Increased Lipolysis