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Achieving Glucose Balance in Type 2 Diabetes - Pharmacy Times

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


Faculty Information

Presenter

Curtis Triplitt, PharmD, CDE

Texas Diabetes Institute

Assistant Professor, Medicine/Diabetes

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.

2


Disclosures

Curtis 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.

3


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

4


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

5


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


ETIOLOGY OF T2DM

Impaired Insulin

Increased Lipolysis

Secretion

Hyperglycemia

Increased

Decreased Glucose

HGP

Uptake

DEFN75-3/99

Decreased Insulin

Secretion

Islet–a cell

OMINOUS OCTET

Decreased

Incretin Effect

Increased

Lipolysis

Increased

Glucagon

Secretion

Increased

HGP

HYPERGLYCEMIA

Decreased

Glucose Uptake

Increased

Glucose

Reabsorption

Reprinted with permission from DeFronzo RA. Diabetes.

2009;58:773-795.

Neurotransmitter

Dysfunction

7


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: pramlintide

8


Antihyperglycemic Agents:

Drug Class

Sulfonylureas/meglitinides

Pharmacologic Action

Mechanism of action

Increase insulin release via pancreatic β-cell stimulation

Biguanides

Thiazolidinediones

Reduce hepatic glucose output, increase insulin sensitivity

Increase sensitivity of muscle, fat, and liver to insulin

Alpha-glucosidase inhibitors

Glucagon-like peptide-1 receptor agonists

dipeptidyl peptidase-4 inhibitors

Amylin agonists

Reduce rate of polysaccharide digestion in proximal small intestine,

primarily lowering postprandial glucose levels

bind to GLP-1 receptor on pancreatic beta-cells to augment glucose-mediated

insulin secretion

Prolong effects of GLP-1 and GIP, increasing glucose-mediated insulin secretion

and suppressing glucagon secretion

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


D From Baseline in Insulin

AUC 0–12 h (pmol/L)

Nateglinide Stimulates Early

Insulin

to Mimic Normal Physiology

300

250

200

150

100

NAT 120 mg (n = 51)

GLY 10 mg (n = 50)

Placebo (n = 51)

GLY

NAT

50

Placebo

0

-50

P < 0.05 GLY & NAT vs. placebo.

P < 0.05 GLY vs. NAT.

0 1 2 3 4 5 6 7 8 9 10 11 12

Time (hours)

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


Glucose-Stimulated Secretion of Insulin

SUR

Glucose

GLUT2

Pancreatic β Cell

Potassium

channel

Calcium

channel

K +

ATP

Glucose

GK

Pyruvate

TCA

Cycle*

[Ca 2+ ]

ATP

AC

cAMP

+

+

GLP-1

GIP

Triggering

Amplifying

AC = adenylyl cyclase; ATP = adenosine triphosphate;

cAMP = cyclic adenosine monophosphate; GK = glucokinase;

GLUT2 = glucose transporter; SUR = sulfonylurea receptor;

TCA = tricarboxylic acid (Krebs cycle).

Insulin

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.


Change in AIC (%)

Change in AIC (%)

Durability of Glycemic Control:

Assessed by Serial A1C

Sulfonylureas

Thiazolidinediones

Glimepiride

Glyburide

Glyburide

0

Glyburide

0

Pioglitazone (PIO)

Rosiglitazone

Gliclazide

Glyburide

PIO

-1

-1

PIO

PIO

-2

0 1 2 3 4 5 6 10

Hanefeld (n = 250)

Tan (n = 297)

ADOPT (n = 1441)

Time (years)

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

-2

0 1 2 3 4 5 6

UKPDS (n = 1573)

Chicago (n = 230)

PERISCOPE (n = 181)

Time (years)

13


Etiology of β -Cell Failure in T2DM

Age

Incretin

Effect

Amyloid (IAPP)

Deposition

β-Cell

Failure

Genetics

(TCF7L2

protein)

Insulin

Resistance

Glucose

Toxicity

Lipotoxicity

Free Fatty Acids

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


Effect of Pioglitazone in Patients

With Nonalcoholic Steatohepatitis

(NASH)

Subjects:

Study Design:

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

Randomized, placebo-controlled, double blind

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

Placebo run-in (4 wks)

PIO, 45 mg/d x 24 wks

Measurements:

Liver biopsy

Liver function tests, liver fat (MRS)

OGTT, adipocytokines

Before/after 24 weeks

18

Belfort R, et al. N Engl J Med. 2006;355:2297-2307.


Effect of Pioglitazone on Liver Histology

2

Inflammation

Ballooning Necrosis

P = .008

2

P = .019

Mean score

1.5

1

0.5


*

Mean score

1.5

1

0.5

**

0

Before After

Placebo

Steatosis

Before After

Pioglitazone

P =.003

0

Before After

Placebo

Fibrosis

Before After

Pioglitazone

2

2

P = .08

Mean score

1.5

1

0.5

*

Mean score

1.5

1

0.5


Reprinted with

permission from Belfort

R, et al. N Engl J Med.

2006;355:2297-2307.

0

Before After

Placebo

Before After

Pioglitazone

0

Before After

Placebo

Before After

Pioglitazone

19


Effect of Pioglitazone on Liver

Steatosis in NASH

Pretreatment biopsy

After treatment

biopsy

Patient with 2 grade steatosis and inflammation-necrosis improvement

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


Glitazones: Documented Issues

• Fluid retention

• CHF

– Edema, congestive heart failure (CHF) risk

– 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 postmenopausal

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.


ETIOLOGY OF T2DM

Impaired Insulin

Increased Lipolysis

Secretion

Hyperglycemia

Increased

Decreased Glucose

HGP

Uptake

DEFN75-3/99

Decreased Insulin

Secretion

Islet–a cell

OMINOUS OCTET

Decreased

Incretin Effect

Increased

Lipolysis

Increased

Glucagon

Secretion

Increased

HGP

HYPERGLYCEMIA

Increased

Glucose

Reabsorption

Decreased Glucose

Uptake

Reprinted with permission from DeFronzo RA. Diabetes.

2009;58:773-795.

Neurotransmitter

Dysfunction

22


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

Insulin

Hyperglycemia

Parasympathetic

system

0

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


Proportion Not Experiencing

Secondary Failure

1.0

0.8

0.6

Kaplan-Meier Plot of Secondary Failure of Metformin

Monotherapy (n =1051) by Categories of Duration

of Diabetes at Metformin Initiation

12-23 Months

21.4% year

0-3 Months

12.2% year

4-11 Months

17.7% year

0.4

0.2

24-35 Months

18.4% year

>36 Months

21.9% year

0

0 12 24 36 48 60

Months on Metformin

Reprinted with permission from JB Brown, et al.

Diabetes Care. 2010;33:501-506.


Proportion Not Experiencing

Secondary Failure

Kaplan-Meier Plot of Secondary Failure of Metformin

Monotherapy (n = 1051) by Categories of A1C at

Metformin Initiation

1.0

0.8

0.6

8-8.9%

19.2% year

9.0%

19.4% year

0

0 12 24 36 48 60

Months on Metformin

Reprinted with permission from JB Brown, et al.

Diabetes Care. 2010;33:501-506.


Cases/100 person-yr

Diabetes Incidence Rates by Age

12

Lifestyle Metformin Placebo

8

4

0

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

Age (years)

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

28


Cases/100 person-yr

16

Diabetes Incidence Rates by BMI

12

Lifestyle Metformin Placebo

8

4

0

22 - < 30 30 - < 35 > 35

Knowler WC, et al; for the Diabetes Prevention

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

Body Mass Index (kg/m 2 )


Grams of Glucose Flux/min

Multihormonal Regulation of Glucose

Appearance and Disappearance

Mixed Meal (With ~85 g Dextrose)

0.6

0.4

Regulated by hormones:

amylin, CCK, GLP-1, GIP

0.2

0

-0.2

Meal-derived glucose

Hepatic glucose production

Total glucose uptake

Balance of insulin

stimulation and glucagon

suppression

-0.4

-0.6

-30

0 120 240 360 480

Insulin-mediated

glucose uptake

Time (min) From Start of Mixed Meal

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

30


Basal HGP (mg/m 2 X min)

Contribution of Basal Glucagon Levels

to the Maintenance of Basal Hepatic Glucose

Production (HGP) in Type 2 Diabetic Subjects

160

250

120

80

40

0

P


Plasma Amylin, pmol/L

Plasma Insulin, pmol/L

Plasma Amylin, pmol/L

Amylin Is Cosecreted With Insulin

and Deficient in Diabetes

Meal Meal Meal

Meal

30

25

Amylin

Insulin

Healthy male adults (n = 6)

600

20

15

Without diabetes (n = 27)

20

15

10

400

200

10

5

Insulin-using T2DM (n = 27)

T1DM (n = 190)

5

7 AM 12 Noon 5 PM Midnight

Time, 24 h

0

0

-30 0 30 60 90 120 150 180

Time After Sustacal Meal, min

Central satiety, decreases glucagon, slows gastric emptying

32

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


Plasma Glucagon, pg/mL

D Plasma Glucagon, pg/mL

Effect of Pramlintide on Postprandial Glucagon

60

Type 2 Diabetes, Late Stage 1

Insulin

Meal

N = 12

30 Insulin

Meal

N = 9

20

Type 1 Diabetes 2 Time, h

50

10

40

30

Infusion of 100 µg/h pramlintide or placebo

0 1 2 3 4

Time, h

T2DM: AUC 1–4 h : P = .005.

T1DM: AUC 1–5 h : P


D A1C (%)

Time Course of Effect of

Exenatide on A1C

0.5

0

Time (weeks)

0 20 40 60 80 156

Placebo

Exenatide

10 g bid

Baseline A1C = 8.3%

-1.0

-2.0

Exenatide-

10 g bid

Placebo-Controlled

Trials

Open-Label Extension

34

Data on file. Amylin Pharmaceuticals; DeFronzo et al.

Diabetes Care.2005;28:1092-1100.


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.


Effect of Vildagliptin on Plasma Glucose and Hormone

Levels in Diet-Treated Patients With T2DM

pg/mL

pmol/L

pmol/L mg/dL

275

225

175

125

300

200

100

Glucose

Insulin

Placebo

Placebo

(n = 19)

Vildagliptin

(n = 18)

Vildagliptin

20

10

0

120

100

80

GLP-1

Glucagon

Vildagliptin

Placebo

Placebo

Vildagliptin

0

60

0 60 120

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

0 60 120

Time (min)


Plasma GLP-1 or GLP-1 R

“Activity”

DPP-4 Inhibitors vs Incretin Mimetics

No Satiety Effect

Weight Neutral

No Gastric Emptying

Delay

Oral Medication

DPP-4

inhibitor

Satiety

Weight Loss

Gastric Emptying Delay

Injectable

Incretin Mimetics

Pharmacologic levels

Physiologic

37


ETIOLOGY OF T2DM

Impaired Insulin

Increased Lipolysis

Secretion

Hyperglycemia

Increased

Decreased Glucose

HGP

Uptake

DEFN75-3/99

Decreased Insulin

Secretion

Islet–a cell

OMINOUS OCTET

Decreased

Incretin Effect

Increased

Lipolysis

Increased

Glucagon

Secretion

Increased

HGP

Reprinted with permission from DeFronzo RA. Diabetes.

2009;58:773-795.

HYPERGLYCEMIA

Neurotransmitter

Dysfunction

Increased

Glucose

Reabsorption

Decreased Glucose

Uptake

38


Renal Handling of Glucose

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

Glucose

SGLT 2

90%

S1

10%

S3

S

G

L

T

1

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

NO

GLUCOSE

39


Effect of Dapagliflozin in

Metformin-Treated T2DM Patients

Subjects:

Study Design:

Primary End Point:

Age = 54 y BMI = 31.5 kg/m 2

Metformin-treated

Diabetes duration = 6.1 years

A1C = 8.0% FPG = 163 mg/dL

Randomized, placebo-controlled (n = 546)

Placebo vs dapagliflozin 2.5, 5, 10 mg/day

24 weeks

A1C

Secondary End Points:

Change in body weight, lipids, blood pressure

Hypoglycemia

Adverse events

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

40


Change in A1C (%)

Change in BW (kg)

Placebo

DAPA

2.5 mg

DAPA

5 mg

DAPA

10 mg

Placebo

DAPA

2.5 mg

DAPA

5 mg

DAPA

10 mg

Effect of Dapagliflozin on A1C and Body

Weight in Metformin-Treated T2DM Patients

0

0

-0.2

-0.4

-0.3

-0.9

-1

-0.6

-0.8

-1.0

-0.67

-0.70

-0.84

-2.2

-3.0

-2.9

-2

-3

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


Increment in HDL Chol (%)

DAPA

2.5 mg

DAPA

5 mg

DAPA

10 mg

DAPA

2.5 mg

DAPA

5 mg

DAPA

10 mg

Change in Triglyceride (%)

Effect of Dapagliflozin on Serum Lipids

In Metformin-Treated T2DM Patients

5

4.4

2.1

Placebo

2

4

3

2

1.8

3.3

-2.4

0

-2

1

0.4

-4

0

Placebo

-6.2 -6.2

-6

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

42


D Systolic BP

D Diastolic BP

DAPA

2.5 mg

DAPA

5 mg

DAPA

10 mg

DAPA

2.5 mg

DAPA

5 mg

DAPA

10 mg

Effect of Dapagliflozin on Blood Pressure

in Metformin-Treated T2DM Patients

0

-1

Placebo

-0.2

Placebo

-0.1

0

-1

-2

-3

-2.1

-2

-3

-4

-4

-5

-4.3

-5.1

-5

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

43


Safety Considerations

● Urinary tract infection

● Intravascular volume depletion (osmotic diuresis)

● Electrolyte imbalance (Na + , K + , Ca ++ , PO

3-

4 )

● Nephrotoxicity (AGEs)

● Nocturia

● Drug-drug interactions

44


Weight

Safety and

tolerability

Unanswered Questions

About SGLT2 Inhibition

May wane over time loss

The long-term safety of this class

remains to be proven

Risk of genitourinary infections may limit

use in some patients

Cancer risk must be negative

Renal

impairment

Efficacy wanes as eGFR declines

45


Pathophysiologic Basis of Treatment

TZDs

Increase

glucose

uptake

Skeletal muscle

Decrease

glucose uptake

α-Glucosidase

inhibitors

Delay intestinal

carbohydrate

absorption

TZDs

Liver

Biguanides

Decrease

hepatic glucose

production

Increase glucose

production

INSULIN RESISTANCE

Incretin mimetics

Pramlintide

Nutrient absorption

Carbohydrate

absorption

TZDs

Decrease

lipolysis

Adipose tissue

Increase lipolysis

Lipotoxicity

Increase

free fatty

acids

Glucotoxicity

HYPERGLYCEMIA

Colesevelam

Bromocriptine

Lipotoxicity

Sulfonylureas

and

nonsulfonylurea

secretagogues

INCRETIN

DEFICIENCY

HIGH

GLUCAGON

Increase insulin

secretion

Pancreatic β cells

Decrease insulin

secretion

DEFECTIVE INSULIN

SECRETION

Incretin mimetics

DPP-4 inhibitors

Pramlintide

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


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

Tier 1: Well-Validated Core

Therapies

At diagnosis:

Lifestyle

Intervention

+ Metformin

Lifestyle + Metformin

+

Basal Insulin

Lifestyle + Metformin

+

Sulfonylurea *

Lifestyle + Metformin

+

Intensive Insulin

Step 1 Step 2 Step 3

Tier 2: Less Well-Validated

Therapies

* Excludes glyburide or chlorpropamide.


Insufficient clinical use to be confident regarding safety.

Reprinted with permission from Nathan DM, et al. Diabetes

Care. 2009;32:193-203.

Lifestyle + Metformin

+

Pioglitazone

• No hypoglycemia

• Edema/CHF

• bone loss

Lifestyle + Metformin

+

GLP-1 Agonist †

• No hypoglycemia

• Weight loss

• Nausea/vomiting

Lifestyle + Metformin

+

Pioglitazone

+

Sulfonylurea*

Lifestyle + Metformin

+

Basal Insulin

48


AACE/ACE Algorithm for Glycemic Control

*May not be appropriate for all patients.

**For patients with diabetes and A1C


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


Targeted Pharmacotherapy

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


Thank You!

53

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