Diabetes Strategies

7/29/2019 Diabetes Strategies

1/47

Diabetes Strategies

for the Internist:2007

Irl B. Hirsch, M.D.

Professor of Medicine

Division of Metabolism, Endocrinology, & Nutrition


2/47

% of time learning diabetes @

UW School of Medicine

Putting the Problem in Perspective

0.005%7%

11%

26%

US Adults w/DM

GIMC, UW Roosevel

Adult Med Clinic, HM

Seattle VA GIMC 28%


3/47

Top 5 Diagnoses By Internists,2005

0

2

4

6

8

10

12

14

16

HTN HYPERLIPID DM HYPERCHOL Routine PE

Internal Med News 39:1, 2006


4/47

Case 1: Sharon

This is a 54 year-old obese woman (BMI 34) with an8 year history of T2DM. She was diagnosed with anA1C of 8.2%, and after 3 months of strict diet andexercise her A1C dropped to 6.8% (BMI 32).

1 year after her diagnosis her A1C increased backto 7.9% and glimeperide was started. She had anexcellent response but 3 years later her A1Ctrended back up to 7.6% and metformin was added.Again, she had an initial excellent response (BMI

now 35) Now her A1C is now 9.0% (BMI 35). What should

you do?


5/47

Choices For Sharon (A1C = 9.0%)

Add a TZD (pioglitazone or rosiglitazone)

Add exenatide

Add a DPP-4 inhibitor (sitagliptin)

Add basal insulin

Add prandial insulin

Add both basal and prandial insulin

Refer to Virginia Mason

All of a sudden, the choices for diabetes therapy

has exploded!


6/47

When Do You Transition Your T2Patients To Insulin Rx?

HbA1C > 7.5%?

HbA1C > 8%?

HbA1C > 8.5%?

HbA1C > 9%

When they are catabolic, losing weight

When their insurance lets them go to Virginia

Mason


7/47

0

20

40

60

80

100

%o

fSubjects

Percentage of Subjects advancing when A1C > 8%

(n=7208)

Clinical InertiaFailure to advance therapy when required

Diet

66.6%

Sulfonylurea

35.3%

Metformin

44.6%

Combination

18.6%

At Insulin Initiation, the average patient had:

5 years with A1C > 8%

10 years with A1C > 7%

Brown J, et al. Diabetes Care. ;27:1535-40, 20


8/47

Nichols, Koo, Menditto, presented June, 2006, ADA

Scientific Sessions, Washington DC

Insulin Initiation-Very Late in the DiseaseProcess


9/47

Durability of Effects ?

Insulin Resistan

Insulin Secretio

ImpairedGlucose Tolerance

UndiagnosedDiabetes Known Diabetes

Postprandial BG

Fasting BG

Timing of Intervention (Window of Opportunity)

OADs

Redefining Insulin Therapy in T2 DMNatural History...

Insulin Rx

+


10/47

Nathan D, et al. Diabetologia 2006;49:171Diagnosis

Lifestyle Intervention and Metformin

HbA1c7%No Yes

Add Basal Insulin (most effective)

Add Sulfonylurea (least expensive)

Add GLitazone ( no hypoglycemia)

Add GlitazoneIntensify Insulin Add Basal Insulin Add Sulfonylurea

Add Basal or intensify insulin

Intensive insulin + metformin glitazone

Yes Yes

Yes HbA1c7%No Yes

HbA1c7%No HbA1c7%NoHbA1c7%No Yes

HbA1c7%No

ADA/EASD Consensus Algorithm for Type 2 DM

Check HbA1c every 3 months and act until HbA1c is


11/47

Lets Go Back To Sharon

BMI 35 A1C = 9%

Metformin and glimeperide

If you decide to add a TZD, what will happen to her

A1C (on average)? Her weight (on average)?

And what will happen (on average) if you instead

add exenatide (Byetta)?


12/47

Adding a TZD or Glargine toMetformin/SFU Combination

N = 217; 26 week study 8 mg rosiglitazone vs. final dose of 38 units glargine

Baseline A1c 8.7%; A1C reduction about 1.6% both

groups (P=NS)

Glargine more effective in A1C reduction with

baseline A1C > 9.5% (p


13/47

Exenatide (Byetta)

Available since June 2005 for the treatment ofT2DM

How many of you are familiar with this agent?

How many of you have prescribed this agent?

The first of many GLP-1

receptor agonists


14/47

GLP-1 Modes of Action in Man

GLP-1 is secreted

from the L-cells

in the jejunum

and ileum

This in turn

Stimulates insulin secretion

Suppresses glucagon secretion

Slows gastric emptying

Long term effectsdemonstrated in animals

Increases beta-cell cell mass and

maintains beta-cell efficiency

Reduces food intake

Upon ingestion of food

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412

Drucker DJ. Mol Endocrinol2003; 17:161-171


15/47

Exenatide Showed Durable Effect on A1C

Change in

A1C From

Baseline (%)

Time (weeks)0

10

20

30

40

50

60

70

80

-1.5

-1.0

-0.5

0.0

0.5

PBO

N=128

10 g BID

N=137

Blinded Open-label

10 g

BID

5 gBID

5 g BIDN=128

Combined baseline A1C = 8.3%; Completer population (n=393) at 82 weeks

E d h d l Eff h


16/47

Exenatide Showed Durable Effect on Weight

Blinded

PBO

N=128

10 g BID

N=137

5 g

BID

Open-label

10 g

BID

0

10

20

30

40

50

60

70

80-12

-10

-8

-6

-4

-2

0

Time (weeks)

Combined baseline body weight = 218.3 lbs; Completer population (n=393) at 82 weeks

Change in

Body Weight

From Baseline

(lbs)

5 g BID

N=128


17/47

So what about Sharon? Shouldwe add exenatide?

BMI 35

A1C = 9%

Metformin and glimeperide


18/47

*P < .001 vs placebo; p < .0001 vs placebo; Met = metformin; SU = sulfonylurea

Buse JB, et al. Diabetes Care. 2004;27:2628-2635.DeFronzo RA, et al. Diabetes Care. 2005;28:1092-1100.Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.

Exenatide: Effects on Glycemic Control inCombination With Current Oral Therapies

Sharon!


19/47

What About a Direct Head-on-HeadComparison of Glargine vs. Exenatide?

551 patients failing SFU, metformin, or both

randomized to glargine or exenatide

Exenatide titrated to 10 mcg BID (A1C 8.2%)

Glargine titrated to FBG < 100 mg/dL (A1C 8.3%)

Ann Intern Med 2005;143:559


20/47

Both groups

reduced A1c

by 1.1% at26 weeks

Weight

increased 1.8 kg

with glargine

and decreased

2.3 kg with

exenatide



21/47

SMBG Data


But goal FBG was < 5.6 mM!

W Thi d Bi d i


22/47

Was This Study Biased AgainstGlargine?

FBG target was not reached with glargine group, theprimary treatment target

Only 21.8% of those receiving glargine reached the

target glucose level

Mean insulin dose was only 25 units (0.28 units/kg)

On the other hand


23/47

What Would the Weight Differences Beif Glargine was Titrated Appropriately?

week 0 week 2 week 4 week 8 week 12 week 18 week 26

ChangeinW

eight(kg)

-3

-2

-1

0

1

2

3

Glargine

Exenatide Ann Intern Med 2005;143:559

4.1 kg


24/47

But lets be clear: if initiated early,basal insulin added to OHAs will beeffective in reaching A1C targets.

Success will depend on initial A1C anddegree of insulin deficiency


25/47

Treat-to-Target TrialChange of A1c over 24 Weeks

6

7

8

0 4 8 12 16 20 24

Weeks

8.6 8.6

6.9 6.9

9Glargine (47 U) NPH (41 U)

Mean

A1c %

Riddle MC et al. Diabetes Care 2003;26: 3080-86

58% 7%


26/47

Basal Insulin Alone: What to Consider

With progressive insulin deficiency, wont workunless inadvertently replace prandial insulin with

basal insulin

Require to measure HS BG to ensure not using

HS basal insulin to correct post-dinnerhyperglycemia

With oral agents failing, the higher the A1c the less

likely basal insulin alone will suffice

Most with A1c levels > 10% (and many > 9%)require prandial insulin to reach A1c target


27/47

The Higher The A1C The greater the insulin deficiency

The more prandial insulin will be required

75

45

0

10

20

30

40

50

60

70

80

< 8.5% > 8.5%

% to


28/47

Basal Insulin Alone: What to Consider

Inability to adequately treat postprandialhyperglycemia and glycemic variability

Will not be effective long-term


29/47

Basal Insulin Alone Only Works Short-Term

4

4.5

5

5.5

6

6.5

7

7.5

8

8.5

0 1 2 3 4 5 6

conventiona

insulin

SFU

UKPDS. Diabetes 44:1249, 1995


30/47

The Most Frequent Mistake in Insulin Rx

Not replacing the

prandial insulin!


31/47

Things to Consider

Simplicity will usually to beat complexity The more insulin deficient, the more prandial insulin

will be required

Some elements of a diabetes team must be

present; logistically, a physician will needassistance!

The more home glucose monitoring, the greater the

ability to make appropriate insulin decisions

So why not just start everyone on classicsplit-mix?

Physiologic Insulin Replacement?


32/47

INSU

LINEFFEC

T

B L S HS B

MEALS

Morning Afternoon Evening Night

REG REG

NPH NPH

Physiologic Insulin Replacement?

spike

IOB 3

insulins!

WILL NOT WORK W/SEVERE INSULIN DEFICIENCY

BUT, early in the course of T2DM

this may be very effective!


33/47

So What About Pre-Mixed Insulins? Pros

VERYsimple for both doctor and patient; works welwhen consistent with diet/exercise

Particularly simple with pen therapy

May be a good way to start insulin for those withoutsevere insulin deficiency and those sight impaired

Cons Difficult to reach targets with severe insulin

deficiency or need for more flexibility withdiet/exercise

Analogues poor choice with large lunch unless take

lunch shot Pens and correction dosing not possible


34/47

Case 2: Gloria 76 year-old woman with known T2DM for 8 years

A1C 1 year ago 6.9% on very strict diet; A1C now

7.6% on no drugs for DM

NPDR found during routine exam; ACR = 120 on

enalapril, HCTZ, and amlodipine. Is also receiving

simvastatin.

BP = 126/76, BMI = 25.5, LDL-C = 68, creatinine =

1.5.

What else should be noted on PE? How would youtreat her DM differently, if at all?


35/47

PE: The Foot Exam

What is the most sensitive measure

on PE of polyneuropathy? Of risk for

a neuropathic foot ulcer?


36/47

What are the Rx options for the


37/47

What are the Rx options for thehyperglycemia?

Metformin? Glyburide?

Glipizide?

Glimeperide?

Repaglinide?

Exenatide?

Rosiglitazone?

Pioglitazone?

Sitagliptin?

Detemir?

Glucophage Micronase, Diabeta

Glucotrol

Amaryl

Prandin

Byetta

Avandia

Actos

Januvia

Levamir

Strategies to Turn On GLP-1


38/47

Strategies to Turn On GLP 1Receptors

Native GLP-1 chronic infusion Natural GLP-1 like-peptide: Exendin-4

GLP-1 analogue: exenatide, luraglitide

DPP-4 inhibitor: sitagliptin, vildagliptin

GLP-1 Secretion and Inactivation


39/47

Adapted from Deacon CF, et al. Diabetes. 1995;44:1126-1131.

GLP-1 Secretion and Inactivation

IntestinalGLP-1release

GLP-1 (7-36)

active

Mixedmeal

GLP-1 (9-36)

inactive(>80% of pool)

DPP-4

t = 1 to 2 min

Inhibition of DPP-4 Increases Active GLP-


40/47

Inhibition of DPP 4 Increases Active GLP

GLP-1 (9-36)inactive

IntestinalGLP-1release

Mixedmeal

GLP-1 (7-36)

active

DPP-4

Adapted from Rothenberg P, et al. Diabetes. 2000;49(suppl 1):A39.

DPP-4

inhibitor

Monotherapy Studies: As Is Typical in Trials of Agents to Treat Type 2Diabetes, Mean Response to JANUVIA (sitagliptin phosphate) in A1C

Sec

t

i


41/47

Pooled Analysis*

1.4

0.70.6

0.7

-1.8

-1.6

-1.4

-1.2

-1.0

-0.8-0.6

-0.4

-0.2

0.0

Reductions are placebo-subtracted. *P


42/47

Issues to Consider with DPP IVInhibitors

To date very safe Weight neutral

No hypoglycemia

Safe in renal insufficiency

Still, cant expect dramatic A1C reductions

L t C


43/47

Last Case

25 year-old Korean man referred for new-onsetdiabetes. No family history. BMI = 27.

Presented with ketoacidosis after drinking with

friends; however, no EtOH levels measured

Comes to you 3 weeks after startingglargine/aspart. Well-controlled on 0.5 units/kg/day

of insulin

What type of diabetes does he have?


44/47

ACANTHOSIS NIGRICANS

B t R m mb


45/47

But Remember

20-25% of the US population is obese, while 2/3 areoverweight

This can and does occur in type 1 diabetes too!

Always think autoimmunity, especially if familyhistory of T1DM, thyroid disease, celiac disease, orAddisons disease; ketonuria usually but notalways present at Dx

GAD, IA-2, IAA, ICA

Always think T2DM if obese, family history,

dyslipidemia, PCOS, and AN

With our Epidemic of Diabetes, Many Peopleh B th A t i D t ti f th B


46/47

have Both Autoimmune Destruction of the B-Cells and Insulin Resistance

Double Diabetes

Type 3 Diabetes

Type 1.5 Diabetes (?)

Hybrid Diabetes*


47/47

Thank You!

Documents

Diabetes Strategies