Diabetes Strategies for the Internist: 2007

Irl B. Hirsch, M.D. Professor of Medicine Division of Metabolism, Endocrinology, & Nutrition

Putting the Problem in Perspective

0.005% 7%
US Adults w/DM

11% % of time learning diabetes @ UW School of Medicine

Seattle VA GIMC

GIMC, UW Roosevelt

28%

26%
Adult Med Clinic, HMC

Top 5 Diagnoses By Internists, 2005

16 14 12 10 8 6 4 2 0
HTN HYPERLIPID DM HYPERCHOL Routine PE

Internal Med News 39:1, 2006

Case 1: Sharon
This is a 54 year-old obese woman (BMI 34) with an 8 year history of T2DM. She was diagnosed with an A1C of 8.2%, and after 3 months of strict diet and exercise her A1C dropped to 6.8% (BMI 32). 1 year after her diagnosis her A1C increased back to 7.9% and glimeperide was started. She had an excellent response but 3 years later her A1C trended 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?

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!

When Do You Transition Your T2 Patients 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

Clinical Inertia
Failure to advance therapy when required
Percentage of Subjects advancing when A1C > 8% (n=7208)
100 % of Subjects 80 60
35.3% 66.6% 44.6%

At Insulin Initiation, the average patient had: 5 years with A1C > 8% 10 years with A1C > 7%

40 20 0
Diet Sulfonylurea Metformin Combination 18.6%

Brown J, et al. Diabetes Care. ;27:1535-40, 2004.

Insulin Initiation-Very Late in the Disease Process

Nichols, Koo, Menditto, presented June, 2006, ADA Scientific Sessions, Washington DC

Redefining Insulin Therapy in T2 DM

Natural History...
Timing of Intervention (Window of Opportunity)
Impaired Glucose Tolerance Undiagnosed Known Diabetes Diabetes

Insulin Resistance
OADs

+
Insulin Rx

Insulin Secretion Postprandial BG Fasting BG

Durability of Effects ?

ADA/EASD Consensus Algorithm for Type 2 DM

Diagnosis
Nathan D, et al. Diabetologia 2006;49:171121.

Lifestyle Intervention and Metformin

No

HbA1c 7%

Yes

Add Basal Insulin

(most effective)
No

Add Sulfonylurea
(least expensive)
Yes No

Add GLitazone
( no hypoglycemia)
Yes No

HbA1c 7%

HbA1c 7%

HbA1c 7%

Yes

Intensify Insulin
No

Add Glitazone
Yes

Add Basal Insulin

No

Add Sulfonylurea
Yes

HbA1c 7%

HbA1c 7%

Add Basal or intensify insulin

Intensive insulin + metformin glitazone

Check HbA1c every 3 months and act until HbA1c is <7%
Although 3 oral agents can be used, insulin therapy is preferred based on effectiveness and expense

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)?

Adding a TZD or Glargine to Metformin/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<0.05) Wt gain 3.0 kg with rosiglitazone, 1.7 kg with glargine (p<0.05)

Diabetes Care 29:554, 2006

Exenatide (Byetta)
Available since June 2005 for the treatment of T2DM 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

GLP-1 Modes of Action in Man

Upon ingestion of food

Stimulates insulin secretion

Suppresses glucagon secretion Slows gastric emptying Reduces food intake

GLP-1 is secreted from the L-cells in the jejunum and ileum

This in turn

Long term effects demonstrated in animals Increases beta-cell cell mass and maintains beta-cell efficiency

Drucker DJ. Curr Pharm Des 2001; 7:1399-1412 Drucker DJ. Mol Endocrinol 2003; 17:161-171

Exenatide Showed Durable Effect on A1C

Blinded
0.5
5 g BID

Open-label
10 g BID

0.0

PBO N=128

Change in A1C From Baseline (%)

-0.5 5 g BID N=128 -1.0 10 g BID N=137 -1.5 0 10 20 30 40 50 60 70 80

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

Exenatide Showed Durable Effect on Weight

Blinded
0 PBO N=128
5 g BID

Open-label
10 g BID

-2 5 g BID N=128 10 g BID N=137

Change in Body Weight From Baseline -6 (lbs)

-8

-4

-10

-12 0 10 20 30 40 50 60 70 80

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

So what about Sharon? Should we add exenatide?

BMI 35 A1C = 9% Metformin and glimeperide

Exenatide: Effects on Glycemic Control in Combination With Current Oral Therapies

*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.

Sharon!

What About a Direct Head-on-Head Comparison 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

Both groups reduced A1c by 1.1% at 26 weeks

Weight increased 1.8 kg with glargine and decreased 2.3 kg with exenatide
Ann Intern Med 2005;143:559

SMBG Data

But goal FBG was < 5.6 mM!

Ann Intern Med 2005;143:559

Was This Study Biased Against Glargine?

FBG target was not reached with glargine group, the primary 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

What Would the Weight Differences Be if Glargine was Titrated Appropriately?

3 2
Change in Weight (kg)

1 0 -1 -2 -3
week 0 week 2 week 4 week 8 week 12 week 18 week 26

4.1 kg

Glargine Exenatide

Ann Intern Med 2005;143:559

But lets be clear: if initiated early, basal insulin added to OHAs will be effective in reaching A1C targets. Success will depend on initial A1C and degree of insulin deficiency

Treat-to-Target Trial
Change of A1c over 24 Weeks
Glargine (47 U)
9

NPH (41 U)

8.6 8.6
8

Mean A1c %

6.9 6.9
7

58% 7%
6

12

16

20

24

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

Basal Insulin Alone: What to Consider

With progressive insulin deficiency, wont work unless inadvertently replace prandial insulin with basal insulin Require to measure HS BG to ensure not using HS basal insulin to correct post-dinner hyperglycemia 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

The Higher The A1C

The greater the insulin deficiency The more prandial insulin will be required
80 70 60 50 75

% to <7% A1C

40 30 20 10

45

*personal communication, Matthew Riddle

0 < 8.5% > 8.5%

Baseline A1C in TTT

Basal Insulin Alone: What to Consider

Inability to adequately treat postprandial hyperglycemia and glycemic variability Will not be effective long-term

Basal Insulin Alone Only Works Short-Term

8.5 8 7.5 7 6.5 6 5.5 5 4.5 4
conventional insulin SFU

UKPDS. Diabetes 44:1249, 1995

The Most Frequent Mistake in Insulin Rx

Not replacing the prandial insulin!

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 need assistance! The more home glucose monitoring, the greater the ability to make appropriate insulin decisions So why not just start everyone on classic split-mix?

Physiologic Insulin Replacement?

WILL NOT WORK W/SEVERE INSULIN DEFICIENCY

INSULIN EFFECT

Morning Afternoon Evening REG

spike

Night

REG NPH

NPH

S
MEALS

HS
IOB 3 insulins!

BUT, early in the course of T2DM this may be very effective!

So What About Pre-Mixed Insulins?

Pros

VERY simple for both doctor and patient; works well when consistent with diet/exercise Particularly simple with pen therapy May be a good way to start insulin for those without severe insulin deficiency and those sight impaired
Cons

Difficult to reach targets with severe insulin deficiency or need for more flexibility with diet/exercise Analogues poor choice with large lunch unless take lunch shot Pens and correction dosing not possible

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 you treat her DM differently, if at all?

PE: The Foot Exam

What is the most sensitive measure on PE of polyneuropathy? Of risk for a neuropathic foot ulcer?

What are the Rx options for the hyperglycemia?

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 Receptors

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

Mixed meal Intestinal GLP-1 release
GLP-1 (7-36) active

t = 1 to 2 min

DPP-4 GLP-1 (9-36) inactive (>80% of pool)

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

Inhibition of DPP-4 Increases Active GLP-1

Mixed meal Intestinal GLP-1 release
GLP-1 (7-36) active

DPP-4 DPP-4 inhibitor

GLP-1 (9-36) inactive

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

S e c t i o n 14.1

Monotherapy Studies: As Is Typical in Trials of Agents to Treat Type 2 Diabetes, Mean Response to JANUVIA (sitagliptin phosphate) in A1C Lowering Appears to Be Related to the Degree of A1C Elevation at Baseline
Inclusion Criteria: 7%10%
Pooled Analysis*

Baseline A1C (%)

0.0 -0.2 -0.4

Overall

<8

8<9

Change in A1C (%)

-0.6 -0.8 -1.0

n=769**

n=411**

n=239**

0.7

0.6

0.7
n=119**

-1.2
-1.4 -1.6 -1.8

1.4

The magnitude of A1C lowering by strata varied by study.

Reductions are placebo-subtracted. *P<0.001 overall and for treatment by subgroup interactions. ** Combined number of Patients on JANUVIA or Placebo

Issues to Consider with DPP-IV Inhibitors

To date very safe Weight neutral No hypoglycemia Safe in renal insufficiency Still, cant expect dramatic A1C reductions

Last Case
25 year-old Korean man referred for new-onset diabetes. No family history. BMI = 27. Presented with ketoacidosis after drinking with friends; however, no EtOH levels measured Comes to you 3 weeks after starting glargine/aspart. Well-controlled on 0.5 units/kg/day of insulin
What type of diabetes does he have?

ACANTHOSIS NIGRICANS

But Remember
20-25% of the US population is obese, while 2/3 are overweight This can and does occur in type 1 diabetes too! Always think autoimmunity, especially if family history of T1DM, thyroid disease, celiac disease, or Addisons disease; ketonuria usually but not always 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 People have Both Autoimmune Destruction of the BCells and Insulin Resistance
Double Diabetes Type 3 Diabetes Type 1.5 Diabetes (?) Hybrid Diabetes*

Thank You!