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Introduction

· Type 2 Diabetes and Insulin · John Palmer DO · Regional Endocrinology

· Type 2 diabetes is a progressive disease in which beta cell function continually declines and eventually fails, ultimately requiring nearly all patients to be placed on insulin therapy · An increasing body of evidence suggests that early intensive glycemic control reduces l l i t l d long-term vascular outcomes and t l t d potentially may prolong beta-cell lifespan and function

Introduction

· Tight glycemic control is crucial for reducing the incidence of retinopathy, nephropathy, and neuropathy in patients with diabetes · Evidence suggests that early control prevents macrovascular events many years down the road.....induces a " t b li t d th d i d "metabolic memory"

United Kingdom Prospective Diabetes Study (UKPDS)

· 3867 patients with newly diagnosed DM2 · Randomized to conventional-therapy group (diet alone) or intensivetherapy group: sulfonylurea (chlorpropamide, glibenclamide, glipizide) or insulin · Metformin added to sulfonylurea if optimal control not achieved · Insulin initiated if combination of oral agents was ineffective

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998 Sep 12;352(9131):837-53.

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UKPDS: Results

· 11 percent reduction in A1C ( 7.0% vs. 7.9%)

UKPDS: The Benefits of Improved Glycemic Control

· Improved glycemic control significantly reduces risk of diabetes-related complications · UKPDS results indicated that a 1% reduction in A1C would reduce the risk of microvascular complications by 37%, but have less effect (16%) on macrovascular complications · Further improvement in sustained glycemic control and reduction in the burden of cardiovascular disease are needed

· 25 percent risk reduction in microvascular disease (P = 0.001) · defined as renal failure, death from renal failure, retinal photocoagulation, or vitreous hemorrhage

UKPDS Follow Up Mean HbA1c levels (years 1-5 post-trial) · 3277 participants were monitored in the 10-year post-trial follow-up via annual clinical visits for first 5 years and annual questionnaires for last 5 years

UKPDS=United Kingdom Prospective Diabetes Study

Differences in mean HbA1c between participants originally assigned to intensive or conventional therapy were lost by year 1 of post-trial follow-up. A: sulfonylurea/insulin vs conventional therapy; B: metformin vs conventional therapy

Relative risk reductions with sulfonylurea/insulin After 8.5 years (median) of post-trial follow-up Aggregate Endpoint Any diabetes-related endpoint Microvascular disease Myocardial infarction All-cause mortality

RRR=relative risk reduction P-values calculated with use of log-rank test

Relative risk reductions with metformin After 8.8 years (median) of post-trial follow-up Aggregate Endpoint Any diabetes-related endpoint Microvascular disease Myocardial infarction All-cause mortality

RRR=relative risk reduction P-values calculated with use of log-rank test

1997

RRR: P-value: RRR: P-value: RRR: P-value: RRR: P-value:

2007 9% 0.04 24% 0.001 15% 0.01 13% 0.007

1997

RRR: P-value: RRR: P-value: RRR: P-value: RRR: P-value:

2007 21% 0.01 16% 0.31 33% 0.005 27% 0.002

12% 0.029 25% 0.0099 16% 0.052 6% 0.44

32% 0.0023 29% 0.19 39% 0.01 36% 0.011

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Clinical implications

· The 10-year UKPDS follow-up observed a `legacy effect' of intensive glucose therapy: continued vascular benefits despite loss of glycaemic differences from conventional treatment · Sustained benefits were noted with sulfonylurea/insulin and metformin as intensive regimens · Reductions in myocardial infarction and all-cause mortality, which had not been statistically significant in the original trial, became significant for the intensively treated participants during the post-trial · UKPDS follow-up supports initiation of intensive glucose therapy as early as possible in course of diabetes

Why Is It Difficult to Control Type 2 DM?

It is a progressive disease!

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Type 2 diabetes is a progressive disease: early intervention is critical

Macrovascular complications Microvascular complications

-cell function

Insulin resistance Blood glucose

­10

Prevention

IFG/IGT

0 Diagnosis

Treatment

Type 2 diabetes

10+

Years

IFG: impaired fasting glucose IGT: impaired glucose tolerance

Adapted from DeFronzo RA. Med Clin N Am 2004;88:787­835.

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19

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The case for early combination therapy: reaching and maintaining glycemic goals

Diet and exercise OAD monotherapy OAD combination Mean OAD uptitration

Primary sites of action of anti-diabetic agents

Muscle

Metformin1 Thiazolidinediones4

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OAD + basal insulin

OAD + multiple daily insulin injections

H HbA1c(%)1

9 8 7 6

DPP-4 inhibitors2

Adipose tissue

Liver

Sodium glucose transporter-2 inhibitors5

Pancreas P

DPP-4 GLP-1 Insulin Glucose

Kidney

Duration of diabetes

Intestines

GLP-1 agonists3 Complications2

1Adapted 1Adapted

Sulphonylureas and meglitinides1

-glucosidase inhibitors1

OAD = oral anti-diabetic

from Del Prato S, et al. Int J Clin Pract 2005;59:1345­1355. 2Stratton IM, et al. BMJ 2000;321:405­412.

3Todd

from Krentz A and Bailey C. Drugs 2005;65:358­411. 2Ahren B. Expert Opin Emerg Drugs 2008;3:593­607. JF, et al. Diabet Med 2007;24:223­232. 4Nattrass M, et al. Baillieres Best Pract Res Clin Endocrinol Metab 1999;13:309­329. 5Jabbour S and Goldstein B. Int J Clin Pract 2008;62:1279­1284.

All type 2 diabetic patients will eventually require insulin therapy!!

The Lower The A1c Goal, The Earlier This Will Happen!

Glycemic goals: non-pregnant adults with diabetes

· HbA1c < 7.0% · Preprandial capillary plasma glucose 70-130 mg/dl · Peak postprandial capillary plasma glucose < 180 mg/dl*

When to start insulin?

As early in the course of DM as needed!

· HbA1c is the primary target for glycemic control

· * Postprandial measurements should be made 1-2 h after the beginning of the meal, generally peak levels in patients with diabetes.

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Glycemic Goals

· Goals should be individualized based on:

· · · · · · duration of diabetes age/life expectancy comorbid conditions known CVD or advanced microvascular complications hypoglycemia unawareness individual patient considerations

ADA Treatment Algorithm

· More or less stringent glycemic goals may be appropriate for individual patients · Postprandial glucose may be targeted if HbA1c goals are not met despite reaching preprandial glucose goals

Diabetes interventions by tiers

· Tier 1 Interventions (`well-validated core') Lifestyle changes to reduce weight/increase exercise (1.0-2.0)* Metformin (1.0-2.0)

Clinical Implications

· Algorithm encourages flexibility and clinical judgment in Type 2 diabetes treatment · Algorithm is cautious in use of newer treatments · Lack of head-to-head trials continues to impede informed comparisons of strategies · In severely uncontrolled diabetes, lifestyle + insulin is preferred regimen · Long-term ability to control diabetes or reduce cardiovascular complications still a concern

Insulin (1.5-3.5)

Sulfonylureas (1.0-2.0) · Tier 2 Interventions (`less well-validated' core) Thiazolidinediones (pioglitazone) (0.5-1.4) Glucagon-like peptide-1 (GLP 1) agonists ( Gl lik tid 1 (GLP-1) i t (exenatide) (0 5 1 0) tid ) (0.5-1.0) · Others (less effective glucose reduction, less evidence, or costlier) -Glucosidase inhibitors (0.5-0.8) Glinides (0.5-1.5) Pramlintide (0.5-1.0) Dipeptidyl peptidase-4 (DPP-4) inhibitors (0.5-0.8)

*Numbers in parentheses are expected percentage point decrease in HbA1c with monotherapy

Why Insulin?

· Worsening glycemic control in Type 2 DM is due to progressive decrease of insulin production Most potent agent for lowering glucose levels Very wide therapeutic range ­ Easily titrated and the ability to fine tune Only limitation to achieving goal is hypoglycemia ­ Otherwise very few side effects ­ No drug-drug interactions Has been shown to be effective in decreasing microvascular and macrovascular complications · ·

·

·

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Treat to Target: Less Hypoglycemia With Glargine Than NPH

Cumulative # of Documented PG < 72 mg/dl

Cumulative # of Documented PG < 56 mg/dl

Treat-toTreat-to-Target: addition of detemir or NPH to oral therapy

475 People with Type 2 Diabetes on 1 or 2 Oral Agents

Glycaemic Control

Baseline HbA1c

0.0

Glargine NPH

Glargine NPH

Hypoglycaemia (events pt-yr-1)

8.6% 12

8.5%

HbA1c

-0.5 05 -1.0 -1.5 -2.0 -1.9% -1.8%

8 NPH 4 detemir 0 6.8%

P=NS Final HbA1c 6.6% NPH insulin

5.0

6.0

7.0 HbA1c (%)

8.0

9.0

Diabetes Care 26:3080­3086, 2003

Insulin detemir

Hermansen K et al. Diabetes Care. 2006;29:1269-1274

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Normal Insulin Secretion

70

Prandial Phase (Bolus)

Insulin (mU/L)

50

Serum insulin

30

Basal Phase

10 0

9:00

AM

12:00

PM

3:00

PM

6:00

PM

9:00

PM

12:00

AM

3:00

AM

6:00

AM

Breakfast

Lunch

Dinner

Time of day

Polonsky. N Engl J Med. 1996;334:777-783.

How Do We Control Glucose Throughout The Day Using Insulin

· Use basal insulin and rely on sulfonylureas and/or other agents to control postprandial glucose · Provide basal insulin once daily and rapid acting insulin before each meal (Basal Bolus or MDI)

­ Provides most flexibility ­ Four shot day, more work and training

· Combine actions of basal and bolus insulin into one product (Premix)

­ Human premixed insulin 70/30 ­ Premixed analog insulin (70/30, 75/25, 50/50)

Premixed Insulin

· Usually start twice daily unless special reasons · Need a stable meal plan, 3x daily, dose and time · Large lunches may require 3rd small dose

Weakness of Premixed Insulins

Post Lunch Hypoglycemia Coverage

Nocturnal

· Look for nocturnal hypoglycemia · Can get variable post prandial effect by choosing between 75/25, 70/30 or 50/50 premix ratios · Variable meal times, size of meals, or skipped meals require basal bolus therapy!

The Diabetes Educator 2007; 33; 66

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Goals of Prandial Insulin Therapy for DM Management

· Provide fast onset of Action and rapid decline in activity

Basal Bolus (MDI)

· Reduce the risk of therapy-associated hypoglycemia

· Reduce variability of response

Basal Bolus Insulin Treatment

Insulin

Lispro (Humalog) or Aspart (NovoLog) or Glulisine (Apidra)

Glargine (Lantus) or Detemir (Levemir) as Basal Insulin

Breakfast

Lunch

Supper HS

Breakfast

Case #1

· Chase is a 63-year-old male with a BMI of 37 kg/m2. His A1C is 11.2%, and his FPG is 280 mg/dl. · His initial therapy consisted of metformin 2,000 mg daily, plus a diet and exercise plan. · At his 3-month follow-up visit, his A1C was 9.4%, and his FPG was 210 mg/dl.

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Case #1

· What Next? One approach would be to add a second oral agent

­ Sulfonylurea?

· Recent meta-analysis has shown: ­ Adding an SU to metformin is unlikely to reduce A1C by > 1% ­ Deterioration of glycemic control after addition of an SU is frequent within 6 months ­ This approach is associated with weight again and a higher incidence of hypoglycemia

Case #1

· Other alternatives might include an oral DPP-4inhibitor or a GLP 1 analog ­ Neither would be predicted to reach the A1CA1C lowering goal of 7.0%

Case #1

· Insulin? · He could be started on a basal insulin such as detemir or glargine. · Initiation of basal insulin might be expected to reduce the A1C level by 2­2.5%, avoiding the addition of a second oral agent.

Case #2

· Blaine is a 58-year-old man with hypertension, dyslipidemia, and type 2 diabetes. · His BMI is 32 kg/m2, and his weight is 83 kg. · His A1C is 8.5%, his FPG is 160 mg/dl, and his PPG is 218 mg/dl. · He is being managed with metformin 1,000 mg twice daily plus pioglitazone, 30 mg daily, and glimepiride, 4 mg daily.

Case #2

· Detemir is initiated and titrated to a dose of 25 units daily · At follow up his A1c is 7.2%. · When looking at his blood glucose values, his fasting readings have been improved, though on occasion he has had some mild hypoglycemia overnight (60-70mg/dl). · Despite this, he post meal readings have been · What next?

Case #2

· What is the defect?

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Case #2

· You decide to initiate prandial insulin in addition to his basal insulin. · Key questions: ­ How much? ­ What meal(s)? ­ What about the SU? ­ What about the fasting hypoglycemia?

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