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· 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


· 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.


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


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


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


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!


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

Macrovascular complications Microvascular complications

-cell function

Insulin resistance Blood glucose




0 Diagnosis


Type 2 diabetes



IFG: impaired fasting glucose IGT: impaired glucose tolerance

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




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


Metformin1 Thiazolidinediones4


OAD + basal insulin

OAD + multiple daily insulin injections

H HbA1c(%)1

9 8 7 6

DPP-4 inhibitors2

Adipose tissue


Sodium glucose transporter-2 inhibitors5

Pancreas P

DPP-4 GLP-1 Insulin Glucose


Duration of diabetes


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.


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.


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 · ·




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


Glargine NPH

Glargine NPH

Hypoglycaemia (events pt-yr-1)

8.6% 12



-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



7.0 HbA1c (%)



Diabetes Care 26:3080­3086, 2003

Insulin detemir

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


Normal Insulin Secretion


Prandial Phase (Bolus)

Insulin (mU/L)


Serum insulin


Basal Phase

10 0




















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


· 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


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


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

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



Supper HS


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.


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?


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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