Early Insulinization

John N Clore MD Virginia Commonwealth University Richmond Virginia

T2DM Is Characterized by Insulin Deficiency and Insulin Resistance
Inherited/Acquired Factors Overweight, Inactivity (Inherited/Acquired) ↑ FFA

Insulin Deficiency

Insulin Resistance

Glucolipotoxicity

↓ Glucose Uptake ↑ Production of Glucose in the Liver

Hyperglycemia T2DM

FFA, free fatty acid; T2DM, type 2 diabetes mellitus®. Yki-Järvinen H. In: Pickup JC, Williams G, eds. Textbook of Diabetes 1. 3rd ed. 2003:22.1-22.19.

Glucolipotoxicity Hyperglycemia and lipemia aggravate – Impaired β -cell function – Insulin resistance Agents which reduce glucose and lipid levels would be expected to improve beta cell function and enhance glucose control ? Insulin .

HbA1c overweight patients cohort. median values 9 Conventional Insulin Chlorpropamide Glibenclamide Metformin 8 HbA 1c (%) 7 6 0 0 2 4 6 8 Years from randomisation 10 .

0% • Preprandial plasma glucose 70-130 mg/dL (3.9-7.2 mM) • Peak postprandial plasma glucose < 180 mg/dL (<10 mM) Diabetes Care 2008 .ADA Recommendations • HbA1c < 7.

Achievement of Targets • HbA1c < 7.5% NHANES 2002 .3% 35.0% 42.0% • LDL < 100 • BP < 140/90 38.

HbA1c overweight patients cohort. median values 9 Conventional Insulin Chlorpropamide Glibenclamide Metformin 8 HbA 1c (%) 7 6 0 0 2 4 6 8 Years from randomisation 10 .

0023 0.6 Conventional (411) Intensive (951) Metformin (342) 0.4 M v C p=0.0 0 MvI p=0.2 0.0034 3 6 9 12 Years from randomisation 15 .UKPDS-Any diabetes related endpoint overweight patients Proportion of patients with events 0.

2006. European Association for the Study of Diabetes. thiazolidinedione.Strategies for Management of T2DM ADA/EASD Consensus Statement Diagnosis Lifestyle intervention + biguanide If A1C ≥ 7% after 2-3 months Add basal insulin If A1C ≥ 7% Intensify insulin If A1C ≥ 7% Add sulfonylurea If A1C ≥ 7% Add TZD—if A1C < 8% Add basal insulin Add TZD If A1C ≥ 7% Add sulfonylurea— if A1C < 8% If A1C ≥ 7% Intensive insulin + biguanide ± T2D* Add basal insulin or intensify insulin EASD. . TZD.29:1963-1972. Adapted from Nathan DM et al. Diabetes Care.

Diabetes. . 1995.44:1249-1258.Type 2 Diabetes is a Progressive Disease 100 80 60 40 20 0 -10 -9 -8 -7 -6 -5 -4 -3 β -cell function (%) -2 -1 0 1 2 3 4 5 6 Time (years) 04/07/11 07:34 PM Cardiovascular 10 Adapted from UKPDS Group.

N Engl J Med 2006.Kaplan-Meier Estimates of the Cumulative Incidence of Monotherapy Failure at 5 Years Kahn SE et al.355:2427-2443 .

Choices in Medication Percentages of adults 50 45 40 35 30 25 20 15 10 5 0 Oral Insulin I + Oral 1997 1998 1999 2000 2001 2002 2003 .

Treatment in Type 2 Diabetes • Monotherapy – 44.0% SU • 3rd Drug – 37.0% Insulin .7% SU • 2nd-Drug – 36.3% Metformin 36.6% TZD 33.9% Metformin 43.

0 HbA1c increased above 7% within 11 months • HbA1c averaged 8.8% < 7.4% for another 32.4% Addition of SU + Metformin 50.8 months without intervention Kaiser Permanente 2007 .Delay in Treatment Escalation • • • • 4365 patients with Type 2 Diabetes Baseline HbA1c 8.

Barriers to Insulin therapy • Injections • Weight Gain • Hypoglycemia • Lack of confidence .

1989 .Insulin Requirements Clore et al.

2 Monnier L et al. % 80 60 40 20 0 <7.26:881–885.4 8.3 7.Relative Contribution of FPG and PPG to Overall Hyperglycemia Depending on A1C Quintiles Postprandial glucose 100 Fasting glucose Contribution. Diabetes Care. 2003.2 >10.3–8.2 9. A1C .3–10.5–9.

Insulin Preparations Rapid-Acting – Insulin lispro (analogue) – Insulin aspart (analogue)* – Insulin glulisine (analogue) Short-Acting – Regular (soluble) Intermediate-Acting – NPH (isophane) Long-Acting – Insulin glargine (analogue) – Insulin detemir .

the total basal insulin dose required will be ~ 0. Based on available data.4-0. .2 U/kg basal insulin ● Titrate every 4-7 days based on home glucose monitoring until the fasting glucose is 100 mg/dl.8 U/kg.A Basal Insulin Strategy Continue oral agents ● Add 0.

June 2001. ADA Annual Meeting. mg/dL (±SE) 43 44 .Insulin Dosage and FPG During Study (Both treatment groups) 50 ) ES ± 40 30 20 206 31 33 36 37 39 41 200 175 28 25 16 10 153 142 135 135 128 125 121 118 117 116 150 10 0 100 0* 2 4 6 8 10 12 14 16 18 es o D yi a Dl a oT l t Weeks in Study Preliminary data. *Mean FPG. Adapted from Rosenstock et al. Abst. 520-P. *Week 0 based on a starting dose of 10 units. Philadelphia. PA.

7 1.Comparison of Glargine and Detemir Comparisons of clinical efficacy of basal insulin preparations in patients with type 2 diabetes mellitus during 24-week insulin titration studies Insulin HbA1c reduction Weight gain.8 3 1. kg/24 wk (Baseline 8.6%) 1.8   2.63 [24]   NPH Glargine Detemir Clore and Thurby-Hay.2 Nocturnal hypoglycemi a (RR vs NPH) — 0. 2007 .7 1.66 [24] 0.

2 to 6.Insulin vs SU in Newly Diagnosed Type 2 diabetes • Small study in 51 patients • Subjects randomized to two injections of 70/30 insulin or glibenclamide • Glucagon stimulated C-peptide • Similar HbA1c reductions (7. 2003 .3%) • Greater C-peptide response with insulin after 1 and 2 years of treatment Diabetes Care 26:2231.

6%) • Randomized to – Baseline orals + glargine at bedtime – Up-titration of oral medications Diabetic Medicine 23:736. 2006 .INSIGHT • 405 patients with Type 2 diabetes mellitus • Inadequately controlled on oral medications (baseline HbA1c 8.

INSIGHT 45 40 35 30 25 20 15 10 5 0 HbA1c < 6.5% HbA1c < 7. 2006 .0 % Glargine Conventional Diabetic Medicine 23:736.

55 3.25 2.89 1. 2006 .38 0.31 0.INSIGHT Fall in Metabolic Parameters HbA1c % FPG (mM) Tg (mM) TC (mM) Non-HDL Glargine 1.47 0.11 0.13 Diabetic Medicine 23:736.37 Control 1.08 0.

4 units/kg) • Cost effective alternative to multiple oral agents • Patient acceptance higher than appreciated .Early (Basal) Insulin Therapy • More effective to achieve HbA1c targets – ? Decreased gluocolipotoxicity – Must be used in sufficient dosage (>0.

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