Practical Considerations in Clinical Management

Guideline-recommended glycemic targets in diabetes

A1C(%)

FPG(mg/dL)

Postprandialglucose(mg/dL)

ADA <7 90-130 <180*

ACE ≤6.5 <110 <140†

*Plasma; †BloodADA = American Diabetes AssociationACE = American College of Endocrinology

ADA. Diabetes Care. 2007;30(suppl 1):S4-41.ACE. Endocr Pract. 2002;8(suppl 1):5-11.

Glucose dynamics: Basal and prandial

Riddle MC. Am J Med. 2004;116(suppl):3S-9.

Plasma glucose (mg/dL)

Time of day

200

250

150

100

50

0

0600 1200 1800 0600

Type 2diabetes

2400

Normal

Basal hyperglycemia

Postprandial hyperglycemia

Relative contributions of postprandial glucose and FPG to A1C

20

40

60

80

100

Fasting plasma glucose Postprandial plasma glucose

Monnier L et al. Diabetes Care. 2003;26:881-5.

A1C quintiles (%)

0>10.29.3–10.28.5–9.27.3–8.4<7.3

Contribution(%)

Glycemic control deteriorates with standard therapies

Cook MN et al. Diabetes Care. 2005;28:995-1000.

N = 2220 with T2DM treated with SU + MET

≥109.0-9.98.0-8.94.0-7.9

~85% of patients had A1C ≥8% after 4 years

Patients with

A1C ≥8%(%)

SU = sulfonylurea, MET = metformin

Pre-SU A1C levels (%)100

80

60

40

20

00 1 2 3 4

Time from sulfonylurea initiation (years)

A1C reduction with glucose-lowering medications

Nathan DM. N Engl J Med. 2007;356:437-40.

Oral agents A1C (%)*

Sulfonylureas 1.5

Biguanides (metformin) 1.5

Glinides 1.0–1.5

Thiazolidinediones 0.8–1.0

DPP-IV inhibitors 0.5–0.9

α-Glucosidase inhibitors 0.5–0.8

Parenteral/inhaled agents

Insulin ≥2.5

Inhaled insulin 1.5

GLP analogues 0.6

Amylin analogues 0.6

*MonotherapyDPP = dipeptidyl peptidase; GLP = glucagon-like peptide

Oral diabetes agents

Drug class Agent(s) Mechanism(s) of action

α-Glucosidase inhibitors

Acarbose, miglitol Delay carbohydrate absorption

Biguanides Metformin Hepatic glucose production Insulin sensitivity in liver + muscle

Sulfonylureas Glimepiride, glipizide, glyburide

Insulin secretion from pancreatic cells

Meglitinides Nateglinide, repaglinide

Insulin secretion from pancreatic cells

Thiazolidinediones Pioglitazone, rosiglitazone

Insulin sensitivity in fat cells + muscle

DPP-IV inhibitors Sitagliptin, vildagliptin (Phase III)

GLP-1 degradation; Glucose-dependent insulin secretion

Trujillo J. Formulary. 2006.Luna B, Feinglos MN. Am Fam Physician. 2001.

Smyth S, Heron A. Nat Med. 2006.

Incretin agents in glucose control

DPP-IV inhibitors Incretin mimetics

• Significant A1C

• Weight neutral

• Oral administration

• Almost no GI side effects

• Very low rate of hypoglycemia

• Multiple targets (GLP-1 and GIP)

• Significant A1C

• Weight loss

• Injection

• Higher rate of GI side effects

• Low rate of hypoglycemia

• Single target (GLP-1)

Trujillo J. Formulary. 2006;41:130-41.GIP = gastric inhibitory peptide

ADA: Managing hyperglycemia in T2DM

Adapted from ADA. Diabetes Care. 2007;30(Suppl 1):S4-41.

Lifestyle intervention + metformin

If A1C > goal

Add sulfonylurea(least expensive)

Add basal insulin(most effective)

Add glitazone(no hypoglycemia)

Add basal or intensify insulin

Intensive insulin + metformin +/- glitazone

If A1C > goal If A1C > goal

Intensify insulin Add glitazone Add basal insulin Add sulfonylurea

If A1C > goalIf A1C > goal If A1C > goal

ADA goal: A1C <7%

ACE road map to glycemic goals in T2DM: Treated patients

Maximize OAD combinationsMaximize insulin therapy

A1C (%)

Mono- or combination therapy

Mono- or combination therapy

Current therapy Intervention

• Monitor every2–3 months

• Adjust treatment to meet ACE glycemic goals

Monotherapy

Combination therapy

ACE/AACE. www.aace.com.

Initiate insulin therapy (basal-bolus)

Initiate combination therapy*

Continue therapy oradjust as needed to meet ACE glycemic targets

*Add rapid-acting insulin analogs at any time to address persistent postprandial hyperglycemia

Co

ntin

ue lifestyle m

od

ification6.0–6.5

6.5–8.5

>8.5

Treat-to-Target study: Basal insulin lowers FPG and A1C

Riddle MC et al. Diabetes Care. 2003;26:3080−6.

N = 756 previously treated with 1–2 OADs; Mean A1C 8.6%

~60% reached A1C ≤7%

FPG, mean

(mg/dL)

NPHInsulin glargine

A1C,mean (%)

Weeks of treatment

200

150

1000 4 8 12 16 20 24 0 4 8 12 16 20 24

6

7

8

9

NPH = neutral protamine Hagedorn insulin

Treat-to-Target: Nocturnal hypoglycemia vs glycemic control

Riddle MC et al. Diabetes Care. 2003;26:3080―6.

Insulin glargine (n = 367)

NPH (n =

389) P

A1C ≤7% (%) 58 57

Without nocturnal hypoglycemia (%) 33 27 <0.05

FPG ≤100 mg/dL (%) 36 34

Without nocturnal hypoglycemia (%) 22 16 <0.03

Dose, mean (units/day) 47.2 41.8 <0.005

Fewer hypoglycemic episodes withinsulin analogueN = 371 with poorly controlled T2DM on SU + MET

Janka HU et al. Diabetes Care. 2005;28:254-9.

0

2

4

6

8

10

12

Total Symptomatic Nocturnal

Insulin glargine + OAD Premixed insulin*

Hypoglycemic events, mean

(per patient-years)

P < 0.0001

P = 0.0009

P = 0.0449

*30% regular/70% NPH insulin

Insulin glargine + OAD effect on weight, A1C

0.9

-0.3

-1.3

-2.1

-0.5

-3.0

-2.0

-1.0

0.0

1.0

N = 12,216 with poorly controlled T2DM on OAD; 9-month outcomes

Schrieber SA, Haak T. Diabetes Obes Metab. 2007;9:31-8.

<25 25 to <30 30 to <35 ≥35

BMI subgroup analysis

BMI(kg/m2)

BMI (kg/m2)

A1C (%) -1.6 -1.6 -1.7 -1.8

All

-1.6

= change from baseline at 9 months

Glycemic control and weight change with detemir vs NPH insulin

Hermansen K et al. Diabetes Care. 2006;29:1269-74.

N = 475 with poorly controlled T2DM on OAD; add-on detemir or NPH

>70% achieved A1C ≤7% Mean weight gain (lbs) Detemir: 2.6; NPH: 6.2(P < 0.001)

A1C (%)

Study week

Body weight (lbs)

Study week

10

9

8

7

6

-2 0 4 8 12 16 20 24

189

187

185

182

178

-2 0 4 8 12 16 20 24

NPHDetemir

180

00

Add-on treatment with glargine vs rosiglitazone + SU/MET: A1C and FPGN = 217 with T2DM

Rosenstock J et al. Diabetes Care. 2006;29:554-9.*P < 0.05, †P = 0.001 between groups

A1C, from

baseline(%)

FPG, mean

(mg/dL)

Time (weeks)RosiglitazoneInsulin glargine

†

†

† †

0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

-3.5

200

180

160

140

120

100

7 8 9 10 11

0 4 12 20 248 16

**

**

Glargine vs rosiglitazone added to SU + MET: Lipid effects

Rosenstock J et al. Diabetes Care. 2006;29:554-9.

Change from

baseline(%)

Total-C LDL-C TG HDL-C

*

*P = 0.0001, †P = 0.0004, ‡P = 0.001, §P = 0.04 between groups

†

‡ §

Insulin glargine Rosiglitazone

N = 217 with T2DM

-4.4-1.4

-19.0

0

10.113.1

4.6 4.4

-20

-10

0

10

20

Add-on Rx with glargine vs rosiglitazone + SU/MET: Comparative adverse effects

Insulin glargine(n = 105)

Rosiglitazone(n = 112) P

Nocturnal hypoglycemia* (%) 27.6 10.7 0.02

Weight gain (lb) 3.7 6.6 0.02

Peripheral edema (%) 0 12.5 0.001

Adverse events (%) 6.7 28.6 <0.0001

Rosenstock J et al. Diabetes Care. 2006;29:554-9.*Plasma glucose <70 mg/dL

N = 217 with T2DM

Basal and bolus insulin pharmacodynamics

Formulation Coverage Duration (hr) Dosing

Glargine Basal 24 Once daily

Detemir Basal 14 Once or twice daily

NPH Basal 13 Twice daily

Lispro Prandial 3–4 ≤15 min premeal to immediately postmeal

Aspart Prandial 3–4 ≤15 min premeal to immediately postmeal

Glulisine Prandial 3–4 ≤15 min premeal to ≤20 min postmeal

RHI Prandial 6–8 30 min premeal

Flood TM. J Fam Practice. 2007;56(suppl):S1-12.RHI = regular human insulin

Bas

alB

olu

s

Dispelling misconceptions about insulin

Traditional thinking

• Atherogenic

• Fear of hypoglycemia

• Fear of weight gain

• Frequent injections

Newer concepts

• Anti-atherogenic

• Less nocturnal hypoglycemia with steady-state once-daily basal insulins

• Weight neutral

• Long-acting basal insulins require fewer injections

Dandona P et al. Am J Cardiol. 2007;99(suppl):15B-26.Stotland NL. Insulin. 2006;1:38-45.

II IIaIIa IIbIIb IIIIII

B

B

C

Aggressively modify other CV risk factors (physical activity, weight, BP, cholesterol)

Coordinate care with endocrinologist or PCP

ACC/AHA secondary prevention guidelines: Diabetes management

Smith SC et al. Circulation. 2006;113:2363-72.

Initiate lifestyle and pharmacotherapy to achieve A1C <7%

Class and level of evidence

Discharge strategies for patients with hyperglycemia

ACE/ADA. Diabetes Care. 2006;29:1955-62.

Lifestyle modification (nutrition and exercise)

Insulin vs OAD for long-term management

Patient educationeg, self-monitoring of glucose

Continuity of carePCP ± Endocrinologist

Managing glucose in T2DM

• Diabetes is a progressive disease

• Most patients will require multiple therapies to achieve A1C goals

• Utilize lifestyle intervention and metformin as initial treatment

• Add medications rapidly and transition to new agents when A1C target is not achieved/sustained

• Add insulin early in patients who do not meet A1C targets

Nathan DM et al. Diabetologia. 2006;49:1711-21.

Continuity of care for diabetes: It takes a health care team

ADA. www.diabetes.org.

Patient

Physician

Dietician

Podiatrist

Social worker or psychologist

Exercise physiologist

Eye doctor

Diabeteseducator