Post on 02-Feb-2016
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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