Practical Considerations in Clinical Management

1
Practical Considerations in Clinical Management
2
Guideline-recommended glycemic targets in diabetes
A1C () FPG (mg/dL) Postprandialglucose (mg/dL)
ADA lt7 90-130 lt180
ACE 6.5 lt110 lt140
Plasma Blood ADA American Diabetes
AssociationACE American College of
Endocrinology
ADA. Diabetes Care. 200730(suppl 1)S4-41. ACE.
Endocr Pract. 20028(suppl 1)5-11.
3
Glucose dynamics Basal and prandial
250
Postprandial hyperglycemia
200
Type 2diabetes
Plasma glucose (mg/dL)
150
Basal hyperglycemia
100
50
Normal
0
0600
1200
1800
0600
2400
Time of day
Riddle MC. Am J Med. 2004116(suppl)3S-9.
4
Relative contributions of postprandial glucose
and FPG to A1C
100
80
60
Contribution ()
40
20
0
9.310.2
8.59.2
7.38.4
lt7.3
gt10.2
A1C quintiles ()
Fasting plasma glucose Postprandial
plasma glucose
Monnier L et al. Diabetes Care. 200326881-5.
5
Glycemic control deteriorates with standard
therapies
N 2220 with T2DM treated with SU MET
Pre-SU A1C levels ()
100
10 9.0-9.9 8.0-8.9 4.0-7.9
80
Patients withA1C 8 ()
60

• 85 of patients had A1C 8 after 4 years

40
20
0
0
1
2
3
4
Time from sulfonylurea initiation (years)
SU sulfonylurea, MET metformin
Cook MN et al. Diabetes Care. 200528995-1000.
6
A1C reduction with glucose-lowering medications
Oral agents ?A1C ()
Sulfonylureas 1.5
Biguanides (metformin) 1.5
Glinides 1.01.5
Thiazolidinediones 0.81.0
DPP-IV inhibitors 0.50.9
a-Glucosidase inhibitors 0.50.8
Parenteral/inhaled agents
Insulin 2.5
Inhaled insulin 1.5
GLP analogues 0.6
Amylin analogues 0.6
Monotherapy DPP dipeptidyl peptidase GLP
glucagon-like peptide
Nathan DM. N Engl J Med. 2007356437-40.
7
Oral diabetes agents
Drug class Agent(s) Mechanism(s) of action
a-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.
8
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)
GIP gastric inhibitory peptide
Trujillo J. Formulary. 200641130-41.
9
ADA Managing hyperglycemia in T2DM
ADA goal A1C lt7
Adapted from ADA. Diabetes Care. 200730(Suppl
1)S4-41.
10
ACE road map to glycemic goals in T2DM Treated
patients
A1C ()
Current therapy
Intervention
Mono- or combination therapy
Initiate insulin therapy (basal-bolus)
gt8.5

• Monitor every23 months
• Adjust treatment to meet ACE glycemic goals

Maximize OAD combinations Maximize insulin therapy
Combination therapy
6.58.5
Continue lifestyle modification
Monotherapy
Initiate combination therapy
Mono- or combination therapy
Continue therapy oradjust as needed to meet ACE
glycemic targets
6.06.5
Add rapid-acting insulin analogs at any time to
address persistent postprandial hyperglycemia
ACE/AACE. www.aace.com.
11
Treat-to-Target study Basal insulin lowers FPG
and A1C
N 756 previously treated with 12 OADs Mean
A1C 8.6
200
9
8
FPG, mean(mg/dL)
A1C,mean ()
150
7
100
6
0
4
8
12
16
20
24
0
4
8
12
16
20
24
Weeks of treatment
60 reached A1C 7
NPH
Insulin glargine

NPH neutral protamine Hagedorn insulin
Riddle MC et al. Diabetes Care. 2003263080-6.
12
Treat-to-Target Nocturnal hypoglycemia vs
glycemic control
Insulin glargine (n 367) NPH (n 389) P
A1C 7 () 58 57
Without nocturnal hypoglycemia () 33 27 lt0.05
FPG 100 mg/dL () 36 34
Without nocturnal hypoglycemia () 22 16 lt0.03
Dose, mean (units/day) 47.2 41.8 lt0.005
Riddle MC et al. Diabetes Care. 2003263080?6.
13
Fewer hypoglycemic episodes withinsulin analogue
N 371 with poorly controlled T2DM on SU MET
P lt 0.0001
Hypoglycemic events, mean(per patient-years)
P 0.0009
P 0.0449
Insulin glargine OAD
Premixed insulin
30 regular/70 NPH insulin
Janka HU et al. Diabetes Care. 200528254-9.
14
Insulin glargine OAD effect on weight, A1C
N 12,216 with poorly controlled T2DM on OAD
9-month outcomes
BMI subgroup analysis
? BMI (kg/m2)
lt25
25 to lt30
30 to lt35
35
BMI (kg/m2)
All
? A1C ()
-1.6
-1.6
-1.7
-1.8
-1.6
? change from baseline at 9 months
Schrieber SA, Haak T. Diabetes Obes Metab.
2007931-8.
15
Glycemic control and weight change with detemir
vs NPH insulin
N 475 with poorly controlled T2DM on OAD
add-on detemir or NPH
10
189
187
9
185
8
Body weight (lbs)
A1C ()
182
7
180
6
178
0
0
-2
0
4
8
12
16
20
24
-2
0
4
8
12
16
20
24
Study week
Study week
gt70 achieved A1C 7
Mean weight gain (lbs) Detemir 2.6 NPH 6.2 (P
lt 0.001)
NPH
Detemir
Hermansen K et al. Diabetes Care. 2006291269-74.
16
Add-on treatment with glargine vs rosiglitazone
SU/MET A1C and FPG
N 217 with T2DM
7
8
9
10
11
0
200
-0.5
180
-1.0

A1C, ? from baseline()
160
FPG, mean (mg/dL)

-1.5



-2.0


140

-2.5
120
-3.0
-3.5
100
0
4
12
20
24
8
16
Time (weeks)
Rosiglitazone
Insulin glargine
P lt 0.05, P 0.001 between groups
Rosenstock J et al. Diabetes Care. 200629554-9.
17
Glargine vs rosiglitazone added to SU MET
Lipid effects

N 217 with T2DM
HDL-C
Total-C
LDL-C
TG
20


13.1
10.1
10


4.6
4.4
Change from baseline ()
0
0
-1.4
-4.4
-10
-20
-19.0
Insulin glargine
Rosiglitazone
P 0.0001, P 0.0004, P 0.001, P 0.04
between groups
Rosenstock J et al. Diabetes Care. 200629554-9.
18
Add-on Rx with glargine vs rosiglitazone
SU/MET Comparative adverse effects
N 217 with T2DM
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 lt0.0001
Plasma glucose lt70 mg/dL
Rosenstock J et al. Diabetes Care. 200629554-9.
19
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 34 15 min premeal to immediately postmeal
Aspart Prandial 34 15 min premeal to immediately postmeal
Glulisine Prandial 34 15 min premeal to 20 min postmeal
RHI Prandial 68 30 min premeal
Basal
Bolus
RHI regular human insulin
Flood TM. J Fam Practice. 200756(suppl)S1-12.
20
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. 200799(suppl)15B-
26. Stotland NL. Insulin. 2006138-45.
21
ACC/AHA secondary prevention guidelines Diabetes
management
Class and level of evidence
I
IIa
IIb
III
Initiate lifestyle and pharmacotherapy to achieve
A1C lt7
B
Aggressively modify other CV risk factors
(physical activity, weight, BP, cholesterol)
B
C
Coordinate care with endocrinologist or PCP
Smith SC et al. Circulation. 20061132363-72.
22
Discharge strategies for patients with
hyperglycemia
Lifestyle modification (nutrition and exercise)
Insulin vs OAD for long-term management
Patient educationeg, self-monitoring of glucose
Continuity of carePCP Endocrinologist
ACE/ADA. Diabetes Care. 2006291955-62.
23
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. 2006491711-21.
24
Continuity of care for diabetes It takes a
health care team
Patient
Physician
Diabeteseducator
Dietician
Eye doctor
Exercise physiologist
Podiatrist
Social worker or psychologist
ADA. www.diabetes.org.