8. Current FDA Approved
Combination Therapy Options in Type 2
Combination Additional Additional
Lowering of Lowering of FBG
HbA1c (mg/dl)
SU + MTF 1.5 – 2.0 60 – 80
SU + TZD 1.0 – 1.5 40 – 60
MTF + TZD 0.6 – 0.8 20 – 40
SU + AGI 1.0 – 1.5 20 – 40
07/15/12 8
Bonnie Kimmel, MD and Silvio E. Inzucchi, MD Clinical Diabetes 23:64-76, 2005
9. Staged Diabetes
Management at IDC
*
07/15/12 9
Mazze, Strock, Simonson, Kendall, Cuddihy, Bergenstal. SDM Quick Guide 5th Edition, International Diabetes Center, 2009
10. Stages of Type 2 Diabetes—
UKPDS
100
75
β-Cell Function (%)
50
IGT Postprandial Type 2 Type 2 Diabetes
25 Hyperglycemia Diabetes
Type 2 Phase III
Phase I
Diabetes
Phase II
0
-12 -10 -6 -2 0 2 6 10 14
Years From Diagnosis
07/15/12 H. Diabetes Review. 1999;7:139.
Lebovitz 10
13. The Miracle of Insulin
Patient J.L., December 15, 1922 Februray 15, 1923
07/15/12 13
14. UKPDS: decreased risk of diabetes-related complications
associated with a 1% decrease in A1C
Observational analysis from UKPDS study data
corresponding to a 1% decrease in HbA1C
Any
Percentage decrease in relative risk
diabetes- Diabetes- All Peripheral Micro-
related related cause Myocardial vascular vascular Cataract
endpoint death mortality infarction Stroke disease† disease extraction
12%
14% 14%
* 19%
21% 21% ** **
**
** **
37%
†
Lower extremity amputation or fatal peripheral vascular disease 43%
*P = 0.035; **P < 0.0001
**
07/15/12
**
Adapted from Stratton IM, et al. UKPDS 35. BMJ 2000; 321:405–412. 14
15. What are the anabolic effects of Insulin?
Stimulates entry of amino acids into cells,
enhancing protein synthesis
Enhances fat storage (lipogenesis) and prevents
mobilization of fat for energy (Lipolysis and
Ketogenesis)
Stimulates entry of glucose into cells for utilization as
energy source
Promotes storage of glucose as glycogen in muscle and
liver cells (glycogenesis)
07/15/12 15
16. When should Insulin be used in
Type 2 diabetes mellitus?
“The Magnificent Seven”
07/15/12 16
17. When should Insulin be used in
Type 2 diabetes mellitus?
1. Type 2 diabetes not controlled with maximal doses of
Oral Hypoglycaemic agents
What do you mean by maximal doses of OHAs?
Metformin 2500/3000mg a day
+
Glipizide 20mg/glibenclemide15-20mg/day
Gliciazide 320mg/ Glimepride 6-8mg/day
+
Rosiglitazone 8mg/ Pioglitazone 45mg/day
07/15/12 17
18. When should Insulin be used in
Type 2 diabetes mellitus?
2. Type 2 diabetes during periods of physiological
stress (surgery, infection)
Continue OHAs simultaneously.
Stop metformin in case of severe infections or
impending reduction in renal perfusion
07/15/12 18
22. When should Insulin be used in
Type 2 diabetes mellitus?
3. gestational diabetes
Metformin may be continued
Discontinue other medications
07/15/12 22
26. Indications of Insulin therapy?
6. Progressive complications:
proliferative retinopathy/maculopathy,
progressive or painful neuropathy
For rapid control and tighter adjustment
07/15/12 26
27. Indications of Insulin therapy?
7. Chronic Renal Failure
For all above a creatinine of 4.0mg/dl
Cutoffs for other OHAs:-
Metformin: 1.5mg/dl
Glimeperide/Glibenclemide: 2.0mg/dl
Glipizide: 2.5mg/dl
Pioglitazone/Rosiglitazone: 4.0mg/dl
07/15/12 27
28. Normal Pancreas
‘Bolus’ Insulin
(Meal Associated)
Insulin Effect
Basal Insulin
(~0.5-1.0 U/hr)
Insulin is released in response to varying blood
07/15/12
glucose levels and hypoglycemia does not occur 28
29. How does one classify the types of insulin?
♦ Generally classified according to peak effect
and duration of action
♦ Rapid acting/lispro /aspart/glulisine
♦ Short acting: regular.
♦ Intermediate acting: NPH.
♦ Long acting(basal) lantus. /levimer.
♦ Premixed:(30/70), (50/50), (75/25)
07/15/12 29
30. What are the types of Insulin ?
• Short acting : Regular insulin
• Intermediate acting NPH insulin
• Analogs
rapid acting : Lispro, Aspart /glulisine
Long acting : Glargine/levimer
07/15/12 30
31. Insulin Time Action Curves
Rapid-Acting: Lispro (Humalog®), Aspart (NovoLog®),
Glulisine (Apidra®)
Relative Insulin Effect
Short-Acting: Regular (Humulin® R, Novolin® R)
Intermediate: NPH (Humulin® N, Novolin® N)
Long-Acting: Glargine (Lantus®)
Detemir (Levemir®)
0 2 4 6 8 10 12 14 16 18 20
Time (Hours)
Bergenstal, “Effective insulin therapy,” International Textbook of Diabetes Mellitus
vol 1. 3rd ed, Chichester NY, John Wiley and Sons, Inc., 2004:995-1015.
07/15/12 31
32. What are the types
of insulin regimens?
• Premixed regimen
• Split mix regimen
• Basal bolus regime (multidose)
• Bedtime dosing alone (NPH/Lente/Glargine)
• Infusion
07/15/12 32
37. Basic Insulin Regimen:
Split-Mixed Regimen or
Premix
Endogenous insulin
Regular
NPH
B L D HS B
07/15/12 37
38. Basic Insulin Regimen:
Split-Mixed Regimen or
Premix
• Does not
Endogenous insulin mimic normal
Regular
physiology
NPH
Hyperglycemia • Requires
meal
consistency
• Snacking may
result in
weight gain
• Hypo- and
B L D HS B
hyperglycemi
07/15/12 a 38
40. Premixed insulin
• Dose adjustment:
• The fasting sugar depends on the
night dose of insulin
• The post breakfast sugar depends on the
morning dose of insulin
• Rough calculation increase the insulin
by one unit to reduce the sugars by 25mg/dl
07/15/12 40
41. Self Monitoring is crucial
Glucometers
At least 6-8 times a week ideally
07/15/12 41
42. Premixed insulin
Advantages
• more accurate dosing
• lesser injections
• Pen devices administer premixed forms
Disadvantages
• Fine tuning may not be possible
• Strict meal pattern
• Nocturnal hypoglycemia
• May need “diet changes for insulin” rather than
“insulin changes for diet”
07/15/12 42
43. Starting insulin in type 2 diabetes
- patient on full dose OHA
• Continue the OHA
• Start on insulin (approx 0.2-0.4 U/kg/day,morning
2/3, evening 1/3)
• Reassess control with SMBG & titrate dosage
07/15/12 43
44. TIMING OF INJECTION
• 70/30 30 MINUTES BEFORE
BREAKFAST AND SUPPER
• NOVO MIX 70/30
• HUMALOG MIX 25/75 5—15
MINUTES
• BEFORE BREAKFAST AND SUPPER
07/15/12 44
45. ADVANTAGES
• SIMPLE AND EASY TO USE ;draw A
SINGLE DOSE OF A COMBINATION OF
INSULIN IN ONE SYRINGE
• MINIMUM INSULIN DOSING THAT
PROVIDES 24-HOUR INSULIN
COVERAGE
• HUMALOG MIX 75/25 INSULIN OR
NOVO MIX 70/30 INSULIN CAN BE
TAKEN 5-15 MINUTES BEFORE A MEAL
07/15/12 45
46. DISADVANTAGES
• 70/30 INSULIN ;SHOULD WAIT 30
MINUTES AFTER INSULIN INJECTION
BEFORE EATING THE MEAL
• FIXED RATIO OF INTERMEDIATE AND
SHORT OR RAPID ACTING INSULIN
MAY NOT CONTROL BLOOD GLUCOSE
LEVELS
• CAN NOT ADJUST INTERMEDIATE-
ACTING INSULIN COMPONENT
WITHOUT ADJUSTING THE SHORT OR
RAPID ACTING INSULIN COMPONENT
07/15/12 46
47. DISADVANTAGES
• CAN NOT ADJUST REGULAR
INSULIN,INSULINASPART, OR INSULIN
LISPRO FOR VARIATION IN FOOD
INTAKE, BLOOD GLUCOSE LEVELS OR
EXERCISE
• MUST TAKE INSULIN AND EAT MEALS
ABOUT THE SAME TIME EVERY DAY
MUST EAT ACONSISTANT AMOUNT OF
CARBOHYDRATES AT EACH MEAL
FROM DAY TO DAY
• LEAST FLEXABLE OF ALL REGIMENS
07/15/12 47
48. INDICATIONS
• PATIENTS WITH LIMITED
CAPABILITIES
• PATIENTS WHO ARE UNWILLING
TO INTENSIFY REGIMEN
• INITIAL REGIMEN AFTER
DIAGNOSES TO LEARN AND
ADAPT TO INJECTIONS
• TYPE 2 DIABETES
07/15/12 48
50. STARTING DOSE
• 2/3 TOTAL DAILY DOSE
BEFORE
BREAKFAST ,1/3
TOTAL DAILY DOSE
BEFORE SUPPER
• 0.5—1.0 U/KG/DAY
07/15/12 50
51. Pre-mix (70/30)
• Gaps in insulin coverage
• Poor long-term control
• Failure to match endogenous secretion pattern
• Dawn phenomenon
• Increased glycaemia
07/15/12 51
52. Can Oral hypoglycaemic agents
be continued at the same time with insulin?
• Metformin
Best continued if renal function is normal. May
reduce insulin requirements
by 15-30%.
• Adjunctive weight reducing effect
• Thiazolidinediones
• May be continued with insulin.
• Can reduce insulin requirements from
15-60%
• Major issue of weight gain, accentuated by
insulin: 7.5%. 15%>5kg.
07/15/12 52
53. Can Oral hypoglycaemic agents
be continued at the same time with insulin?
• Sulphonylureas
• Glimeperide: doses of 2-4mg a day have a
peripheral GLUT-4 activity reducing insulin
requirement by 10-20%.
• Glipizide and Glibenclemide can reduce insulin
requirements by 5-15%.
• Unpredictable- recommended previously in those
with high C-peptide levels
07/15/12 53
54. Summarizing……..
Insulin administration is suitably as premixed fashion for
most type 2 diabetes. Split-mix may be required in a
subset.
The neccessity of self blood glucose monitoring as a
accessory is emphasized.
07/15/12 54
56. Comparison of Common
Insulin Regimens*
Variable Glargine* NPH1 Premix2,3 Detemir4
Efficacy Insulin Works
Hypoglycemia† 1.0 1.4X 2.5-5.0X 1.0
Insulin Dose 1.0 1.0 1.5-2.0X 1.6-2.1X
Weight Gain 1.0 1.0 1.5X 0.7-1.0X
*
Normalized to glargine; sponsored comparator trials
†
Confirmed hypoglycemia
1
Riddle MC et al. Diabetes Care 2003;26:3080-3086
2
Janka HU et al. Diabetes Care 2005;28:254-259 07/15/12
3
Raskin P et al. Diabetes Care 2005;28:260-265
56
4
Rosenstock J et al. ADA 2006; Abstract 555-P
Slide 1-24 Stages of Type 2 Diabetes Epidemiological studies suggest that the onset of diabetes occurs 10 to 12 years before a clinical diagnosis is made. (Harris 1997) In the UKPDS study of type 2 diabetics, at least 50% of the patients had evidence of diabetic tissue damage when diabetes was first diagnosed. (UKPDS Study 16, 1995) In the earliest phase, when beta-cell function is not impaired, the ability of the beta-cells to hypersecrete insulin masks the impaired glucose tolerance, often for years. During the IGT phase, the FPG will be higher than the normal 110 mg/dL but lower than the 126 mg/dL that is indicative of diabetes. As beta-cell function continues to decline, mild postprandial hyperglycemia develops, reflecting the inability of the beta-cell to hypersecrete enough insulin to overcome insulin resistance. At the end of this prediabetic phase, the first phase of type 2 diabetes typically produces symptoms that lead to a diagnosis. During phase I, in the first 2 years after diagnosis of diabetes, beta-cell function decreases to between 70% and 40% of normal function. CORE
UKPDS 35 was a prospective observational study to determine the relationship between exposure to hyperglycemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes who were participants in the UKPDS. 3,642 white, Asian Indian and Afro-Caribbean UKPDS patients who had HbA 1c measured 3 months after their diabetes diagnosis and with complete data for potential confounders were included in the sub-analysis of relative risk. Reductions in the risk of microvascular and macrovascular complications that might be achieved by lowering HbA 1c by 1% were estimated. The incidence of clinical complications was found to be significantly associated with hyperglycemia. While any reduction in HbA 1c is likely to reduce the risk of complications, the lowest risk was observed in those with HbA 1c values in the normal range (< 6.0%). A 1% decrease in HbA 1c was estimated to correspond with significant reductions in any diabetes-related endpoint, diabetes-related death, all cause mortality, myocardial infarction, stroke, peripheral vascular disease, microvascular disease and cataract extraction. Stratton IM, et al. UKPDS 35. BMJ 2000; 321 :405–412.
This is Mr. M.C.’s left heel ulcer. Note the maggots infesting – but perhaps also debriding – this wound.
Slide 6-23 INSULIN TACTICS Twice-daily Split-mixed Regimens Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years. In some cases, premixed 70/30 insulin is used for this purpose. Patient profiles of insulin levels resulting from this method, as shown in this figure, do not come close to matching the normal endogenous secretory pattern, shown in the shaded background. Patients with type 1 diabetes using this “split-mixed” regimen rarely achieve reasonably good glycemic control by present standards, since they lack endogenous insulin to supplement the partially adequate profile of injected insulin. Type 2 diabetes patients who have substantial endogenous insulin may fare much better with this regimen, but may experience late morning or nocturnal hypoglycemia because of excessive levels of insulin at these times. Berger M, Jorgens V, Mühlhauser I. Rationale for the use of insulin therapy alone as the pharmacological treatment of type 2 diabetes. Diabetes Care . 1999;22(suppl 3):C71-C75; Edelman SV, Henry RR. Insulin therapy for normalizing glycosylated hemoglobin in type II diabetes: applications, benefits, and risks. Diabetes Reviews . 1995;3:308-334.
Slide 29 Twice-Daily Split-Mixed Regimens Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years Patient profiles of insulin levels shown in this slide do not come close to matching the normal endogenous secretory pattern seen in the shaded background Dawn phenomenon refers to the early morning fall of tissue insulin sensitivity counteracted by increased insulin secretion in nondiabetic individuals but manifested as rising glycemia in diabetic patients In some patients with marked dawn phenomenon, NPH insulin may be beneficial. Early morning hyperglycemia may also be managed by dividing the dose of NPH insulin between dinner and bedtime Berger M et al. Diabetes Care . 1999;22(suppl 3):C71-C75 Edelman SV, Henry RR. Diabetes Reviews . 1995;3:308-334
Slide 29 Twice-Daily Split-Mixed Regimens Twice-daily mixtures of NPH and regular insulins have been widely used for type 2 diabetes for many years Patient profiles of insulin levels shown in this slide do not come close to matching the normal endogenous secretory pattern seen in the shaded background Dawn phenomenon refers to the early morning fall of tissue insulin sensitivity counteracted by increased insulin secretion in nondiabetic individuals but manifested as rising glycemia in diabetic patients In some patients with marked dawn phenomenon, NPH insulin may be beneficial. Early morning hyperglycemia may also be managed by dividing the dose of NPH insulin between dinner and bedtime Berger M et al. Diabetes Care . 1999;22(suppl 3):C71-C75 Edelman SV, Henry RR. Diabetes Reviews . 1995;3:308-334
Patients are anxious when being started on insulin and when changes in therapy are made. This anxiety will block learning and memory. Always write down these directions for your patients What type(s) of insulin do you want them to take How much insulin do you want them to take When do you want them to take the insulin: If an injection is to be given before a meal-explain how long before the meal (30 minutes, 45 minutes etc.) Use large print, write legibly, and use a dark coloured pen (felt tip pens are a good choice).