Principles and limitations of standard insulin therapy
Rapid acting analogs
Glargine insulin
Detemir insulin
Starting Type 2s on insulin
Normal Insulin Secretion: The Basal-Bolus Insulin Concept
B D L HS Insulin effect Bolus Insulin Basal Insulin Endogenous Insulin B, breakfast; L, lunch; D, dinner; HS, bedtime.
Adapted from:
1. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.
2. Bolli GB, et al. Diabetologia. 1999;42:1151–1167. Time of administration
In individuals with normal weight who do not have diabetes, two patterns of insulin output are seen: basal insulin, which is secreted at a fairly constant rate between meals and at night to maintain euglycemia, and during early morning hours; and bolus insulin, which is meal-related.1
The therapeutic challenge for patients with diabetes is to provide enough basal insulin to control between-meal hyperglycemia – which is due to hepatic glucose production – and enough bolus insulin to minimize hyperglycemia immediately after meals. The provision of adequate levels of basal and bolus insulin may reduce risk for hypoglycemia in individuals with erratic schedules or in those who have greater insulin requirements.1,2
Principles of Insulin Treatment Principles of Insulin Treatment - 7
Pre-mixed Insulin (e.g. 30/70)
Does not correspond well to basal- bolus concept
Requires rigid schedule of meal and snack timing and content to prevent hypo- and hyperglycemia
Can not adjust dose to ambient bs, expected intake or activity
Usually can not even properly adjust doses to long-term glycemic patterns
Not appropriate for anyone interested in standard-of-care levels of glycemic control
Some of the barriers to regular insulin include1:
Slower onset of action than required to mimic physiologic bolus insulin
Risk of preprandial hypoglycemia if meal is further delayed
Longer duration of action than necessary, causing risk of late postprandial hypoglycemia
Principles of Insulin Treatment A. NPH/lente X - 0 - X - 0
Regular/ X - 0 - X - 0
Rapid acting Most standard option, since only two insulins and two injections are required
Potential for nighttime hypoglycemia because of NPH peak of action in the middle of the night B L Supp Bed B R/RA R/RA N N N Principles of Insulin Treatment - 7.5 Twice a day regimen
Limitations of Bolus Insulin: Regular
Wittlin SD, et al. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002. Slow onset of action
Requires inconvenient administration 30–45 minutes before meal
Risk of hypoglycemia if meal is further delayed
Mismatch with postprandial hyperglycemic peak
Long duration of action
at higher dosages
Potential for late postprandial hypoglycemia
Necessitates rigid timing of meals
Some of the barriers to regular insulin include1:
Slower onset of action than required to mimic physiologic bolus insulin
Risk of preprandial hypoglycemia if meal is further delayed
Longer duration of action than necessary, causing risk of late postprandial hypoglycemia
Time-Action Curves of Regular and Lispro/Aspart Insulin
Meal
SC injection Time (min) Time (min) Aspart Glucose infusion rate (mg/min)1 Plasma insulin (pmol/L)2 Meal
SC injection SC, subcutaneous.
1. Campbell RK, et al. Ann Pharmacother. 1996;30:1263–1271. 2. Mudaliar SR, et al. Diabetes Care. 1999;22:1501–1506. 0 50 100 150 200 300 250 400 350 300 250 200 150 100 50 0 450 500 Lispro Regular
human
insulin 0 60 120 180 240 400 300 200 100 0 500 600 700 300 Regular
human
insulin
In comparison to regular human insulin, the pharmacologic peak of activity for the insulin analogues lispro and aspart occurs between 30 and 60 minutes after subcutaneous injection, showing a quick peak of insulin activity on injection.1–3
The regular human insulin time-action profiles were different between these two studies.1,2
These insulin analogues are also quickly utilized, with exogenously administered peak insulin levels returning to basal levels within 3 to 4 hours.4
In addition, lispro and aspart result in a lower incidence of postprandial hypoglycemia compared with regular human insulin when used in a basal-bolus regimen in tightly controlled patients with type 1 or type 2 diabetes.3
Short-Acting Insulin Analogues: Lispro and Aspart
Adapted from Wittlin SD, et al. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002. Administration immediately before or after meals
Fast onset of action
Limit postprandial hyperglycemic peaks
Short duration of action
Minimizes hypoglycemia prior to subsequent meal, and therefore minimizes need for snacks
Allows flexibility with timing of meals
Short-acting insulins are used as prandial (or bolus) insulins.1
Their fast onset of action provides an immediate response to prandial glucose, and their short duration of action limits the risk of postprandial hypoglycemia.
Because of their short duration of action and peaked profile of activity, short-acting insulin analogues may require a long-acting basal insulin to supplement the need for basal insulin between meals.1
Greater Contribution of PPG as A1C Approaches Target
Monnier L et al. Diabetes Care 2003;26:881. a,b b c c a a a. Significant difference between FPG and PPG (paired t-test). b. Significant difference from all other quintiles (ANOVA) c. Significant difference from quintile 5 (ANOVA)
Recent research looked at the relative contributions of postprandial (red) and fasting (blue) hyperglycemia (%) to the overall diurnal hyperglycemia over quintiles of A1C.
Study involved 290 non-insulin and non-acarbose using patients with type 2 diabetes, plasma glucose (PG) concentrations were determined at fasting (8:00 am), and during postprandial and a post-absorptive periods (11:00 am, 2:00 pm, and 5:00 pm).
The relative contributions of PPG and FPG differed over quintiles of A1C as shown in this graph. This suggests that in order to reach target A1C it is essential to consider the contribution of both FPG and PPG.
Notes: laboratory FPG & PPG instead of self-monitoring blood glucose, French diet may have affected 24-hour glucose profile
Relationship Between Elevated PPG and CV Events in Non-diabetic Individuals (meta-analysis; n=95,783)
5 6 7 8 9 5 6 8 9 10 7 11 12 Relative Risk of CV event Fasting plasma glucose (mmol/L)
Postprandial plasma glucose (mmol/L)
Coutinho M et al. Diabetes Care 1999; 22: 233. P=0.056 P=0.00064 0 0.5 1 1.5 2 2.5 3
PURPOSE To assess the relationship between nondiabetic glucose levels and cardiovascular risk.
A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years
RESEARCH DESIGN AND METHODS - MEDLINE (1966- 1996) Data had to be reported in at least three quantiles or intervals so that the nature of the relationship between glucose and cardiovascular events (i.e., linear or nonlinear) could be explored, and to ensure that any incremental cardiovascular risk was consistent across quantiles or intervals.
RESULTS - Analyzed studies comprised 95, 783 people (94% male) who had 3, 707 cardiovascular events over 12.4 years (1, 193, 231 person-years). Studies reporting fasting glucose levels (n = 6), 2-h glucose levels (n = 7), 1-h glucose levels (n = 5), and casual glucose levels (n = 4) were included. The glucose load used varied from 50 to 100 g. The highest glucose interval for most studies included glucose values in the diabetic range. The relationship between glucose levels and the risk of a cardiovascular event was modeled for each study and the p- coefficients were combined. Compared with a glucose level of 4.2 mmol/l (75 mg/dl), a fasting and 2-h glucose level of 6.1 mmol/l (110 mg/dl) and 7.8 mmol/l (140 mg/dl) was associated with a relative cardiovascular event risk of 1.33 (95% CI 1.06-1.67) and 1.58 (95% CI 1.19-2.10), respectively.
CONCLUSIONS - The progressive relationship between glucose levels and cardiovascular risk exten...
Limitations of Intermediate Insulins: NPH
1. Chan JL, et al. Mayo Clin Proc. 2003;78:459–467.
2. Leahy JL. In: Leahy JL, Cefalu WT, eds. Insulin Therapy. New York, NY: Marcel Dekker, Inc.; 2002.
3. Bergenstal RM, et al. In: DeGroot LJ, Jameson JL, eds. Endocrinology. 4th ed. Philadelphia, Pa: WB Saunders Co.; 2001:821–835. Does not mimic basal insulin profile1,2
Variable absorption
Pronounced peak
10- to 20-hour duration
Requires twice-daily administration to provide 24-hour basal insulin coverage
Fear of hypoglycemia3
Major factor limiting insulin adjustments
The exogenous insulin NPH has been used as a basal insulin supplement, but its pharmacologic profile is unlike the normal physiologic basal insulin profile.1
NPH insulin has a variable absorption rate and, most importantly, results in a pronounced peak of insulin serum concentration that can lead to episodes of hypoglycemia.2
In order to mimic basal insulin therapy with NPH, two injections per day are required.1 This may result in a higher total insulin dose and potential weight gain.
Insulin Glargine
Rx 1. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. 2002.
2. Lantus® receives European approval for pediatric use. Aventis Pharma Web site. Available at: http://www.aventis.no/nyheter/nyheter/nyheter_lantus_eu_approval_pediatric.shtml. Accessed March 19, 2003. Recombinant human insulin analogue1
Basal (long-acting) insulin1
Relatively constant peakless concentration/time profile over 24 hours1,2
Once-daily SC administration1
For adult and paediatric (aged 6 years) patients with type 1 diabetes2 and adults with type 2 diabetes
Less nocturnal hypoglycaemia1
More flexible dosing1
Lantus® (insulin glargine) is a recombinant human insulin analogue for once-daily subcutaneous administration1
Lantus is indicated for the treatment of adult and paediatric patients1,2 with type 1 diabetes or adult patients with type 2 diabetes who require basal (long-acting) insulin for the control of hyperglycaemia1
It is slowly released after injection, resulting in a relatively constant peakless concentration/time profile over 24 hours1,2
This profile allows once-daily dosing as a patient’s basal insulin1
Insulin Glargine Structure
1. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. 2002.
2. McKeage K et al. Drugs. 2001;61:1599-1624. Substitution Extension A chain B chain 1 15 10 5 10 15 20 Asn 30 Gly Arg Arg 5 10 15 19 25 1 Asparagine at position A21 replaced by glycine
Provides stability
Addition of 2 arginines at the C-terminus of the B chain
Soluble at slightly acidic pH
Lantus® (insulin glargine) is manufactured using recombinant DNA technology1
Two arginine molecules added to the B chain shift the isoelectric point from pH 5.4 to pH 6.72
Substitution of one glycine unit in place of an asparagine results in a stable hexamer2
Lantus is soluble in a slightly acidic condition within the vial (pH 4), but is less soluble in the neutral pH of subcutaneous tissue1
The change of pH allows Lantus to form microprecipitates in subcutaneous tissue, resulting in delayed absorption and a prolonged duration of action1
Lantus, injected once daily, results in steady-state levels 2 to 4 days after the first dose, and there is no evidence of accumulation after 12 days of injections1
Insulin Glargine Mechanism of Action
Injection of an acidic solution (pH 4.0)3
Microprecipitation of insulin glargine
in subcutaneous tissue (pH 7.4)3
Slow dissolution of free insulin glargine hexamers from microprecipitates (stabilised aggregates)3
Protracted action3 1. Lantus® (insulin glargine) EMEA Summary of Product Characteristics. 2002.
2. McKeage K et al. Drugs. 2001;61:1599-1624.
3. Kramer W. Exp Clin Endocrinol Diabetes. 1999;107(suppl 2):S52-S61. The mechanics of sustained release1,2
Insulin Glargine: 24-Hour Peakless Profile
Hourly mean values Time After SC Injection (hours) = End of observation period Glucose Utilisation Rate (mg/kg/min) Adapted from Lantus (insulin glargine) EMEA Summary of Product Characteristics. 2002. 30 0 1 2 3 4 5 6 0 20 10 Insulin Glargine (n=20) NPH Insulin (n=20)
In contrast to NPH insulin, Lantus® (insulin glargine) had a peakless, long-lasting concentration/action profile closely mimicking a “square wave” shape1,2
The peakless profile over 24 hours seen with Lantus helps to reduce the risk of nocturnal hypoglycaemia3-5
Lantus mimicks the normal physiological basal insulin profile6
Insulin Glargine: Glycemic Control with Less Hypoglycemia
Porcellati F, et al. Diab Med. 2003;(21);11:1213–1220. Incidence of hypoglycemia
(daily episodes) 0 2 4 6 8 10 12 14 16 All* Nocturnal* Total daily episodes per patient-month p<0.05 p<0.05 Insulin Glargine (n=61) NPH Insulin (n=60) Type 1 DM * Blood glucose 4 mmol/L (<72 mg/dL ). A1C (%) A1C from baseline to endpoint p<0.05 0.0 0.8 1.6 2.4 3.2 4.0 4.8 5.6 6.4 7.2 Baseline Endpoint
LANTUS (insulin glargine) helps patients achieve optimal glycemic control.1
Porcellati and colleagues studied 121 patients with type 1 diabetes who were randomized to treatment with lispro/NPH insulin mixtures at meals plus bedtime NPH insulin or once-daily LANTUS at dinnertime plus lispro at each meal for 12 months.1
There was a statistically significant difference (p<0.05) in patients in the LANTUS group who achieved an A1C of 6.7% after 12 months compared with the NPH insulin group who exhibited no change in A1C.1
The incidence of all forms of symptomatic hypoglycemia and nocturnal symptomatic hypoglycemia, as determined by blood glucose levels ≤4 mmol/L (<72 mg/dL), was statistically significantly lower in the LANTUS group as compared with the NPH insulin group (p<0.05).1
This study demonstrates that LANTUS can be used to achieve a statistically significant improvement (p<0.05) in A1C with a decreased risk of hypoglycemia vs. NPH insulin.1
LysB29(N-tetradecanoyl)des(B30)human insulin Insulin detemir Thr Glu Lys Val Phe Asn Glu Leu Gln Tyr Leu Ser Cys Ile Ser Cys Cys Gln Glu Val Ile Gly Tyr Cys Asn Lys Pro Thr Tyr Phe Phe Arg Gly Glu Gly Cys Val Leu Tyr Leu Ala Val Leu His Ser Gly Cys Asn Gln Leu His B1 A21 A1 B29 C14 fatty acid chain
(Myristic acid) Thr DEs ThrEonine + myristic (MIR) acid
Potential sites of protraction
Subcutaneous depot Plasma compartment Interstitial compartment Protracted absorption ‘Buffering’ effect In the subcutaneous depot
self-association
albumin-binding
In the circulation
albumin binding
In the interstitial space
albumin-binding
When an insulin is injected into subcutaneous tissue, it forms a depot. It must then pass through capillary walls into the circulation, and from there must pass back through capillary walls to reach the interstitial fluid of the target tissues. Thus, the route to the receptor involves passage through three compartments.
The fatty-acid side chains enable insulin detemir to bind to albumin. This is possible in all three compartments between injection and receptor interaction – in the sc depot, in the circulation and in the interstitium of the target tissue itself. Thus, there are three potential sites where protraction of action could take place.
A series of physico-chemical experiments have clarified the mechanisms by which insulin detemir’s action becomes protracted.
It is a relatively stable hexamer, and the fatty-acid side chains enable weak hexamer-hexamer contacts to be made at high concentration. Osmolarity and elution experiments have suggested that insulin detemir forms a hexamer-dihexamer equilibrium in the injection depot, which increases the depot residence time as associated insulin is slower to penetrate the capillary wall than monomeric insulin.
This delay in absorption provides the opportunity for albumin binding to occur in the depot and this further protracts the absorption process. This has been shown in elution and subcutaneous disappearance rate studies using radio-labelled insulin analogue/albumin in pigs. Thus, most of the protraction of detemir’s ...
Safety of albumin binding (1)
HSA: human serum albumin FFA: free fatty acid P. Kurtzhals et al. Journal of Pharmaceutical Sciences 1997;86(12) Plasma concentration of HSA: ~600 x 10-6 M
FFA binding sites/HSA molecule: at least 8
Plasma concentration of FFA: ~300 x 10-6 M
Insulin detemir concentration at therapeutic dose: <0.01 x 10-6 M
Therefore, insulin detemir occupies only a minute fraction of available albumin binding sites
That albumin binding is likely to be a safe strategy for protracting insulin is illustrated by these data, showing that therapeutic doses of insulin detemir will have negligible impact upon the binding capacity of the serum albumin pool.
There are eight or more binding sites per human soluble albumin (HSA) molecule. There is more than one HSA molecule per circulating FFA and more than 50 HSA molecules per insulin detemir molecule. That is, more than 80% of the binding sites will still be free.
As insulin detemir has 105 fold higher affinity to the insulin receptor than to HSA, insulin detemir will be stripped from HSA by the receptor.
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