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OPTIMIZING INSULIN THERAPY: INNOVATIVE REGIMES

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OPTIMIZING INSULIN THERAPY: INNOVATIVE REGIMES

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    1. OPTIMIZING INSULIN THERAPY: INNOVATIVE REGIMES Dr SANJAY KALRA BHARTI HOSPITAL KARNAL, HARYANA

    3. EXISTING REGIMES Basal – bolus regular – regular – premixed Premixed b.d Premixed o.d + OHAs BIDS Insulin + sulfonylureas Insulin + sensitizers

    4. LACUNAE Mismatch between glycemic excursions PP and insulin levels Delay in insulin absorption due to self-association Poor PP control, with pre-meal hypo Lack of a truly basal insulin Poor F control Hypoglycemia

    5. LACUNAE PATIENT RESISTANCE PHYSICIAN RESISTANCE Number of injections Inconvenience Injection – meal gap Human insulin is physiological, but SC route is not !

    6. WE WANT TO BE BETTER! Create physiological regimes with newer insulins which mimic the natural variation in insulin levels Provide adequate basal levels Achieve post-prandial peaks when needed

    7. BASAL REGIMES

    8. Ideal basal insulin should be slowly & evenly absorbed with no peak have consistent bioavailability have a long half-life that permits once-daily administration have a reproducible response to allow consistent dosing

    9. Limitations of conventional basal insulins Do not mimic basal insulin profile Variable absorption (inter & intra subject variability) Pronounced peaks Less than 24-hr duration of action Cause unpredictable hypoglycemia Major factor limiting insulin adjustments

    10. Innovative basal regimes

    11. Variability in time-action profile of basal insulins Study 1450. Importantly, the time-action profile of insulin detemir has also been shown to be reproducible – significantly more so than NPH insulin or insulin glargine. These data are taken from a comparative study in which patients underwent glycaemic clamps following 4 injections on 4 separate visits. Here we see three typical examples of the GIR curves required to maintain a glycaemic target following injection in three patients – one receiving insulin glargine, one NPH insulin and one insulin detemir. Abstract: Lower Within-Subject Variability of Insulin Detemir in Comparison to NPH Insulin and Insulin Glargine in Subjects with Type 1 Diabetes TIM C. HEISE 1 , LESZEK NOSEK 1 , EBERHARD DRAEGER 2 , ANNETTE STENDER 2 , BIRGITTE BIILMANN RØNN 2 , CHRISTOPH KAPITZA 1 , LUTZ HEINEMANN 1 . 1 Neuss, Germany, 2 Bagsvaerd, Denmark. We compared the within-subject variability of the effect of the novel long-acting insulin analogue insulin detemir (IDet) with that of NPH insulin and insulin glargine (GL) in a randomized, controlled, parallel group, double blind study. Fifty-four patients with type 1 diabetes (32 males; age 38±10 years (mean±SD); BMI 24±2 kg/m 2 ; HbA 1c 7.5±1.2%; diabetes duration 18±9 years) received the same dose (0.4 U/kg) of either NPH insulin, GL or IDet s.c. on four identical study days under euglycemic glucose clamp conditions (target blood glucose concentration 5.5 mmol/L). The pharmacodynamic and pharmacokinetic effects of the basal insulin preparations were recorded for 24 and 28 hours post-dose, respectively. IDet showed significantly less within-subject variability compared to NPH and GL (2.5 and 1.8 fold lower CV for GIR-AUC(0–24h), respectively), see table. Similar findings were also observed for pharmacokinetic parameters. In conclusion, this first systematic investigation of the variability in the pharmacodynamic and pharmacokinetic properties of the most commonly used basal insulin preparations in type 1 diabetes shows significantly less within-subject variability for insulin detemir. This suggests that this novel basal insulin will provide a more predictable therapeutic effect compared to both NPH insulin and insulin glargine. Within-Subject Variability, expressed as Coefficients of Variations (CV) in % Insulin Detemir NPH Insulin Insulin Glargine Pharmacodynamics (assessed by Glucose Infusion Rates (GIR)) GIR-AUC (0–12h) 27 59* 46* GIR-AUC (0–24h) 27 68* 48* GIR max 23 46* 36* Pharmacokinetics (assessed by plasma concentrations of insulin (INS), insulin glargine and insulin detemir) INS-AUC (0–12h) 15 26 34 INS-AUC (0–?) 14 28 33 *: p<0.001 compared with insulin detemir (no statistical analyses were performed to compare pharmacokinetic CVs). CVs were determined using an ANOVA model after log-transformation of the parameters. Study 1450. Importantly, the time-action profile of insulin detemir has also been shown to be reproducible – significantly more so than NPH insulin or insulin glargine. These data are taken from a comparative study in which patients underwent glycaemic clamps following 4 injections on 4 separate visits. Here we see three typical examples of the GIR curves required to maintain a glycaemic target following injection in three patients – one receiving insulin glargine, one NPH insulin and one insulin detemir. Abstract: Lower Within-Subject Variability of Insulin Detemir in Comparison to NPH Insulin and Insulin Glargine in Subjects with Type 1 Diabetes TIM C. HEISE 1 , LESZEK NOSEK 1 , EBERHARD DRAEGER 2 , ANNETTE STENDER 2 , BIRGITTE BIILMANN RØNN 2 , CHRISTOPH KAPITZA 1 , LUTZ HEINEMANN 1 . 1 Neuss, Germany, 2 Bagsvaerd, Denmark. We compared the within-subject variability of the effect of the novel long-acting insulin analogue insulin detemir (IDet) with that of NPH insulin and insulin glargine (GL) in a randomized, controlled, parallel group, double blind study. Fifty-four patients with type 1 diabetes (32 males; age 38±10 years (mean±SD); BMI 24±2 kg/m 2 ; HbA 1c 7.5±1.2%; diabetes duration 18±9 years) received the same dose (0.4 U/kg) of either NPH insulin, GL or IDet s.c. on four identical study days under euglycemic glucose clamp conditions (target blood glucose concentration 5.5 mmol/L). The pharmacodynamic and pharmacokinetic effects of the basal insulin preparations were recorded for 24 and 28 hours post-dose, respectively. IDet showed significantly less within-subject variability compared to NPH and GL (2.5 and 1.8 fold lower CV for GIR-AUC(0–24h), respectively), see table. Similar findings were also observed for pharmacokinetic parameters. In conclusion, this first systematic investigation of the variability in the pharmacodynamic and pharmacokinetic properties of the most commonly used basal insulin preparations in type 1 diabetes shows significantly less within-subject variability for insulin detemir. This suggests that this novel basal insulin will provide a more predictable therapeutic effect compared to both NPH insulin and insulin glargine. Within-Subject Variability, expressed as Coefficients of Variations (CV) in % Insulin Detemir NPH Insulin Insulin Glargine Pharmacodynamics (assessed by Glucose Infusion Rates (GIR)) GIR-AUC (0–12h) 27 59* 46* GIR-AUC (0–24h) 27 68* 48* GIR max 23 46* 36* Pharmacokinetics (assessed by plasma concentrations of insulin (INS), insulin glargine and insulin detemir) INS-AUC (0–12h) 15 26 34 INS-AUC (0–?) 14 28 33 *: p<0.001 compared with insulin detemir (no statistical analyses were performed to compare pharmacokinetic CVs). CVs were determined using an ANOVA model after log-transformation of the parameters.

    12. Implications of within-subject variability Study 1450. In order to illustrate what the observed variability (in combination with the mean treatment effect) means for an individual patient we calculated a prediction interval containing 95% of the predicted values for an average patient. The lower and upper limit of this prediction interval were calculated for each insulin preparation by subtracting and adding the observed standard deviation multiplied by 1.96. In the top bar of the table the calculation is done for the same endpoint, the mean area under the time-action profiles over 24 h. In the bottom bar of the table the calcuation is done for the another endpoint, the variance of Max GIR. The predicted clinical consequences of these calculations are illustrated here: For example, observed differences in variability can be illustrated by considering a patient in which an average glucose-lowering effect over 24 hours of 1 mg/(kg?min) was induced by application of a given long-acting insulin preparation. In this patient, the probability of experiencing an average effect of less than half the usual effect (i.e., <0.5 mg/(kg?min)), which can result in the clinical consequence of hyperglycaemia is 0.5% if the subject uses insulin detemir, above 7% with insulin glargine, and above 15% with NPH insulin. Study 1450. In order to illustrate what the observed variability (in combination with the mean treatment effect) means for an individual patient we calculated a prediction interval containing 95% of the predicted values for an average patient. The lower and upper limit of this prediction interval were calculated for each insulin preparation by subtracting and adding the observed standard deviation multiplied by 1.96. In the top bar of the table the calculation is done for the same endpoint, the mean area under the time-action profiles over 24 h. In the bottom bar of the table the calcuation is done for the another endpoint, the variance of Max GIR. The predicted clinical consequences of these calculations are illustrated here: For example, observed differences in variability can be illustrated by considering a patient in which an average glucose-lowering effect over 24 hours of 1 mg/(kg?min) was induced by application of a given long-acting insulin preparation. In this patient, the probability of experiencing an average effect of less than half the usual effect (i.e., <0.5 mg/(kg?min)), which can result in the clinical consequence of hyperglycaemia is 0.5% if the subject uses insulin detemir, above 7% with insulin glargine, and above 15% with NPH insulin.

    13. Kinetics of basal insulin Glargine – acidic solution; microprecipitates form and dissolve in SC tissue; MAY BE PAINFUL [3%] Detemir: clear neutral solution; increased self-association [hexamer stabilization and hexamer-hexamer interaction] ; albumin binding

    14. Choosing a basal insulin analogue Receptor binding, metabolic & mitogenic potency of analogues Another reason why a new basal insulin analogue may be desirable concerns receptor interaction profiles. This is important because changes in the structure of the insulin molecule relative to human insulin may affect receptor interaction in unexpected ways. An increased residence time at the insulin receptor or an increased affinity for IGF-I receptors may increase the mitogenic potential of the analogue hormone; such pharmacological effects were associated with carcinogenicity in rodents with the prototype insulin analogue, Asp B10. Thus, concerns about the risk of cancer and retinopathy have been debated when insulin analogues have increased insulin receptor residence times or act as IGF-I receptor agonists, as is the case for insulin glargine. In the case of insulin detemir, the ratio of insulin receptor affinity to IGF-I receptor affinity is not increased relative to insulin receptor affinity, and this is reflected in a low mitogenic potency in a human cancer cell line.Another reason why a new basal insulin analogue may be desirable concerns receptor interaction profiles. This is important because changes in the structure of the insulin molecule relative to human insulin may affect receptor interaction in unexpected ways. An increased residence time at the insulin receptor or an increased affinity for IGF-I receptors may increase the mitogenic potential of the analogue hormone; such pharmacological effects were associated with carcinogenicity in rodents with the prototype insulin analogue, Asp B10. Thus, concerns about the risk of cancer and retinopathy have been debated when insulin analogues have increased insulin receptor residence times or act as IGF-I receptor agonists, as is the case for insulin glargine. In the case of insulin detemir, the ratio of insulin receptor affinity to IGF-I receptor affinity is not increased relative to insulin receptor affinity, and this is reflected in a low mitogenic potency in a human cancer cell line.

    15. Only basal insulin is not enough… Over time, the need to intensify insulin regimens arises in response to disease progression Basal insulin is required for periods between meals, meal-time insulin supplementation becomes important to control PPG Controlling PPG is important Epidemiological evidence - peak levels of BG after a glucose load may have a greater influence on CV outcomes than do fasting BG epidemiological evidence suggests that peak levels of blood glucose after a glucose load may have a greater influence on cardiovascular outcomes than do fasting blood glucose levels DECODE study, Helsinki Policemen study, DIS (Diabetes Intervention study), epidemiological evidence suggests that peak levels of blood glucose after a glucose load may have a greater influence on cardiovascular outcomes than do fasting blood glucose levels DECODE study, Helsinki Policemen study, DIS (Diabetes Intervention study),

    16. PRE-MIXED REGIMES

    17. AIM:‘Physiological insulin ’ Non-diabetic individuals show pronounced prandial insulin peaks with lower level of basal secretion Insulin replacement therapy must aim to mirror the physiological situation The dynamic insulin requirement Continuous, tight glycaemic control reduces late complications in Type 2 diabetes1. However, for treatment with exogenous insulin to be both effective and well tolerated, plasma insulin levels should be appropriate at all times, whatever the prevailing blood glucose conditions. Following a meal, when blood glucose concentrations are rising, there must be a corresponding increase in insulin availability. Conversely, between meals, the absolute insulin concentration must fall if the patient is to avoid hypoglycaemia. A minimum basal level of insulin must be available at all times.   One approach to this problem is to use ‘basal-bolus’ insulin regimens, in which a slowly absorbed insulin (providing basal plasma concentrations) is used together with a more rapidly acting insulin taken prior to meals. Such regimens, when tailored to the patient and complied with, can achieve good control of both postprandial and fasting blood glucose. The dynamic insulin requirement Continuous, tight glycaemic control reduces late complications in Type 2 diabetes1. However, for treatment with exogenous insulin to be both effective and well tolerated, plasma insulin levels should be appropriate at all times, whatever the prevailing blood glucose conditions. Following a meal, when blood glucose concentrations are rising, there must be a corresponding increase in insulin availability. Conversely, between meals, the absolute insulin concentration must fall if the patient is to avoid hypoglycaemia. A minimum basal level of insulin must be available at all times.   One approach to this problem is to use ‘basal-bolus’ insulin regimens, in which a slowly absorbed insulin (providing basal plasma concentrations) is used together with a more rapidly acting insulin taken prior to meals. Such regimens, when tailored to the patient and complied with, can achieve good control of both postprandial and fasting blood glucose.

    18. Innovative premixed regimes

    19. Premix regimens are simple ‘Optimized’ insulin therapy may involve several daily injections Multiple injections may reduce acceptability of therapy Premixed insulin aims to provide acceptable insulin profile with a minimum number of injections The simplicity of insulin premixes When rapid-acting and slowly-absorbed insulins are given separately, the treatment regimen can become complicated and burdensome, reducing patient compliance. The number of injections necessary per day may be excessive.   Certain patient categories are likely to find multiple-injection regimens daunting and impractical: Patients with Type 2 diabetes, particularly if elderly, may be less motivated than younger patients with Type 1 diabetes to learn the complexities of self-management with insulin. They frequently require a multitude of other medications and find the addition of complicated multiple-injection regimens confusing. Young children with Type 1 diabetes may have school routines that limit the opportunity for supervised injections. Compliance with multiple-injection regimens is also reduced by anxieties about injections16 and/or hypoglycaemia, or by the fear of failing to correctly self-medicate.   One obvious solution to this problem is to administer a combination of insulins with different properties in one injection. Typically, such ‘pre-mixes’ comprise a short-acting insulin together with protaminated insulin, which is slowly absorbed. When injected prior to main meals, the short-acting component curtails the prandial blood glucose excursion, while the protaminated insulin ensures basal insulin availability. The simplicity of insulin premixes When rapid-acting and slowly-absorbed insulins are given separately, the treatment regimen can become complicated and burdensome, reducing patient compliance. The number of injections necessary per day may be excessive.   Certain patient categories are likely to find multiple-injection regimens daunting and impractical: Patients with Type 2 diabetes, particularly if elderly, may be less motivated than younger patients with Type 1 diabetes to learn the complexities of self-management with insulin. They frequently require a multitude of other medications and find the addition of complicated multiple-injection regimens confusing. Young children with Type 1 diabetes may have school routines that limit the opportunity for supervised injections. Compliance with multiple-injection regimens is also reduced by anxieties about injections16 and/or hypoglycaemia, or by the fear of failing to correctly self-medicate.   One obvious solution to this problem is to administer a combination of insulins with different properties in one injection. Typically, such ‘pre-mixes’ comprise a short-acting insulin together with protaminated insulin, which is slowly absorbed. When injected prior to main meals, the short-acting component curtails the prandial blood glucose excursion, while the protaminated insulin ensures basal insulin availability.

    20. Conventional premix vs. Premix analogue Rapid-acting component of premix analogue (Insulin Aspart) is absorbed much faster than conventional Better PPG control- 24 hr physiological control Simple convenient meal-time regimen no need to inject 30-45 min before meal Premix analogue- can be given pre- or post-meal Low risk of hypoglycaemia Can be combined with OHAs

    21. Premix analogue: can be given pre- or post-meal Blood glucose levels (mg/dl): Preprandial dosing Postprandial dosing (NovoMix® 30, bid) (NovoMix® 30, bid) Before Breakfast 139 ± 43 134 ± 55 Dinner 143 ± 59 149 ± 65 2 hrs after Breakfast 159 ± 66 177 ± 61 Dinner 143 ± 60 175 ± 59 Plasma glucose profiles during test meals were also similar: AUC 0-240min 38.169 ± 15.288 vs. 43.680 ± 15.024 mg/dL/min-1 There was no difference in the number of hypoglycaemic episodes for either treatment group (47 vs 55 episodes during pre- vs. postprandial treatment periods, respectively; p=ns) Blood glucose levels (mg/dl): Preprandial dosing Postprandial dosing (NovoMix® 30, bid) (NovoMix® 30, bid) Before Breakfast 139 ± 43 134 ± 55 Dinner 143 ± 59 149 ± 65 2 hrs after Breakfast 159 ± 66 177 ± 61 Dinner 143 ± 60 175 ± 59 Plasma glucose profiles during test meals were also similar: AUC 0-240min 38.169 ± 15.288 vs. 43.680 ± 15.024 mg/dL/min-1 There was no difference in the number of hypoglycaemic episodes for either treatment group (47 vs 55 episodes during pre- vs. postprandial treatment periods, respectively; p=ns)

    22. Better 24 hour control Blood glucose concentration was significantly lower after breakfast and dinner, before lunch and at bedtime in the NovoMix® 30 group. Analysis of 8-point blood glucose profiles revealed significantly lower blood glucose concentrations after breakfast and dinner, before lunch and at bedtime in the NovoMix® 30 group. At 12 weeks, values were approximately 1% lower in the NovoMix® group after breakfast and dinner (10.4 versus 11.4 mmol/l in NovoMix® 30 and Human Mixtard 30 groups respectively after breakfast, and 9.22 versus 10.2 mmol/l after dinner; p < 0.05 between groups for breakfast and p < 0.02 for dinner). Before lunch, blood glucose concentrations of 6.64 mmol/l in the NovoMix® 30 group compared favourably with 7.57 mmol/l in the Human Mixtard 30 group (p < 0.02), while at bedtime, concentrations of 8.22 versus 9.10 mmol/l in the NovoMix® 30 and Human Mixtard 30 groups, respectively, again favoured NovoMix® 30 (p < 0.05). At other time points, between-treatment differences did not reach statistical significance. Importantly, mean prandial glucose concentration was significantly lower in the NovoMix® 30 group after 12 weeks (1.66 versus 2.34 mmol/l in NovoMix® 30 and Human Mixtard 30 groups, respectively; p < 0.02). Blood glucose concentration was significantly lower after breakfast and dinner, before lunch and at bedtime in the NovoMix® 30 group. Analysis of 8-point blood glucose profiles revealed significantly lower blood glucose concentrations after breakfast and dinner, before lunch and at bedtime in the NovoMix® 30 group. At 12 weeks, values were approximately 1% lower in the NovoMix® group after breakfast and dinner (10.4 versus 11.4 mmol/l in NovoMix® 30 and Human Mixtard 30 groups respectively after breakfast, and 9.22 versus 10.2 mmol/l after dinner; p < 0.05 between groups for breakfast and p < 0.02 for dinner). Before lunch, blood glucose concentrations of 6.64 mmol/l in the NovoMix® 30 group compared favourably with 7.57 mmol/l in the Human Mixtard 30 group (p < 0.02), while at bedtime, concentrations of 8.22 versus 9.10 mmol/l in the NovoMix® 30 and Human Mixtard 30 groups, respectively, again favoured NovoMix® 30 (p < 0.05). At other time points, between-treatment differences did not reach statistical significance. Importantly, mean prandial glucose concentration was significantly lower in the NovoMix® 30 group after 12 weeks (1.66 versus 2.34 mmol/l in NovoMix® 30 and Human Mixtard 30 groups, respectively; p < 0.02).

    23. Lower prandial glucose increment than conventional premix At 12 weeks, mean prandial glucose excursion was significantly less (p < 0.02) in the NovoMix 30 group compared with the Human Mixtard 30 group. Postprandial glycaemic control was significantly better with NovoMix® 30 when analysed on the basis of mean prandial blood glucose increment - mean increment (post-meal minus pre-meal blood glucose) over the three meals including lunch, when no insulin was given. After 12 weeks, mean prandial glucose increment was 1.66 ± 0.20 mmol/l in the NovoMix® 30 group versus 2.34 ± 0.19 mmol/l for Human Mixtard 30 (p < 0.02). After three months treatment, levels of HbA1c did not differ between the two treatment groups. Only subjects who had a complete set of values for each of the 8-point blood glucose time points were included in the analysis.At 12 weeks, mean prandial glucose excursion was significantly less (p < 0.02) in the NovoMix 30 group compared with the Human Mixtard 30 group. Postprandial glycaemic control was significantly better with NovoMix® 30 when analysed on the basis of mean prandial blood glucose increment - mean increment (post-meal minus pre-meal blood glucose) over the three meals including lunch, when no insulin was given. After 12 weeks, mean prandial glucose increment was 1.66 ± 0.20 mmol/l in the NovoMix® 30 group versus 2.34 ± 0.19 mmol/l for Human Mixtard 30 (p < 0.02). After three months treatment, levels of HbA1c did not differ between the two treatment groups. Only subjects who had a complete set of values for each of the 8-point blood glucose time points were included in the analysis.

    24. Greater HbA1c reduction than NPH Subjects who had been taking NPH insulin monotherapy before the trial achieved significantly greater reductions in HbA1c when switched to NovoMix® 30 twice-daily compared to those who added another NPH injection (p < 0.005). As expected, subjects who were receiving NPH monotherapy (once- or twice-daily) or who were insulin-naïve prior to the study responded more favourably to both NovoMix® 30 and NPH insulin than those who had been taking combination therapy since they did not discontinue any component of treatment before starting on trial medication. Total population: HbA1c concentration decreased by > 0.6 % (p < 0.0001 versus baseline), in parallel, in both groups; metabolic control continued to improve throughout the trial without reaching a stable level Subjects who had been taking NPH insulin monotherapy before the trial achieved significantly greater reductions in HbA1c when switched to NovoMix® 30 twice-daily compared to those who added another NPH injection (p < 0.005). As expected, subjects who were receiving NPH monotherapy (once- or twice-daily) or who were insulin-naïve prior to the study responded more favourably to both NovoMix® 30 and NPH insulin than those who had been taking combination therapy since they did not discontinue any component of treatment before starting on trial medication. Total population: HbA1c concentration decreased by > 0.6 % (p < 0.0001 versus baseline), in parallel, in both groups; metabolic control continued to improve throughout the trial without reaching a stable level

    25. Low risk of nocturnal hypos

    26. Premixed analogue o.d + OHAs <7% includes both patients who achieved <6.5% & <7% <7% includes both patients who achieved <6.5% & <7%

    27. BIAsp 30 vs. Glargine

    28. INTENSIVE REGIMES

    29. Advantages of RAA With lispro/ aspart, hypo may occur 90 mins after a meal, esp. with high fat, low CHO meal [Burge MR et al, 1997] rather than 2-3 hrs after the meal as with regular insulin RAA safer with exercise [Bolli GB et al, 1999] RAA use less snacks [Ronnemaa T et al, 1998] May ameliorate immunologic insulin resistance [ Kumar D, 1997]

    30. Innovative intensive regimes

    31. Short acting analogues Variability only 20 – 30 % [Heinemann, 2002] Approved for IV use as well Can be given pre- or post- meal Dose adjustment can be done after meal/ CHO counting; to cover for incidental hyper/hypo Can be mixed with NPH immediately prior to injection Must not be mixed with glargine

    32. RAA kinetics Present as monomers Do not need time for dissociation of hexamers, unlike conventional insulin Faster absorption, shorter duration Mimics physio insulin concentration

    33. Choosing a RAA Receptor binding, metabolic & mitogenic potency of analogues Another reason why a new basal insulin analogue may be desirable concerns receptor interaction profiles. This is important because changes in the structure of the insulin molecule relative to human insulin may affect receptor interaction in unexpected ways. An increased residence time at the insulin receptor or an increased affinity for IGF-I receptors may increase the mitogenic potential of the analogue hormone; such pharmacological effects were associated with carcinogenicity in rodents with the prototype insulin analogue, Asp B10. Thus, concerns about the risk of cancer and retinopathy have been debated when insulin analogues have increased insulin receptor residence times or act as IGF-I receptor agonists, as is the case for insulin glargine. In the case of insulin detemir, the ratio of insulin receptor affinity to IGF-I receptor affinity is not increased relative to insulin receptor affinity, and this is reflected in a low mitogenic potency in a human cancer cell line.Another reason why a new basal insulin analogue may be desirable concerns receptor interaction profiles. This is important because changes in the structure of the insulin molecule relative to human insulin may affect receptor interaction in unexpected ways. An increased residence time at the insulin receptor or an increased affinity for IGF-I receptors may increase the mitogenic potential of the analogue hormone; such pharmacological effects were associated with carcinogenicity in rodents with the prototype insulin analogue, Asp B10. Thus, concerns about the risk of cancer and retinopathy have been debated when insulin analogues have increased insulin receptor residence times or act as IGF-I receptor agonists, as is the case for insulin glargine. In the case of insulin detemir, the ratio of insulin receptor affinity to IGF-I receptor affinity is not increased relative to insulin receptor affinity, and this is reflected in a low mitogenic potency in a human cancer cell line.

    34. Innovation: daytime insulin, bedtime sulfonylurea Long acting insulin [non-physio hyperinsulism] leads to weight gain, by chronically stimulating lipogenesis and blocking lipolysis. Aspart tds [average 24.1 U/d] + glimepiride [average 4.4 mg] at 8 pm achieved glycemic control in 56% patients without hypo or weight gain Glimepiride increases endogenous insulin portal circulation and suppresses HGO [de Boer et al, 2004]

    35. Innovation: NPH + lispro Addition of NPH to lispro [30% NPH; 70% lispro] covers the short action of lispro [Ahmed ABE, 1998] Individualized mixtures are necessary [Lalli C et al, 1999]; dose of NPH is proportional to the number of hours to the next meal Hypo less with lispro [20 – 30% reduction in severe hypo] [Brunelle RL et al, 1998] as counter regulation, hepatic sensitivity to glucagon [Launay B et al, 1998] is enhanced

    36. INDICATIONS FOR ANALOGUES

    37. Indications for IA Variable lifestyle Uncertain mealtimes Uncertain meal quantity Uncertain snacks Inability to maintain injection-meal gap Children Elderly Busy working people Sportsmen

    38. Indications for IA Renal failure Hepatic failure Malabsorption/ gastrointestinal upset High PPBG Low premeal BG ? pregnancy High FBG Unpredictable FBG Nocturnal hypo Weight gain with conventional insulin

    39. Be dynamic. Be proactive. Innovate, and control.

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