RapidActing Insulin Analogues Mojtaba Malek MD Associate Prof
Rapid-Acting Insulin Analogues Mojtaba Malek, MD Associate Prof. of Endocrinology and Metabolism Tehran University of Medical Sciences Institute of Endocrinology and Metabolism Endocrine Research Center (Hemmat Campus)
AGENDA • Introduction • Pharmacokinetic Properties of Insulin • Molecular Structure – Lispro – Glulisine – Aspart • Comparison between Insulin Regular & Rapid-Acting Insulin in DM 1 • Comparison between Insulin Regular & Rapid-Acting Insulin in DM 2 • Rapid –Acting Insulin in Pregnancy • Rapid –Acting Insulin in Elderly • Conclusion
Regular Human Insulin q After SQ injection regular insulin tends to dissociate from its normal hexameric form, first into dimers and then monomers. § Only dimeric & monomeric forms can pass through the endothelium. q The resulting delay in the onset and duration of action, limits effectiveness in controlling postprandial glucose. q Dose dependent pharmacokinetics, pharmacokinetics with prolonged onset, peak, duration of action with higher doses. Med Clin North Am 1998
Pharmacokinetic Properties of Rapid Acting Insulin Preparation Rapid acting insulin • Onset of action in 15 minutes • Peak activity; 1 hour • Duration of activity ; 3 -4 hours Lancet 1997 Jan
Structural Formula of Insulin Lispro
Structural Formula of Insulin Glulisine
Structural Formula of Insulin Aspart
Type 1 DM
Differences in Hb. A 1 c in DM 1 Insulin Analogues vs. Insulin Regular Treatment No. of Trials Sample Size Hb. A 1 C, weighted mean difference (95% CI) Lispro vs. Regular 22 6021 – 0. 09 (– 0. 16 to – 0. 02)¶ Aspart vs. Regular 7 3035 – 0. 13 (– 0. 20 to – 0. 07)¶ 1 87 0. 25 (– 0. 20 to 0. 71) Rapid-acting insulin analogues Lispro vs. Aspart (continuous SC infusion only)
Differences in Risk of Hypoglycemia in DM 1 Insulin Analogues vs. Regular Lispro vs. Regular Severe hypoglycemia Nocturnal hypoglycemia No. of Trials Sample Size Relative Risk 95% CI 10 4502 0. 80 (0. 67 -0. 96)¶ 4 725 0. 51 (0. 42 -0. 62)¶ 4 1814 0. 83 (0. 65 -1. 04) 1 118 0. 55 (0. 43 -0. 70)¶ 1 87 1. 20 (0. 89 to 1. 68) Aspart vs. Regular Severe hypoglycemia Nocturnal hypoglycemia (continuous SC infusion only) Lispro vs. Aspart (continuous SC infusion only) Nocturnal hypoglycemia
Quality of Life in DM 1 • Patients generally preferred rapid-acting insulin analogues over regular insulin because of flexibility in dosing relative to mealtimes • Some studies that assessed quality of life and patient satisfaction reported statistically significant improvements with the use of rapid–acting insulin compared with regular insulin.
The Comparison between Insulin Lispro & Aspart in DM 1 § No significant differences; ü In Hb. A 1 C (weighted mean difference 0. 25% , 95%CI , 0. 20 -0. 71%) ü Rate of nocturnal hypoglycemia (RR 1. 2, 95% CI, 0. 89 -1. 68)
Insulin Glulisine Compared to Insulin Aspart and to Insulin Lispro Administered by Continuous Subcutaneous Insulin Infusion in Patients with Type 1 Diabetes: A Randomized Controlled Trial Arianne C. van Bon, Bruce W. Bode, Caroline Sert-Langeron, J. Hans De. Vries, and Guillaume Charpentier DIABETES TECHNOLOGY & THERAPEUTICS, Volume 13, Number 6, 2011
Type 2 DM
Differences in Hb A 1 c in DM 2 Insulin Analogues vs. Insulin Regular Treatment No. Of Trials Sample Size Hb A 1 C weighted mean difference (95%CI) Lispro vs. Regular 11 3093 – 0. 03 (– 0. 12 - 0. 06) Aspart vs. Regular 6 1031 – 0. 09 (– 0. 21 - 0. 04) Lispro vs. Aspart 1 266 0. 14 (– 0. 02 - 0. 30)
Differences in Risk of Hypoglycemia in DM 2 Insulin Analogues vs. Insulin Regular Treatment No. Of Trials Sample Size Relative Risk (95% CI) Severe 2 1622 0. 43 (0. 08 - 2. 37) Nocturnal 1 178 1. 63 (0. 71 - 3. 73) Severe 1 121 0. 39 (0. 1 - 1. 36) Nocturnal 1 93 0. 65 (0. 28 - 1. 53) Lispro vs. Regular Aspart vs. Regular
The Comparison in DM 2 Insulin Regular vs. Aspart q The patients given insulin aspart had significantlly fewer events of overall hypoglycemia. q No data on quality of life or patient satisfaction.
Pregnancy
Aspart in Pregnancy, DM 1 q The comparison of insulin aspart (IAsp) with human insulin (HI) for fetal and perinatal outcomes of DM 1 in pregnancy. q Subjects were pregnant (gestational age; <10 weeks) q 322 women with DM 1 received IAsp (n= 157) or HI (n=165). Am J Obstet Gynecol. 2008 Feb
The Comparison between Insulin in Pregnancy Aspart vs. Regular Pregnancy Outcomes Aspart Regular Live Births 137 131 Fetal Losses 14 21 14/1000 Births 22/1000 Births 6 9 3438 Grams 3555 Grams 20. 3 % 30. 6 % 37. 6 Weeks 37. 4 Weeks Perinatal Mortality Number of Congenital Malformations Birth Weight Preterm Delivery Mean Gestational Age Am J Obstet Gynecol. 2008
CONCLUSION : The Comparison between Insulin in Pregnancy Aspart vs. Regular The fetal outcome using aspart insulin in DM 1 was comparable with regular insulin with a tendency toward fewer fetal losses and preterm deliveries Am J Obstet Gynecol. 2008 Feb
Insulin Comparison in Women With GDM Lispro or Aspart vs. Regular § They studied 96 women with GDM diagnosed at 27. 5± 1. 1 weeks of gestation and on diet treatment. § The three groups were comparable for age, parity, BMI, weight gain, and time of gestation. § Blood glucose levels were measured five times daily. Diabetes Care 30: e 11 2007
RESULTS: Lispro or Aspart vs. Regular in GDM § At the end of pregnancy , no differences for insulin dose, weight gain, FPG , and A 1 C. § 1 -h PP level, level was higher in HI patients (135 ± 23 mg/dl) than in LIS (118 ± 18 mg/dl) and ASP (121 ± 20 mg/dl) (P < 0. 05). § Birth weight was higher in HI than in LIS and ASP patients. (P < 0. 04) § Macrosomia resulted in 15. 6% of HI, 12. 1% of LIS, and 9. 6% of ASP (NS) Diabetes Care 30: e 11 2007
CONCLUSION: Lispro or Aspart vs. Regular in GDM v It suggests that both short insulin analogs are associated with better postprandial maternal glucose control and anthropometric measures in newborns than HI. Diabetes Care 30: e 11 2007
Comparing Insulin Pregnant Women Lispro vs. Regular Insulin q In DM 1 no significant differences in § Hb A 1 c (weighted mean difference 0. 20%, 95% CI – 1. 03%-1. 43%) § Risk of severe hypoglycemia (RR 0. 21, 95% CI 0. 01 -4. 10) q In GDM no significant difference in § Hb. A 1 c (weighted mean difference 0. 06%, 95% CI – 0. 11%- 0. 23%)
Comparing Insulins in DM 1 Pregnant Women Aspart vs. Regular Insulin v. No significant differences in: § Hb. A 1 c (weighted mean difference – 0. 08%, 95% CI – 0. 28 - 0. 12%) § Risk of severe hypoglycemia (RR 1. 14, 95% CI 0. 76 -1. 71) § Risk of overall hypoglycemia (RR 1. 04, 95% CI 0. 98 -1. 11)
Elderly
Insulin Aspart in Elderly with DM q Studies were conducted in elderly patients with diabetes. n = 19, aged 72+/-1 yrs, BMI 27+/-1 kg/m 2, Hb. A 1 c 6. 4 +/0. 1%, diabetes duration < 5 yrs) q RESULTS: Insulin and glucose profiles were nearly identical with insulin aspart and regular insulin. Diabetes Obes Metab. 2007
CONCLUSION: Insulin Aspart in Elderly with DM Insulin aspart appears to act similarly to regular human insulin in elderly patients with type 2 diabetes. Diabetes Obes Metab. 2007
CONCLUSION q Rapid-acting insulin in DM 1: DM 1 § § § Reduces rate of hypoglycemia specially nocturnal type Reduces Hb A 1 C Improves quality of life q Rapid-acting insulin in DM 2: DM 2 § Reduces event of hypoglycemia q Rapid-acting insulin in pregnancy: pregnancy § § No difference in Hb. A 1 C, hypoglycemia, May be cause lower fetal losses & preterm delivery
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