Presentation on theme: "DESIGNER INSULINS IN GESTATIONAL DIABETES DR.T.RAMANI DEVI MD DGO FICS FICOG RAMAKRISHNA NURSING HOME TRICHY."— Presentation transcript:
DESIGNER INSULINS IN GESTATIONAL DIABETES DR.T.RAMANI DEVI MD DGO FICS FICOG RAMAKRISHNA NURSING HOME TRICHY
Maternal Diabetes Two lives.. Twice as special An oppurtunity for primary prevention -Maternal health -Child health
Definition GDM is defined as carbohydrate in tolerance of variable severity with onset or first recognition during pregnancy. The definition is applicable regardless of whether insulin is used to treat the disease or if the condition persists after pregnancy. It does not exclude the possibility that unrecognized glucose intolerance may have antedated the pregnancy
Introduction Incidence of GDM is variable from 17% to 29% of all pregnancies Associated with maternal and perinatal complications. 90% of all Diabetics are GDM and 10% are due to pregestational diabetes. 4 million pregnancies in India are complicated by GDM This may contribute a part of MMR in India
GDM IGT 2% Agarwal S, Gupta AN. Gestational Diabetes. J Assoc Physicians India 1982;30:203 2% Ramachandran A, et.al., High prevalence of diabetes in an urban population in south India. BMJ 1988;3; 297(6648): s 7.6% Narendra J, Munichoodappa C, et al, Prevalence of glucose intolerance during pregnancy. Int J Diab Dev Countries 1991;11: % Ramachandran A, Snehalatha c, Dharmaraj D, Viswanathan M. Prevalence of glucose intolerance in Asian Indians. Diabetes Care 1992; 15: s 16.6% V Seshiah, V Balaji, Madhuri S Balaji, CB Sanjeevi, A. Green. Gestational Diabetes Mellitus in India. J Assoc Physicians India 2004;52: % Ramachandran A, Snehalatha C, Kapur A, Vijay V, Mohan V,Das AK, Rao PV, Yajnik CS, Prasanna Kumar KM, Nair JD.For the Diabetes Epidemiology Study Group in India (DESI).Diabetologia 2001;44: s GDM prevalence linked to background IGT rates
Significance of Diabetes and Pregnancy Malformation rate in 94/1000 Vs 9.7/1000 in general population Still birth is 15 times higher 25/1000 Vs 5/1000 PNM is 3 times higher 19.9/1000 Vs 6.8/1000 Recent concept of adult diseases having their origin inutero insults has been established WHO/IDF discussed the problem of hyperglycemia in pregnant women. They wanted to achieve pregnancy outcome in diabetic women same as in non diabetic women.
FREINKEL HYPOTHESIS Uterine After Birth Maternal DM placenta A.A Fat CHO At Birth Macrosomia Hypoglycemia Fetus A Insulin Obesity Metabolic syndrome CVD IGT/DM
Diabetes and Pregnancy – Why it is relevant? Hyperglycaemia during pregnancy is associated with high risk of maternal and perinatal morbidity and mortality and poor pregnancy outcome Diagnosis of GDM identifies women at high risk of future diabetes, offers opportunity of primary prevention Maternal hyperglycaemia is associated with development of metabolic problems including type 2 diabetes in the offspring
IUGR & Macrosomia Solution Optimal nutrition+ Optimal glycemic control=Optimal birth weight 3000 – 3500 g. Predicts development of HTN, Type 2 DM & IGT Barkers Hypothesis Low birth weight Pedersons hypothesis Macrosomia
SCREENING FOR DIABETES
WHO Criteria FPG (mg/dl)2h PG (mg/dl) IGT< Diabetes>126>200
ADA recommendation Screening ProcedureCriteria Perform a 75-g OGTT, with plasma glucose measurement fasting and at 1 and 2 h, at weeks of gestation in women not previously diagnosed with overt diabetes The OGTT should be performed in the morning after an overnight fast of at least 8 hrs. The diagnosis of GDM is made when any of the following plasma glucose values are exceeded -Fasting >= 92mg/dL(5.1mmol/L) -1 hr >=180mg/dL(10.0 mmol/L) -2 hr>=153 mg/dL (8.5mmol/L )
THRESHOLDS FOR DIAGNOSIS OF GDM
GLYCEMIC THRESHOLDS FOR PREVENTION OF DIABETIC COMPLICATION
Comparison of the Foetal Outcome in a NGT & GDM Foetal outcome Normal Abortions Still birth Died after birth Congenital anomalies Premature deliveries Sick babies Big baby ( 3.5 kg) NGT (n = 851) / GDM (n =211) / P value < <
GDM increases the risk of offspring DM Offspring's of women with GDM, have a 4 to 8 fold increased risk of diabetes. Clausen TD et al., Diabetes Care 2008
How to reduce this Early screening for GDM Monitoring frequently Proper uses of diet plan, exercise and insulin. Future concepts of CSII, CGMS, telemedicine, e-health, will revolutionize the management of GDM
How to treat? MNT Exercise Insulin Glyburide Metformin Acarbose? Insulin pump
Calorie allotment 30 kcal per kg current weight per day in pregnant women who are BMI 22 to kcal per kg current weight per day in overweight pregnant women (BMI 26 to 29). 12 to 15 kcal per kg current weight per day for severely obese pregnant women (BMI >30). 40 kcal per kg current weight per day in pregnant women who are less than BMI 22. Jovanovic-Peterson L, Peterson, CM. Nutritional management of the obese gestational diabetic woman. J Am Coll Nutr 1992; 11:246.
How long MNT? Consensus and hard data are lacking regarding how long diet therapy should be maintained before initiating pharmacologic treatment. 70% of the subjects with initial fasting plasma glucose less than 95 mg/dL achieved targeted levels of glycemia within 2 weeks of dietary management, but no significant improvement occurred thereafter McFarland et al obstet gynecol 1999
Exercise Prescription Can continue prepregnancy activity Keeping physically active is essential for good glycemic control Upperbody ergometric exercise useful Do not start new vigorous exercise for glucose control Uterine contractions,fetal tachy, maternal heart rate to be monitored
ORAL AGENTS IN PREGNANCY Glyburide study: Glyburide study: Randomized trial glyburide vs insulin 404 GDMs FPG >95 but 120 on diet Similar success of glucose control in both groups Langer et al: NEJM 200:343:1134
Animal insulin Insulin Analogues Introduction of insulin revolutionized Diabetes Management Introduced insulin had impurities and batch to batch variation higher quality insulin from bovine and porcine sources. Then came recombinant Insulin
IDEAL AGENT SHOULD FULFILL Mimic physiological control No adverse effect upon maternal and fetal outcome. Should not interfere with antenatal, perinatal and post natal care Insulin Analogues fulfills all the criteria when given in right doses in right manner.
ADVANTAGES Batch to Batch consistency No allergy, antibody formation No immune mediated lipoatrophy Glucose control is similar in endogenous insulin production Preprandial hypoglycemia and postprandial hyperglycemia are well controlled. Mealtime flexibility is possible with analogues.
Safety issues with Insulin Analogues Ideal insulin -Mimic physiological insulin secretion -Does not cross placenta -No mitogenic potential -Since IgG bound insulin can cross placenta, therapeutic agent should not induce antibody generation
STRUCTURAL MODIFICATION OF INSULIN ANALOGUE Insulin Lispro28-29 Proline and Lysine are interchanged Insulin AspartProline at 28 replaced by aspartic acid. (decreases hexamer formation ) Insulin glulisinePosition 3 of Lysine with Asparagine ; Lysine at 29 replaced by glutamine Insulin glargineAsparagine at A2 1 is replaced by glycine. 2 arginine added to C terminal of Beta chain Insulin detemirBinds with albumin. Threonine omitted at position 30 th of Beta chain and replaced by myristic acid at C 14 FA chain. (delays absorption by albumin binding)
Pharmacokinetics of HI and IA
RECEPTOR BINDING, METABOLIC AND MITOGENIC POTENCY OF IA
HAPO: Hyperglycemia And Adverse Pregnancy Outcome 9 countries, 25 centers, 23,325 patients 7 year study Women were screened between 24-32weeks with fasting glucose, 1 hour and 2 hour post 75 gm glucose. Medical caregivers were blinded to results except that exceeded pre defined cut offs[ 5.8 fasting, 11.1 post 75 gm glucose] and were then removed from the study. Birth weight, maternal complications, operative delivery, insulin levels in newborn were studied. Int J,Gynecology & Obstetrics. 2002,78, (1);69-77
GLYCEMIC STATUS IN GDM FASTING HYPOGLYCEMIA POSTPRANDIAL HYPERGLYCEMIA Normalisation of this is possible by Insulin Analogues.
Insulin aspart qualifies for use in GDM Insulin analogues does not cross the placenta but placental concentration is higher than in maternal blood.
Insulin Aspart in pregnancy status compared with Human Insulin Moshe Hod et al., Studied insulin aspart in Type I diabetic patient Randomized parallel group open label Multinational study -Decreased hypoglycemic spells -Increased fetal outcome
Insulin Aspart in pregnancy status compared with Human Insulin Primary objective – Hypoglycemic attacks Secondary objective – Analyze maternal/fetal outcome - HbA1c - 8 point glucose profile - Number of mild hypoglycemia - cord blood insulin AB
Mean cord blood insulin level is lower in IA group
Continuous Subcutaneous Insulin Infusion (CSII) Blood glucose levels monitored continuously Pre specified insulin dose is subcutaneously delivered by pump This minimized timing and dosing errors.
Continuous Glucose Monitoring System (CGMS) Blood glucose is assessed periodically Insulin dose is calculated CGMS integrated monitoring system with a delivery device Hence round the clock blood glucose is controlled.
e-health system Patient has her data in USB device which can be analyzed and seek guidance from internet.
CSII & CGMS Paradigm device connects CGMS and delivery device through bluetooth. This early trial is about to be started in USA.