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 prevalence linked to background IGT rates 2% Agarwal S, Gupta AN. Gestational Diabetes. J Assoc Physicians India 1982;30:203 Ramachandran A, et .al., High prevalence of diabetes in an urban population in south India. BMJ 1988;3; 297(6648):587-90 1980s 7.6% Narendra J, Munichoodappa C, et al, Prevalence of glucose intolerance during pregnancy. Int J Diab Dev Countries 1991;11:2-4 8.2% Ramachandran A, Snehalatha c, Dharmaraj D, Viswanathan M. Prevalence of glucose intolerance in Asian Indians. Diabetes Care 1992; 15:1348-55 1990s 16.6% V Seshiah, V Balaji, Madhuri S Balaji, CB Sanjeevi, A. Green. Gestational Diabetes Mellitus in India. J Assoc Physicians India 2004;52:707 14.5% 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;44:1094-1101. 2000s 7

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. 1989 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 At Birth After Birth placenta Macrosomia Obesity Hypoglycemia Maternal DM Metabolic syndrome A Insulin IGT/DM A.A Fat CHO Fetus CVD

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 Pederson’s hypothesis Macrosomia Predicts development of HTN, Type 2 DM & IGT Barker’s Hypothesis Low birth weight Pederson’s hypothesis Macrosomia Solution Optimal nutrition+ Optimal glycemic control=Optimal birth weight 3000 – 3500 g.

SCREENING FOR DIABETES

WHO Criteria FPG (mg/dl) 2h PG (mg/dl) IGT <126 140-200 Diabetes >126 >200

ADA recommendation Screening Procedure Criteria Perform a 75-g OGTT , with plasma glucose measurement fasting and at 1 and 2 h, at 24-28 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 Normal Abortions Still birth Died after birth Congenital anomalies Premature deliveries Sick babies Big baby ( 3.5 kg) NGT (n = 851) 804 6 3 1 8 9 / 831 22 78 GDM (n =211) 122 5 11 / 148 10 90 P value < 0.0001 -- 0.07 0.01 0.23 0.002 0.157

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 25. 24 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: Randomized trial glyburide vs insulin 404 GDMs FPG >95 but <140 mg/dl or 2- hr pp >120 on diet Similar success of glucose control in both groups Langer et al: NEJM 200:343:1134

Animal insulin  Insulin Analogues 1920- Introduction of insulin revolutionized Diabetes Management 1920- Introduced insulin had impurities and batch to batch variation 1980- 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 Lispro 28-29 Proline and Lysine are interchanged Insulin Aspart Proline at 28 replaced by aspartic acid. (decreases hexamer formation ) Insulin glulisine Position 3 of Lysine with Asparagine ; Lysine at 29 replaced by glutamine Insulin glargine Asparagine at A2 1 is replaced by glycine. 2 arginine added to C terminal of Beta chain Insulin detemir Binds with albumin. Threonine omitted at position 30th 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

INSULIN TACTICS Twice-daily Split-mixed Regimens Regular NPH Insulin Effect 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. B L S HS B 6-23

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FUTURE CONCEPTS IN INSULIN THERAPY

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.

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