CME INDIA Presentation by Dr. Anand Shankar, Associate Professor, Dept. of Medicine, Netaji Subhas Medical College & Hospital, Patna. Joint Secretary of Diabetes in Pregnancy Study Group of India.
DIPSI Guidelines for Management Of GDM
The present guideline has been prepared based on the recommendations of the experts & available national/international evidences:
- To address to the urgent need to prevent and minimize maternal and fetal morbidity associated with GDM.
- Integration of GDM diagnosis and management within ANC care package in public health system.
- To address the need of high prevalence of GDM in India.
- To suffice the globally available evidences ere generated on safety and effectiveness on oral hypoglycemic drugs recommending use of “Metformin” for GDM management.
What do the guidelines say?
|Almost all guidelines agree to management of GDM using Medical Nutrition Therapy (Diet plan) & insulin therapy, if needed.|
|Recently, global evidences have also concluded that metformin is safe and effective for GDM management after 20 weeks of gestation if not controlled by MNT.|
|For this reason, GOI constituted an expert group to deliberate on GDM in detail & revise the national guidelines for India incorporating the recent global evidences on use of Metformin and in country experiences.|
Management of GDM
- Metformin or Insulin therapy is the accepted medical management of pregnant women with GDM not controlled on MNT.
- Insulin is the first drug of choice and metformin can be considered after 20 weeks of gestation for medical management of GDM.
- Insulin can be started any time during pregnancy for GDM management.
- If pregnant women with GDM before 20 weeks, and Medical Nutrition Therapy (MNT) failed, Insulin should be started.
- Details of Insulin vial/cartridge.
- Only Injection Human premix insulin 30/70 is to be administered.
- Insulin vial – 40 IU/mL is to be used.
- Insulin cartridge – insulin dose to be adjusted as per units required.
Metformin Pearls in GDM
Insulin: Standard of care for the treatment of uncontrolled gestational diabetes
- Insulin remains the standard of care for the treatment of type 1 diabetes, type 2 diabetes, and uncontrolled gestational diabetes.
- Tight control maintained in the first trimester and throughout pregnancy plays a vital role in:
- Decreasing poor fetal outcomes, including
- Structural anomalies
- Hypoglycemia of the newborn
- Adolescent and adult obesity and
Choice of Insulin regimen
Available Insulin and Insulin Analogs in GDM patients and classification as per FDA, EMA and Indian label guidance
Insulin analogues in HIP – An Indian Experience
- Comparison of Efficacy and Safety of Analog Insulins Vs Human Insulins-Basal Bolus Regimen and Premix Twice Daily Regimen in Indian Hyperglycemia in Pregnancy Anand Shankar (2022)
- Use of insulin glargine during pregnancy: A review Pratap Jethwani et al (2021).
- Consensus on Use of Insulins in Gestational Diabetes NIS-(2016).
- Insulin Therapy in Diabetic Pregnancy: Clinician’s Vision Dr. Sunil Gupta (2016).
- Insulin aspart in patients with gestational diabetes mellitus and pregestational diabetes mellitus M. C. Deepaklal (2015).
- Efficacy of insulin lispro in improving glycemic control in gestational diabetes M.C. Deepaklal et al (2014).
- Gestational Diabetes Mellitus: Insulinic Management Magon Navneet, Seshiah Veerasamy (2014).
- Premixed insulin aspart 30 (BIAsp 30) versus premixed human insulin 30 (BHI 30) in gestational diabetes mellitus: a randomized open-label controlled study Vijayam Balaji et al. (2012).
Premixed insulin aspart 30 (BIAsp 30) versus premixed human insulin 30 (BHI 30) in gestational diabetes mellitus: a randomized open-label controlled study
- A randomized, open-label, parallel study was conducted to assess the efficacy and safety of premixed insulin aspart 30 (biphasic insulin aspart [BIAsp] 30) in managing gestational diabetes mellitus (GDM).
- A total of 323 women with GDM registered at a single center in India were randomly assigned to receive 6 U of either BIAsp 30 (Group A) or premixed human insulin (biphasic human insulin [BHI] 30; Group B) in a 1:1 ratio. Subjects performed home glucose monitoring and visited their care provider twice a month.
- The primary outcome was the degree of neonatal macrosomia (neonatal birth weight >90th percentile). Groups A and B were demographically comparable at study entry. Before labor onset, Groups A and B achieved similar degrees of fasting plasma glucose and postprandial plasma glucose control (92.97 ± 14.44 vs. 95.43 ± 18.96 and 127.59 ± 28.99 vs. 126.98 ± 29.89, respectively; both p = NS). Neonatal macrosomia frequency was 6.3% in Group A and 6.9% in Group B; however, this difference was not statistically significant.
- By last visit, the required insulin dose was significantly lower for Group A than Group B (19.83 ± 15.75 IU vs. 26.34 ± 23.15 IU, respectively; p = 0.006).
- BIAsp 30 was no inferior to BHI 30, producing comparable fetal outcomes when administered during pregnancy.
- Based on final doses, BIAsp 30 may offer greater treat-to-target potential for pregnant women.
- Both BHI 30 & BIAsp 30 were well tolerated, with few hypoglycemic episodes and no adverse events reported by either group.
Efficacy of insulin lispro in improving glycemic control in gestational diabetes
- It was done to assess the safety and efficacy of insulin lispro in improving glycemic control in patients with gestational diabetes.
- It was a retrospective observational study. It was conducted at a single center on 201 gestational women with diabetes. Subjects who received insulin lispro performed blood glucose self monitoring and recorded the readings in the fasting state and 1 h after each meal.
- At each contact (in person or telephonic contact), the insulin dose was adjusted based on the readings measured. A total of 53 subjects also recorded glucose levels post partum.
- Pregnancy and post delivery glucose level and insulin requirements of these 53 patients were compared.
- Analysis of glucose levels both fasting and post prandial glucose levels revealed that after using insulin lispro, the number of episodes of post prandial hyperglycemia (1 h plasma glucose >120 mg/dL) was minimal and so was the incidence of hypoglycemia. There was neither any congenital abnormality except for a poorly formed pinna in the right ear of one baby nor any post partum complications of note.
- Conclusion: Insulin lispro is an effective and safe treatment option in gestational diabetes.
Gestational Diabetes Mellitus : Insulinic Management
(Review article by Pro Seshiah V.)
- The new insulin analogs present undoubted advantages in reducing the risk of hypoglycemia, mainly during the night, and in promoting a more physiologic glycemic profile in pregnant women with diabetes.
- Rapid acting insulin analogs seem to be safe and efficient in reducing postprandial glucose levels more proficiently than regular human insulin, with less hypoglycemia.
- The long-acting insulin analogs do not have a pronounced peak effect as NPH insulin, and cause less hypoglycemia, mainly during the night.
Insulin aspart in patients with gestational diabetes mellitus and pregestational diabetes mellitus
- This study was undertaken to assess the effectiveness and safety of insulin aspart in patients with gestational and pregestational diabetes.
- Settings and Design: An open-label, prospective, nonrandomized, comparative, and observational study conducted at single center in India.
- Subjects and Methods: A total of 276 patients were in gestational diabetes mellitus (GDM) group, 79 were in the pre-GDM group.
- There was no statistically significant difference among the two groups in terms of incidence of macrosomia.
- Conclusions: Insulin aspart was found safe in pregnancy, however, more studies with double-blind, standard controlled studies are required to confirm the findings of this study.
- The results show that by achieving targeted glycemic control of FPG <90 mg/dL and/or 1.0 h PPG <130 mg/dL by insulin aspart ± NPH in GDM and pre-GDM cases improves the perinatal outcomes in terms of reducing the incidence of macrosomia, preterm and post term deliveries and complicated mode of deliveries.
- Real life data shows the role of insulin aspart in achieving targeted glycemic control for improving clinical outcomes in GDM and pre GDM patients.
Insulin Therapy in Diabetic Pregnancy: Clinician’s Vision
(A review article by Dr Sunil Gupta)
- In this study, he evaluated the dose, distribution and factors influencing the insulin requirement in women with GDM, Decreased Gestational Glucose Tolerance (DGGT – women with 2-hour 75gm OGGT value between 120 – 140 mg%) and in Pre GDM-Type 2 women.
- Of 348 pregnant women with varying degree of glucose intolerance 158 subjects (45.4%) required insulin to achieve euglycemia in pregnancy as per DIPSI Guideline. (FBG < 90 mg%, 2hr PPBG < 120 mg%).
- Observations were:
- Mean Insulin Dose required: DGGT < 10 U/ days, GDM: 23 U/day, & Pre GDM: 52.5 U/day. Dose increase significantly from diagnosis till delivery by 1.5 to 2 times.
- GDM required double the dose of DGGT, while Pre GDM required double the dose of GDM.
- DGGT needed 0.2 U/Kg/day, GDM: 0.4 U/Kg/ day while Pre GDM: 0.9 U/Kg/day of their pre pregnancy weight.
- 27.8% of GDM, 77% of Pre GDM and 3.6% DGGT women required pre dinner NPH insulin for controlling fasting hyperglycemia.
- Contrary to the belief, our population required lowest dose during breakfast, higher in lunch while highest dose of short acting insulin with dinner. The pre-dinner dose was almost double than that of pre breakfast in all three groups.
- The insulin dose was directly proportional to FBG and pre pregnancy weight but it couldn’t be correlated to Age and Pre-Pregnancy BMI.
Consensus on Use of Insulins in Gestational Diabetes. (Gangopadhyay KK et al)
The key recommendations are:
|To monitor fasting plasma glucose (FPG) and 2-hour post prandial glucose PPG levels and the glycaemic targets are: FPG < 95 mg/dL and 2-hour PPG < 120 mg/dL.|
|Short-and intermediate acting human insulin are the first choice of insulin regimens.|
|Rapid-acting (Insulin Aspart or Lispro) may be considered, use basal/intermediate acting insulin at bedtime.|
|If FPG>110 mg/dL. During intrapartum, start IV insulin infusion with hourly glucose monitoring.|
|Those women who require insulin < 20 U over 24 hours prior to labor may not need interpartum use of insulin infusion and Insulin dosing is stopped after birth and capillary glucose monitoring for 24-48 hours.|
Use of insulin glargine during pregnancy
A review by Jethwani P, Saboo B, Jethwani L, Chawla R, Maheshwari A, et al
- Insulin glargine, in spite of widespread use in non-pregnant adults, lacks randomized controlled trial evidence as safe basal insulin during pregnancy.
- Evidences related to use of insulin glargine during pregnancy, including animal studies, placental transfer studies, case reports as well as observational studies were retrieved using PUBMED & Google scholar. Recommendations regarding use of insulin glargine during pregnancy by international and Indian organizations were reviewed.
- Results: Trans-placental transfer studies show that insulin glargine does not cross placenta when used at therapeutic concentrations. Although there are no randomized controlled trials on insulin glargine in pregnancy, it’s use during pregnancy is not associated with any adverse maternal or neonatal outcomes as shown in many case reports and observational studies (both prospective and retrospective). It’s use during pregnancy is hence considered safe by many organizations across the globe.
- Insulin glargine can be continued safely during pregnancy in women who are already taking it prior to pregnancy and have achieved good glycemic control with it. However, we require preferably randomized controlled trials or large prospective observational studies to establish it as first line or preferred basal insulin for management of hyperglycemia during pregnancy.
- However, currently, the use of insulin glargine in pregnancy is not approved and well-planned controlled trials are needed to determine the safe use in pregnancy.
Guidelines and recommendations from different organizations about use of basal insulin including insulin glargine (IG) during pregnancy
Faster Acting Insulin Aspart in Patients with Gestational Diabetes Mellitus –an Early Experience from India
(Supratik Bhattacharya et al.)
- Out of 37 full term deliveries, only two had macrosomia.
- No congenital defects were noted in the anomaly scan and at births.
- There were no episodes of neonatal hypoglycemia reported.
- Only one episode of post-meal symptomatic maternal hypoglycemia was reported.
- Mean number of FiASP injections per day was 2.88 ± 0.39.
- Mean daily dose of FiASP used was 22.7 ± 6 international units.
- A total of 89% of the patients received faster aspart thrice daily.
- Remaining received it twice daily.
- Conclusions: Faster acting insulin aspart was found safe in pregnancy, however, more studies with double-blind, standard controlled studies are required to confirm the findings of this study.
Comparison of Efficacy and Safety of Analog Insulins Vs Human Insulins-Basal Bolus Regimen and Premix Twice Daily Regimen in Indian Hyperglycemia in Pregnancy
- Both regular insulin and analog insulin are safe to use in hyperglycemia in pregnancy.
- Both these insulins are subject-friendly and easily convincing for patients.
- Basal bolus regime is more complicated.
- Despite being so, it gives more precise control results in comparison with premix of either human insulins or analog insulin.
- The analogue of premix insulin is also considered to be a useful formulation for the clinical use of both pregnant women and diabetic populations with abnormal tolerance to glucose.
- The pregnant women have found “BIAsp to be convenient as the preparation allows flexibility during each meal time by dozing insulin and does not disturb their pattern of routine”.
- Additionally, BIAsp is found to be safer by using during the course of pregnancy.
Maternal efficacy, safety, and pregnancy outcomes with degludec versus detemir in the treatment of pregnant women with type 1 diabetes (An international, multicentre, randomized trial)
- In pregnant women with T1D, degludec was non-inferior to detemir with respect to HbA1c prior to delivery. Hypoglycaemia rates and pregnancy outcomes were comparable between insulins.
Summary of evidence Indian Experience
|• Insulin is the first drug of choice|
|• Only Injection Human premix insulin 30/70 is to be administered – MOH Govt of India|
|• The new insulin analogs present undoubted advantages in reducing the risk of hypoglycemia, mainly during the night, and in promoting a more physiologic glycemic profile in pregnant women with diabetes.|
|• Rapid acting insulin analogs seem to be safe and efficient in reducing postprandial glucose levels more proficiently than regular human insulin, with less hypoglycemia.|
|• The long-acting insulin analogs do not have a pronounced peak effect as NPH insulin, and cause less hypoglycemia, mainly during the night.|
|• BIAnalog are non-inferior to BHI, produce comparable fetal outcomes when administered during pregnancy.|
|• Basal bolus regime is more complicated.|
|• Despite being so, it gives more precise control results in comparison with premix of either human insulins or analog insulin.|
|• Insulin glargine can be continued safely during pregnancy in women who are already taking it prior to pregnancy.|
|• Faster acting insulin aspart was found safe in pregnancy, however, more studies required.|
Metformin: In Pregnancy
- Decreases insulin resistance and
- Improves insulin sensitivity
- Thereby decreasing the excessive maternal glucose flux to the fetus.
- This in turn serves to prevent fetal hyperinsulinemia and excess adiposity in the fetus.
- Maternal exposure to metformin during pregnancy was not found to be associated with any long-term increased risk of hypoglycemia, hyperglycemia, obesity, diabetes, or problems in motor social development, when compared with insulin.
Glucophage: First Oral Diabetes Treatment Approved in Europe for use during Pregnancy
- Merck, a leading science and technology company, announced in a European work sharing procedure (WSP) an extension to the label for metformin products for use throughout pregnancy.
- No long-term risks for the child later in life have been confirmed.
CME INDIA Learning Edge
- Universal testing of all pregnant women for GDM.
- Pregnant women testing positive (2 hr. OGTT ≥ 140 mg/dL) should be started on MNT for 2 weeks.
- If 2 hr. PPBS ≥120 mg/dL after MNT and physical exercise, medical management (metformin or insulin therapy) of pregnant women to be started as per guidelines.
CME INDIA Tail Piece
Based on a talk delivered at DRWA, Manas Reserve resort, Guwahati on 21st Jan 2023.
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- ACOG Practice Bulletin No. 190: Gestational Diabetes Mellitus Obstetrics & Gynecology: February 2018 – Volume 131 – Issue 2 – p e49–e64.
- IDF. Global Guidelines Pregnanacy & Diabetes. 2009.
- NICE GUIDELINES Diabetes in pregnancy: management from preconception to the postnatal period (NG3).
- V Sehiah et al. DIPSI guidelines, JAPI 2006.5).
- Gangopadhyay KK et al. Consensus on Use of Insulins in Gestational Diabetes. The Journal of the Association of Physicians of India. 2017 Mar;65(3 Suppl):16-22.
- RSSDI Clinical Practice Recommendations for the Management of Type 2 Diabetes Mellitus 2022.
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- Singh AK, Singh R. Metformin in gestational diabetes: An emerging contender. Indian J Endocrinol Metab. 2015 Mar-Apr;19(2):236-44. doi: 10.4103/2230-8210.149317. PMID: 25729685; PMCID: PMC4319263.
- Anand Shankar. Comparison of Efficacy and Safety of Analog Insulins Vs Human InsulinsBasal Bolus Regimen and Premix Twice Daily Regimen in Indian Hyperglycemia in Pregnancy. Archives of Internal Medicine Research 5 (2022): 462-465.
- Elisabeth R M et al., Indian Journal of Endocrinology and Metabolism: March 2022 – Volume 26 – Issue Suppl 1 – p S7-S8 doi: 10.4103/2230-8210.34230
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