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JOURNAL CLUB PPT MOMPOP TRIAL ON DIABETES MELLITUS.pptx

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Hem Gautam
Hem Gautam

RESEARCH JOURNAL on DIABETIC

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Journal Club Dr. HEM Resident, Year III MDGP and EM
JOURNAL CLUB PPT MOMPOP TRIAL ON DIABETES MELLITUS.pptx
JOURNAL CLUB PPT MOMPOP TRIAL ON DIABETES MELLITUS.pptx
JOURNAL CLUB PPT MOMPOP TRIAL ON DIABETES MELLITUS.pptx
Relevant literature Review. Diabetes mellitus is a serious and growing health problem. Type 2 diabetes mellitus (T2DM) is the most common type of diabetes, and is characterized by varying degrees of insulin deficiency and resistance. Pregnancy exacerbates diabetes mellitus. Metformin is preferred treatment of T2DM when not pregnant.
.Metformin is a logical treatment choice for treatment of overt T2DM in pregnancy. .T2DM is associated with significant maternal and infant morbidity. .T2DM is also associated with foetal programming of obesity and T2 DM in adulthood. The American College of Obstetricians and Gynaecologists and the American Diabetes Association both recommend insulin as first-line pharmacotherapy for preexisting type 2diabetes in pregnancy, with metformin reserved for those who cannot use insulin or decline to do so.
Current recommendations for the medical management of overt T2DM complicating pregnancy include frequent monitoring of blood glucose combined with dietary management and insulin therapy to achieve euglycemia. Use of oral hypoglycemic agents has recently gained acceptance for treatment of gestational diabetes (GDM). The efficacy of oral hypoglycemic agents for treatment of GDM is comparable to insulin, with fewer side effects and more patient preference.
Research Question Does metformin added to insulin for the treatment of preexisting type 2 diabetes or diabetes identified early in pregnancy reduce the risk of adverse neonatal outcomes?
Purpose/Background IMPORTANCE; Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes. OBJECTIVE To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on neonatal outcome. The primary objective of the Medical Optimization of Management of Overt Type 2 Diabetes in Pregnancy (MOMPOD) trial was to test the hypothesis the addition of metformin to insulin lowers the odds of composite adverse neonatal outcome of perinatal death or severe neonatal complications compared with insulin alone, without increasing risk for adverse perinatal event.
Methods The MOMPOD Study was a multi centeric, double-blinded randomized clinical trial of metformin vs placebo added to insulin for the treatment of preexisting type 2 diabetes or gestational diabetes diagnosed in early pregnancy.
Basic Study Design 1. Prospective Trial 2.Randomization; among 2667, 831 patients who were comparable were randomized 3.Blinding ; DOUBLE BLINDING 4. RCT 5.Superior/ non-inferior to MITY trial 6.Multi centric ; 17 different centres selected
Sample Size Calculation The MOMPOD Study originally proposed to enrol 1200 participants to achieve 1080. Our original sample size assumed a primary outcome event rate of 25% and had 94% power to detect a 0.60 effect size of metformin compared to placebo. The samples were well matched between treatment groups.
Inclusion criteria Pregnant adults aged 18 to 45 years Singleton gestation between 10 weeks 0 days and 22 weeks 6 days, confirmed by ultrasound . Either preexisting type 2 diabetes or with diabetes identified prior to 23 weeks requiring insulin Willingness to use insulin and study agent only;
Exclusion criteria 1.Multiple gestation 2. Suspected or known foetal structural or chromosomal abnormality 3. Known pre-existing renal disease (creatinine > 1.5 mg/dL) 4. Known medical contraindications to metformin (history of lactic acidosis) 5. Acute liver disease or known liver abnormalities (acute viral hepatitis, AST/ALT > 2x ULN) 6.Those who Did not meet inclusion criteria
Excluded population 1172 Declined to participate 375 Declined metformin 264 No reason given 141 Declined research 117 Wanted metformin 47 Declined insulin 35 Clinician declined
Design, setting, and participants: This randomized clinical trial in 17 US centre's enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks' gestation. Period of study : April 2019 to November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was done every month for all enrolled and was completed in May 2022. 息 2023 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by Hem Gautam on 06/03/2024
JOURNAL CLUB PPT MOMPOP TRIAL ON DIABETES MELLITUS.pptx
JOURNAL CLUB PPT MOMPOP TRIAL ON DIABETES MELLITUS.pptx
INTERVENTION Metformin 1000mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery.
outcome The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. secondary outcomes included maternal hypo glycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy.
DISCUSSION
JOURNAL CLUB PPT MOMPOP TRIAL ON DIABETES MELLITUS.pptx
JOURNAL CLUB PPT MOMPOP TRIAL ON DIABETES MELLITUS.pptx
Discussion continued To our knowledge, this is the largest trial of metformin added to insulin to treat preexisting type 2 diabetes or diabetes identified early in pregnancy. Study strengths include the randomized, blinded, placebo-controlled design and enrollment of a diverse study population with a large proportion of patients of Hispanic ethnicity. These strengths contribute to generalizability of our findings to a US pregnant population.
Among pregnant adults with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks gestation, metformin added to insulin did not reduce the frequency of the composite adverse neonatal outcome. Further, no significant differences were observed in secondary outcomes, including maternal hypo glycemia and neonatal fat mass. Findings were similar regardless of maternal BMI (<30 or 30), timing of diabetes diagnosis, or timing of enrollment(<18 weeks gestation or 18 weeks gestation). However , compared with those randomized to placebo, participants randomized to metformin were less likely to deliver a large-for- gestational-age infant.
Comparision with other similar studies In contrast to the current study, MiTy trial on which RCT was conducted between metformin vs placebo group which was conducted between May 25, 2011, to Oct 11, 2018, in 502 women, in Toronto university Canada , which was of small sample size with respect to current study found to have improved maternal glyemic control, less maternal weight gain, less neonatal adiposity, fewer cesarean deliveries, and more small-for-gestational-age neonates. REF; Lancet 2020;Department of Medicine, University of Toronto, Toronto, ON, Canada (Prof D S Feig MD,
The differences in results may be explained by differences in study population and study variables . In the current trial, approximately 20% were enrolled with diabetes diagnosed early in pregnancy, compared to approximately 10% in the MiTy trial, which may also reflect differences in insulin resistance. Compared with the MiTy trial, this trial had lower prevalence of small-for-gestational-age infants. This trial observed a modest reduction in large-for- gestational-age infants in the metformin group, there were no differences in neonatal outcomes nor delivery by cesarean. REF; Lancet 2020;Department of Medicine, University of Toronto, Toronto, ON, Canada (Prof D S Feig MD
The Metformin in Gestational Diabetes (MiG) trial. The Study conducted this randomized, open-label trial comparing metformin with insulin treatment in 10 New Zealand and Australian urban obstetrical hospitals in 751 GDM pregnant at 20 to 33 week of gestation done in 2007 A.D. In women with gestational diabetes mellitus, metformin (alone or with supplemental insulin) is not associated with increased perinatal complications as compared with insulin . (MOMPOD) trial has consistent finding with that of MIG trial. REF;NEJM2008 (Australian New Zealand Clinical Trials Registry number, 12605000311651.)
Metformin in gestational diabetes: the offspring follow-up (MiG TOFU) Trial ; follow up study.2018 In this follow-up study of offspring aged 7 years and 9 years of women with GDM who had been randomized to metformin or insulin treatment during pregnancy, there were no differences between treatment arms in body fat percent or metabolic measures i.e. MOMPOD) trial has consistent finding with that of MIG TOFU trial. Overall, these data are reassuring for clinicians using metformin in women with GDM. The 9-year-old offspring of women randomized to metformin were larger than those whose mothers had been randomized to insulin.
.EMERGE is a phase III, superiority, parallel, 1:1 randomised, double-blind, placebo-controlled trial comparing the effectiveness of metformin versus placebo initiated by 28 weeks (+6 days) plus usual care conducted in Galway Ireland. The EMERGE trial aims to provide robust evidence for the efficacy of metformin in women with GDM diagnosed using the WHO 2013 criteria. It will inform patients, caregivers and funding agencies regarding the use of metformin in GDM and has the potential to change practice. EMERGE protocol version 8 (27 July 2021) is currently in use. Recruitment began on June 15, 2017, and is expected to be complete soon.
Strength and Weakness of the Study/Trial Strength It took place within routine clinical practice. This is the largest trial of metformin added to insulin to treat preexisting type 2 diabetes or diabetes identified early in pregnancy. Study strengths include the randomized, blinded, placebo- controlled design and enrollment of a diverse study
Weakness/Limitations; Enrollment was suspended for as many as 9 months due to the COVID-19 pandemic . The study was halted at 75% which limit the ability to measure metformin effect on common outcomes. Maternal BMI was comparable between groups, there were more participants with obesity in the metformin group compared with the placebo group, which could skew our findings toward the null because of increased insulin resistance. Third, adherence was only measured by self- report; thus, the negative findings could be explained by poor adherence that was under reported.
Conclusions Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large for gestational age infant observed after adding metformin to insulin warrants further investigation.
Conflict of Interest No potential conflict of interest relevant to this article was reported
Funding/Support Supported by a grant from the NICHD (HD86139) and by support from the University of North Carolina Department of Obstetrics and Gynaecology.
Critical Appraisal Publication:The 2023-2024 Journal Impact Factor of JAMA (Journal of the American Medical Association) is 157.375, which is updated in 2024. Sample size: 831 women Multicenter study in 17 different countries Block Randomization with comparable sample: to eliminate possible biases Double blinding was done Benefit and harm Benefit: Outcome helps in choosing appropriate treatment Opens door for more larger and long term study. Harm: Use of unapproved drugs in pregnancy: Ethical issue
JOURNAL CLUB PPT MOMPOP TRIAL ON DIABETES MELLITUS.pptx
Take Home Message There is a growing interest in the use of oral drugs in pregnant diabetic women Using metformin plus insulin to treat pre existing Type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation. Further follow-up data are needed (some are in progress) before the use of oral therapy in DM with pregnancy is recommended to establish long- term safety.
REFERENCES 1.Center for Disease Control and Prevention. National Diabetes Statistics Report website Accessed June 1, 2023 2. Kim A. Boggess, MD, University of North Carolina at Chapel Hill, 3010 Old Clinic Bldg/CB 7570, Chapel Hill, NC 27599-7570 October 20, 2023 3.Lancet 2020;Department of Medicine, University of Toronto, Toronto, ON, Canada (Prof D S Feig MD, 4.MIG TRIAL ,The New England Journal of Medicine may 8 2008 (Australian New Zealand Clinical Trials Registry number, 12605000311651.)
5.BMJ Open Diab Res Care 2018; MIGTOFU trial 6:e000456. doi:10.1136/bmjdrc- 2017-000456 6.EMERGE protocol version 8 (27th July2021) EudraCT Number: 2016-001644- 19l; NCT NCT02980276, registered 6/6/2017is currently in use

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JOURNAL CLUB PPT MOMPOP TRIAL ON DIABETES MELLITUS.pptx

  • 1. Journal Club Dr. HEM Resident, Year III MDGP and EM
  • 5. Relevant literature Review. Diabetes mellitus is a serious and growing health problem. Type 2 diabetes mellitus (T2DM) is the most common type of diabetes, and is characterized by varying degrees of insulin deficiency and resistance. Pregnancy exacerbates diabetes mellitus. Metformin is preferred treatment of T2DM when not pregnant.
  • 6. .Metformin is a logical treatment choice for treatment of overt T2DM in pregnancy. .T2DM is associated with significant maternal and infant morbidity. .T2DM is also associated with foetal programming of obesity and T2 DM in adulthood. The American College of Obstetricians and Gynaecologists and the American Diabetes Association both recommend insulin as first-line pharmacotherapy for preexisting type 2diabetes in pregnancy, with metformin reserved for those who cannot use insulin or decline to do so.
  • 7. Current recommendations for the medical management of overt T2DM complicating pregnancy include frequent monitoring of blood glucose combined with dietary management and insulin therapy to achieve euglycemia. Use of oral hypoglycemic agents has recently gained acceptance for treatment of gestational diabetes (GDM). The efficacy of oral hypoglycemic agents for treatment of GDM is comparable to insulin, with fewer side effects and more patient preference.
  • 8. Research Question Does metformin added to insulin for the treatment of preexisting type 2 diabetes or diabetes identified early in pregnancy reduce the risk of adverse neonatal outcomes?
  • 9. Purpose/Background IMPORTANCE; Insulin is recommended for pregnant persons with preexisting type 2 diabetes or diabetes diagnosed early in pregnancy. The addition of metformin to insulin may improve neonatal outcomes. OBJECTIVE To estimate the effect of metformin added to insulin for preexisting type 2 or diabetes diagnosed early in pregnancy on neonatal outcome. The primary objective of the Medical Optimization of Management of Overt Type 2 Diabetes in Pregnancy (MOMPOD) trial was to test the hypothesis the addition of metformin to insulin lowers the odds of composite adverse neonatal outcome of perinatal death or severe neonatal complications compared with insulin alone, without increasing risk for adverse perinatal event.
  • 10. Methods The MOMPOD Study was a multi centeric, double-blinded randomized clinical trial of metformin vs placebo added to insulin for the treatment of preexisting type 2 diabetes or gestational diabetes diagnosed in early pregnancy.
  • 11. Basic Study Design 1. Prospective Trial 2.Randomization; among 2667, 831 patients who were comparable were randomized 3.Blinding ; DOUBLE BLINDING 4. RCT 5.Superior/ non-inferior to MITY trial 6.Multi centric ; 17 different centres selected
  • 12. Sample Size Calculation The MOMPOD Study originally proposed to enrol 1200 participants to achieve 1080. Our original sample size assumed a primary outcome event rate of 25% and had 94% power to detect a 0.60 effect size of metformin compared to placebo. The samples were well matched between treatment groups.
  • 13. Inclusion criteria Pregnant adults aged 18 to 45 years Singleton gestation between 10 weeks 0 days and 22 weeks 6 days, confirmed by ultrasound . Either preexisting type 2 diabetes or with diabetes identified prior to 23 weeks requiring insulin Willingness to use insulin and study agent only;
  • 14. Exclusion criteria 1.Multiple gestation 2. Suspected or known foetal structural or chromosomal abnormality 3. Known pre-existing renal disease (creatinine > 1.5 mg/dL) 4. Known medical contraindications to metformin (history of lactic acidosis) 5. Acute liver disease or known liver abnormalities (acute viral hepatitis, AST/ALT > 2x ULN) 6.Those who Did not meet inclusion criteria
  • 15. Excluded population 1172 Declined to participate 375 Declined metformin 264 No reason given 141 Declined research 117 Wanted metformin 47 Declined insulin 35 Clinician declined
  • 16. Design, setting, and participants: This randomized clinical trial in 17 US centre's enrolled pregnant adults aged 18 to 45 years with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks' gestation. Period of study : April 2019 to November 2021. Each participant was treated with insulin and was assigned to add either metformin or placebo. Follow-up was done every month for all enrolled and was completed in May 2022. 息 2023 American Medical Association. All rights reserved. Downloaded from jamanetwork.com by Hem Gautam on 06/03/2024
  • 19. INTERVENTION Metformin 1000mg or placebo orally twice per day from enrollment (11 weeks -<23 weeks) through delivery.
  • 20. outcome The primary outcome was a composite of neonatal complications including perinatal death, preterm birth, large or small for gestational age, and hyperbilirubinemia requiring phototherapy. secondary outcomes included maternal hypo glycemia and neonatal fat mass at birth, and prespecified subgroup analyses by maternal body mass index less than 30 vs 30 or greater and those with preexisting vs diabetes early in pregnancy.
  • 24. Discussion continued To our knowledge, this is the largest trial of metformin added to insulin to treat preexisting type 2 diabetes or diabetes identified early in pregnancy. Study strengths include the randomized, blinded, placebo-controlled design and enrollment of a diverse study population with a large proportion of patients of Hispanic ethnicity. These strengths contribute to generalizability of our findings to a US pregnant population.
  • 25. Among pregnant adults with preexisting type 2 diabetes or diabetes diagnosed prior to 23 weeks gestation, metformin added to insulin did not reduce the frequency of the composite adverse neonatal outcome. Further, no significant differences were observed in secondary outcomes, including maternal hypo glycemia and neonatal fat mass. Findings were similar regardless of maternal BMI (<30 or 30), timing of diabetes diagnosis, or timing of enrollment(<18 weeks gestation or 18 weeks gestation). However , compared with those randomized to placebo, participants randomized to metformin were less likely to deliver a large-for- gestational-age infant.
  • 26. Comparision with other similar studies In contrast to the current study, MiTy trial on which RCT was conducted between metformin vs placebo group which was conducted between May 25, 2011, to Oct 11, 2018, in 502 women, in Toronto university Canada , which was of small sample size with respect to current study found to have improved maternal glyemic control, less maternal weight gain, less neonatal adiposity, fewer cesarean deliveries, and more small-for-gestational-age neonates. REF; Lancet 2020;Department of Medicine, University of Toronto, Toronto, ON, Canada (Prof D S Feig MD,
  • 27. The differences in results may be explained by differences in study population and study variables . In the current trial, approximately 20% were enrolled with diabetes diagnosed early in pregnancy, compared to approximately 10% in the MiTy trial, which may also reflect differences in insulin resistance. Compared with the MiTy trial, this trial had lower prevalence of small-for-gestational-age infants. This trial observed a modest reduction in large-for- gestational-age infants in the metformin group, there were no differences in neonatal outcomes nor delivery by cesarean. REF; Lancet 2020;Department of Medicine, University of Toronto, Toronto, ON, Canada (Prof D S Feig MD
  • 28. The Metformin in Gestational Diabetes (MiG) trial. The Study conducted this randomized, open-label trial comparing metformin with insulin treatment in 10 New Zealand and Australian urban obstetrical hospitals in 751 GDM pregnant at 20 to 33 week of gestation done in 2007 A.D. In women with gestational diabetes mellitus, metformin (alone or with supplemental insulin) is not associated with increased perinatal complications as compared with insulin . (MOMPOD) trial has consistent finding with that of MIG trial. REF;NEJM2008 (Australian New Zealand Clinical Trials Registry number, 12605000311651.)
  • 29. Metformin in gestational diabetes: the offspring follow-up (MiG TOFU) Trial ; follow up study.2018 In this follow-up study of offspring aged 7 years and 9 years of women with GDM who had been randomized to metformin or insulin treatment during pregnancy, there were no differences between treatment arms in body fat percent or metabolic measures i.e. MOMPOD) trial has consistent finding with that of MIG TOFU trial. Overall, these data are reassuring for clinicians using metformin in women with GDM. The 9-year-old offspring of women randomized to metformin were larger than those whose mothers had been randomized to insulin.
  • 30. .EMERGE is a phase III, superiority, parallel, 1:1 randomised, double-blind, placebo-controlled trial comparing the effectiveness of metformin versus placebo initiated by 28 weeks (+6 days) plus usual care conducted in Galway Ireland. The EMERGE trial aims to provide robust evidence for the efficacy of metformin in women with GDM diagnosed using the WHO 2013 criteria. It will inform patients, caregivers and funding agencies regarding the use of metformin in GDM and has the potential to change practice. EMERGE protocol version 8 (27 July 2021) is currently in use. Recruitment began on June 15, 2017, and is expected to be complete soon.
  • 31. Strength and Weakness of the Study/Trial Strength It took place within routine clinical practice. This is the largest trial of metformin added to insulin to treat preexisting type 2 diabetes or diabetes identified early in pregnancy. Study strengths include the randomized, blinded, placebo- controlled design and enrollment of a diverse study
  • 32. Weakness/Limitations; Enrollment was suspended for as many as 9 months due to the COVID-19 pandemic . The study was halted at 75% which limit the ability to measure metformin effect on common outcomes. Maternal BMI was comparable between groups, there were more participants with obesity in the metformin group compared with the placebo group, which could skew our findings toward the null because of increased insulin resistance. Third, adherence was only measured by self- report; thus, the negative findings could be explained by poor adherence that was under reported.
  • 33. Conclusions Using metformin plus insulin to treat preexisting type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The effect of reduction in odds of a large for gestational age infant observed after adding metformin to insulin warrants further investigation.
  • 34. Conflict of Interest No potential conflict of interest relevant to this article was reported
  • 35. Funding/Support Supported by a grant from the NICHD (HD86139) and by support from the University of North Carolina Department of Obstetrics and Gynaecology.
  • 36. Critical Appraisal Publication:The 2023-2024 Journal Impact Factor of JAMA (Journal of the American Medical Association) is 157.375, which is updated in 2024. Sample size: 831 women Multicenter study in 17 different countries Block Randomization with comparable sample: to eliminate possible biases Double blinding was done Benefit and harm Benefit: Outcome helps in choosing appropriate treatment Opens door for more larger and long term study. Harm: Use of unapproved drugs in pregnancy: Ethical issue
  • 38. Take Home Message There is a growing interest in the use of oral drugs in pregnant diabetic women Using metformin plus insulin to treat pre existing Type 2 or gestational diabetes diagnosed early in pregnancy did not reduce a composite neonatal adverse outcome. The reduction in odds of a large-for-gestational-age infant observed after adding metformin to insulin warrants further investigation. Further follow-up data are needed (some are in progress) before the use of oral therapy in DM with pregnancy is recommended to establish long- term safety.
  • 39. REFERENCES 1.Center for Disease Control and Prevention. National Diabetes Statistics Report website Accessed June 1, 2023 2. Kim A. Boggess, MD, University of North Carolina at Chapel Hill, 3010 Old Clinic Bldg/CB 7570, Chapel Hill, NC 27599-7570 October 20, 2023 3.Lancet 2020;Department of Medicine, University of Toronto, Toronto, ON, Canada (Prof D S Feig MD, 4.MIG TRIAL ,The New England Journal of Medicine may 8 2008 (Australian New Zealand Clinical Trials Registry number, 12605000311651.)
  • 40. 5.BMJ Open Diab Res Care 2018; MIGTOFU trial 6:e000456. doi:10.1136/bmjdrc- 2017-000456 6.EMERGE protocol version 8 (27th July2021) EudraCT Number: 2016-001644- 19l; NCT NCT02980276, registered 6/6/2017is currently in use