srinivasa02-03-12(1)

2012 Srinivasa 1

Insulin vs. Oral Therapy for the Treatment of Gestational Diabetes

Maaya Srinivasa, PharmD PGY-‐1 Community Pharmacy Practice Resident

Centro San Vicente Family Health Center UTEP/UT Austin Cooperative Pharmacy Program

Preceptor: Margie E. Padilla, PharmD, CDE

February 3rd, 2012

Objectives 1. Describe diagnosis of gestational diabetes 2. Review current guidelines for management of gestational diabetes 3. Evaluate existing literature in regards to insulin versus oral therapy for the

treatment of gestational diabetes 4. Discuss recommendations regarding pharmacotherapy for gestational diabetes

Source: http://www.wellwomanblog.com/wp-‐content/uploads/19146196.jpg

2012 Srinivasa 2

I. Introduction A. Definitions

1. Gestational Diabetes Mellitus (GDM): “diabetes diagnosed during pregnancy that is not clearly overt diabetes”1

B. Epidemiology2,3,4 1. National: reported rates range from 2% to 10% 2. 6% to 7% of pregnancies are complicated by diabetes; 85% of these cases are due to GDM 3. Local: 11.5% of women in Texas reported they had GDM (2009)

C. Pathophysiology5 1. Insulin resistance increases as pregnancy progresses; insulin sensitivity falls by ~50% in late

pregnancy 2. Increased insulin resistance due to increased maternal adiposity and effects of placental hormones 3. Hormones produced by the placenta: Human chorionic somatomammotropin (HCS), cortisol,

estrogen, progesterone 4. As pregnancy progresses and placenta grows, production of hormones increases; thus leading to

increased insulin-‐resistance 5. GDM occurs when insulin secretion is not sufficient to offset the decrease in insulin sensitivity

Adapted from: http://diabetesmellitustreatments.com/wp-‐content/uploads/2011/05/image_thumb28.png

Figure 2: Pathophysiology of Gestational Diabetes

é HCS é Cortisol é Estrogen é Progesterone

Fetus

Placenta Mother

é Glucose

Source: Texas Department of State Health Services

Figure 1: Pre-‐existing vs. Gestational Diabetes, Texas PRAMS 2004-‐2009 4

2

Prevalence and Outcomes of Pre-existing and Gestational Diabetes, 2004-2009 Texas Pregnancy Risk Assessment Monitoring System (PRAMS)

The CDC sets a threshold response rate for epidemiologic validity of PRAMS data. For years 2006 and earlier, this threshold was 70 percent. Beginning in 2007, it was lowered to 65 percent. Texas did not meet the CDC’s threshold response rate until 2009 (currently the most recent year of data available), with a response rate of 67 percent. Response rates for the previous seven years ranged from 54 percent to 67 percent. While lower response rates warrant caution when interpreting PRAMS data, this surveillance system offers insight into diabetes prevalence and the impact of pre-existing and gestational diabetes on births in the state.

According to Texas PRAMS, in 2009, 11.5 percent of women reported that they had gestational diabetes (95% CI: 9.4-13.7) and 1.9 percent reported that they had pre-existing diabetes (95% CI: 1.2-2.7). The estimated prevalence of combined pre-existing and

The Pregnancy Risk Assessment Monitoring System (PRAMS) is a state-

specific, population-based surveillance system funded by the Centers for Disease Control and Prevention (CDC). PRAMS was developed in 1987 with the goal of reducing infant mortality and low birth weight births. Thirty-seven states currently participate in PRAMS, and Texas has been a PRAMS state since 2002. The current Texas PRAMS survey includes 72 questions designed to identify and monitor selected maternal experiences before, during, and after pregnancy. Each year, approximately 2,400 new mothers in Texas are randomly selected to participate in PRAMS.

The PRAMS sample is collected and structured so that it is representative of all live births to women who are Texas residents; thus, the data can be generalized to represent the entire population of Texas.

gestational diabetes was 12.9 percent (95% CI: 10.7-15.1). Negative health outcomes for both mother and baby were significantly more common for women with diabetes (pre-existing and gestational) than for those without diabetes (Figure 3).

Black and Hispanic respondents reported higher prevalence of diabetes (gestational and pre-existing) than white respondents. Prevalence of diabetes among Hispanic mothers (11.9%) was significantly higher than prevalence among white mothers (8.8%). Prevalence increased significantly with increasing maternal age, and women who were overweight or obese before pregnancy experienced significantly higher prevalence of diabetes when compared to women who were not overweight or obese.

12

10

8

6

4

2

0

Gestational

Pre-existing

2004 2005 2006 2007 2008 2009

1.7

9.2

3.2

9.2

1.6

9.0 9.7

1.7 1.9

10.1

1.9

11.5

Figure 1: Pre-existing vs. Gestational Diabetes, Texas PRAMS 2004-2009

15

12

9

6

3

02004 2005 2006 2007 2008 2009

10.2 10.8 9.7 10.411.5

12.9

Figure 2: Combined Pre-existing and Gestational Diabetes, Texas PRAMS 2004-2009

Prev

alen

ce o

f Dia

bete

s (%

)Pr

eval

ence

of D

iabe

tes

(%)

Table 1: Prevalence of Diabetes by Maternal Race/Ethnicity, 2004-2009 TX PRAMS White 8.8% (95% CI: 7.6-9.9) Black 10.6% (95% CI: 9.1-12.0) Hispanic 11.9% (95% CI: 10.5-13.3)

Table 2: Prevalence of Diabetes by Maternal Age, 2004-2009 TX PRAMS <20 6.9% (95% CI: 4.9-8.8) 20-24 6.1% (95% CI: 4.9-7.3) 25-34 12.2% (95% CI: 10.9-13.5) 35+ 19.2% (95% CI: 16.2-22.2)

Table 3: Prevalence of Diabetes by Overweight/Obese, 2004-2009 TX PRAMS Not Overweight/ 7.1% (95% CI: 6.4-8.1) Obese (BMI<25) Overweight/ 14.8% (95% CI: 13.3-16.2) Obese (BMI>25)

2012 Srinivasa 3

II. Complications A. Mother2,5

1. Increased risk of hypertensive disorders 2. Increased risk of developing diabetes later in life

a. Patients with a history of GDM are 33% -‐ 50% more likely to develop GDM with subsequent pregnancies

b. Immediately after pregnancy, 5% -‐ 10% of women are found to have diabetes, usually Type 2 c. There is a 35% -‐ 60% chance of women with a history of GDM developing diabetes in the next

10 – 20 years

B. Baby2,5 1. Macrosomia: birth weight > 4000 g (8 lbs. 13 oz.) 2. Hyperbilirubinemia: infant jaundice 3. Increase in operative delivery, shoulder dystocia, and birth trauma 4. Obesity and diabetes in children has been linked to those who are offspring of mothers with GDM

C. HAPO Study7,8

1. 25,505 women in 9 countries were given 75-‐g OGTT test between 24-‐32 weeks gestation 2. Primary Outcomes: Birth weight> 90th percentile, cesarean delivery, neonatal hypoglycemia, cord-‐

blood serum C-‐peptide> 90th percentile 3. Secondary outcomes: delivery before 37 weeks gestation, shoulder dystocia or birth injury, need

for intensive care, hyperbilirubinemia, preeclampsia 4. Odds ratios calculated for 23,616 patients with blinded data for adverse pregnancy outcomes

associated with an increase in fasting plasma glucose, 1-‐hour plasma glucose, and 2-‐hour plasma glucose

5. Showed that adverse outcomes were associated with hyperglycemia less severe than that found in diabetes

6. Results were used by IADPSG in determining diagnostic criteria for GDM

T h e n e w e ng l a nd j o u r na l o f m e dic i n e

n engl j med 358;19 www.nejm.org may 8, 20082000

adverse outcomes generally remained significant after adjustment for multiple potential confound-ers — 10 of 12 associations for primary outcomes and 12 of 15 for secondary outcomes — and were generally consistent across centers, except the as-sociation for the fasting plasma glucose level and primary cesarean delivery. Furthermore, findings with respect to cord-blood serum C-peptide levels, and hence fetal insulin levels, support Pedersen’s proposed mechanism to explain the propensity for excessive growth in fetuses of mothers with hyperglycemia. When associations between ma-ternal glucose level and birth weight were esti-mated with the use of birth weight as a continu-ous variable, the difference in mean birth weight between the lowest and highest glucose categories was in the range of 240 to 300 g, even after full adjustment for potential confounders.

Two primary outcomes — birth weight above the 90th percentile and cord-blood serum C-pep-tide level above the 90th percentile — though strongly associated with maternal glycemia, could be viewed as physiological consequences of ma-ternal glycemia rather than as true disorders or problems. However, the other two primary out-comes (primary cesarean delivery and clinical

neonatal hypoglycemia) and the five secondary outcomes reported (premature delivery, shoulder dystocia or birth injury, intensive neonatal care, hyperbilirubinemia, and preeclampsia) also showed continuous linear associations with the 1-hour plasma glucose level (seven analyses), the 2-hour plasma glucose level (six analyses), and the fast-ing plasma glucose level (three analyses). These are well-recognized complications of pregnancies in mothers with preexisting or gestational diabetes, as currently defined.

Questions have been raised regarding the benefits of treating “mild” gestational diabetes mellitus.13,23,24 However, one recently published randomized clinical trial, the Australian Carbo-hydrate Intolerance Study in Pregnant Women (ACHOIS), found reduced perinatal morbidity and mortality when standard contemporary treatment of gestational diabetes mellitus was compared with no intervention25; another study on treatment of “mild” gestational diabetes mellitus is ongo-ing.26 Taken together, the current results and re-sults of the ACHOIS trial25 indicate that mater-nal hyperglycemia less severe than that used to define overt diabetes is related to clinically impor-tant perinatal disorders or problems and that their

Table!3.!Adjusted!Odds!Ratios!for!Associations!between!Maternal!Glycemia!as!a!Continuous!Variable!and!Primary!!and!Secondary!Perinatal!Outcomes.*

Outcome Plasma!Glucose!Level

Fasting At 1 Hr At 2 Hr

odds ratio (95% CI)Primary!outcome

Birth weight >90th percentile 1.38 (1.32–1.44) 1.46 (1.39–1.53) 1.38 (1.32–1.44)

Primary cesarean section† 1.11 (1.06–1.15) 1.10 (1.06–1.15) 1.08 (1.03–1.12)

Clinical neonatal hypoglycemia 1.08 (0.98–1.19)‡ 1.13 (1.03–1.26) 1.10 (1.00–1.12)

Cord-blood serum C peptide >90th percentile 1.55 (1.47–1.64) 1.46 (1.38–1.54) 1.37 (1.30–1.44)

Secondary!outcome

Premature delivery (before 37 wk) 1.05 (0.99–1.11) 1.18 (1.12–1.25) 1.16 (1.10–1.23)

Shoulder dystocia or birth injury 1.18 (1.04–1.33) 1.23 (1.09–1.38) 1.22 (1.09–1.37)

Intensive neonatal care 0.99 (0.94–1.05) 1.07 (1.02–1.13) 1.09 (1.03–1.14)

Hyperbilirubinemia 1.00 (0.95–1.05) 1.11 (1.05–1.17) 1.08 (1.02–1.13)

Preeclampsia 1.21 (1.13–1.29) 1.28 (1.20–1.37) 1.28 (1.20–1.37)

* Odds ratios were for an increase in the glucose level of 1 SD (6.9 mg per deciliter [0.4 mmol per liter] for the fasting plas-ma glucose level, 30.9 mg per deciliter [1.7 mmol per liter] for the 1-hr plasma glucose level, and 23.5 mg per deciliter [1.3 mmol per liter] for the 2-hr plasma glucose level). The model for preeclampsia did not include adjustment for hos-pitalization or mean arterial pressure, and presence or absence of family history of hypertension or prenatal urinary tract infection was included in the model for preeclampsia only. See Table 2 for other details about adjustments in each model.

† Data for women who had had a previous cesarean section were excluded.‡ The P value for the quadratic (nonlinear) association was 0.013.

The New England Journal of Medicine Downloaded from nejm.org at UT EL PASO on December 15, 2011. For personal use only. No other uses without permission.

Copyright © 2008 Massachusetts Medical Society. All rights reserved.

Figure 3: Association Between Maternal Glycemia and Primary and Secondary Perinatal Outcomes in the HAPO Study7

Source: HAPO Study, 2008.

2012 Srinivasa 4

III. Risk Factors5 A. Age

1. Increased risk with increased age; < 25 years old considered low risk

B. Ethnicity 1. Highest risk: Native Americans, Hispanic, Asian decent 2. Moderate risk: African women 3. Lowest risk: Non-‐Hispanic white women

C. Obesity

D. Family History

E. Past Obstetric History 1. Women who have previously delivered a large infant 2. Women with a history of PCOS or previous GDM

IV. Screening and Diagnosis A. Screening9,1

1. ACOG: 50-‐g 1 hour glucose challenge with a threshold of 130 mg/dL or 140 mg/dL 2. ADA: screen at 24-‐28 weeks using a 75-‐g OGTT; use diagnostic cut points listed below

B. Diagnosis

1. ACOG9 a. Evidence supports 100-‐g, 3 hour OGTT; positive diagnosis made when two or more thresholds

are met

Low Risk*

•  Age < 25 yo •  No previous history of poor obstetric outcomes •  Part of a low-‐risk ethnic group •  No DM in first-‐degree relamves •  Normal prepregnancy weight and weight gain throughout pregnancy •  No history of glucose intolerance

Medium Risk

•  Does not fall into low or high risk category

High Risk

•  Obese •  DM in first-‐degree relamve •  Current glycosuria •  History of GDM or glucose intolerance •  Previous delivery of infant with macrosomia

*All listed criteria must be met to be considered Low Risk.

Figure 4: Risk Categories for GDM5

2012 Srinivasa 5

2. ADA1

a. Diagnosis made when fasting blood glucose ≥ 92 mg/dL, OR values after 75-‐g OGTT are 1 hour ≥ 180 mg/dL or 2 hour ≥ 153 mg/dL

3. IADPSG8 a. At first prenatal visit, measure fasting blood glucose, A1c, or random blood glucose for all

women or those that are considered high-‐risk b. Overt diabetes: fasting blood glucose ≥ 126 mg/dL, A1c ≥ 6.5%, or random blood glucose ≥

200 mg/dL c. If not overt diabetes, but fasting blood glucose is ≥ 92 and < 126 mg/dL, diagnose as GDM d. If not overt diabetes, and fasting blood glucose < 92 mg/dL, test for GDM at 24 – 28 weeks gestation

e. At 24 – 28 weeks, perform 75-‐g OGTT test; GDM diagnosed if any of the thresholds are met (Fasting blood glucose ≥ 92 mg/dL, 1 hour ≥ 180 mg/dL, 2 hour ≥ 153 mg/dL)

V. Current Recommendations for Treatment A. ACOG Practice Bulletin: Clinical Management Guidelines for Gestational Diabetes (2001; reaffirmed

2010)9 1. Diet

a. Cites ADA recommendations to provide nutritional counseling with individualization based on height and weight

b. For non-‐obese women, 30 kcal/kg/d recommended c. Current evidence does not provide recommendation for or against caloric restriction

2. Exercise a. Randomized trials examining exercise in addition to, or substituted for insulin found no

difference in birth of macrosomic infants b. Randomized trial of diet versus exercise found improvement in fasting plasma glucose;

another study found no difference in glucose control c. “Regular exercise program has clear benefits for all women and may offer additional benefits

for women with GDM.” 3. Pharmacologic Therapy

a. Insulin i. No specific regimen or dose has been shown to be superior for GDM ii. No clear recommendation about how long glucose values should exceed targets before

adding insulin. (One study suggests 2 weeks of dietary management before adding insulin) iii. May be considered in patients treated with diet therapy when 1-‐hour post-‐prandial values >

130-‐140 mg/dL, 2-‐hour post-‐prandial values > 120 mg/dL, or FPG > 95 mg/dL iv. Insulin does not cross the placenta; all types have been used in GDM

There are no well-designed studies that demonstratewhether these diagnostic criteria are optimal to identifypregnancies at risk for maternal or perinatal morbidity.The relationship between maternal glucose intoleranceand adverse pregnancy outcomes appears to be more orless continuous with no absolute threshold (4). Two setsof criteria were adapted from the original O’Sullivan andMahan values when laboratories switched to venousplasma or serum. These samples yield results approxi-mately 14% higher than does whole blood. The NationalDiabetes Data Group published conversions derived byadding 15% to each of the four thresholds (51). Lowerthresholds were subsequently derived by also correctingfor the change to enzymatic methods of glucose analysis(52). Expert panels have supported both criteria, butthere are no data from clinical trials to determine whichis superior (Table 1) (53).

A positive diagnosis requires that two or morethresholds be met or exceeded. The test is administeredin the morning after an overnight fast. Patients shouldnot smoke before the test and should remain seated dur-ing the test. Patients should be instructed to follow anunrestricted diet, consuming at least 150 g of carbohy-drate per day for at least 3 days prior to the test. Thisshould avoid carbohydrate depletion, which could causespuriously high values on the GTT.

Patients with only one abnormal value have beendemonstrated to manifest increased risk for macrosomicinfants and other morbidities (54, 55). However, becausethe relationship between carbohydrate metabolism,macrosomia, and other morbidity is a continuum (4, 56),and because not all of this morbidity arises from carbo-hydrate intolerance, it should be anticipated that nothreshold will identify all patients at risk.

How should blood glucose be monitored in awoman with GDM?

The optimal frequency of blood glucose testing inpatients with GDM has not been established. Whether

ACOG Practice Bulletin No. 30 5

daily testing is essential for women with GDM has notbeen proven. One large, prospective trial comparedseven-times-daily self-glucose monitoring using memo-ry-based reflectance meters with weekly fasting and 2-hour laboratory glucose determinations supplemented byfour-times-daily self-monitoring with only test strips andno meters (57). The more intensively monitored grouphad fewer primary cesarean deliveries and fewer macro-somic neonates, and their infants were less likely toexperience shoulder dystocia and neonatal hypo-glycemia than the more conventionally monitored group.Other centers have reported similar results with four-times-daily glucose monitoring (25, 58). Although dailyself-glucose monitoring has not been demonstrated toreduce perinatal mortality in women with GDM, itappears to be useful in reducing potentially adverse out-comes such as macrosomia. However, evidence fromwell-designed, randomized trials that compare daily self-glucose monitoring with less frequent assessment inwomen with GDM is still needed.

Further uncertainty surrounds the timing of glucosedeterminations and the selection of appropriate thresh-olds for intervention. In nonpregnant individuals, dia-betes is most often managed using preprandial glucosedeterminations. However, the fetus may be more sensi-tive to glucose excesses than to the nadirs of glucose val-ues at various times of the day. In studies of preexistingdiabetes, 1-hour postprandial glucose values were foundto be more predictive of fetal macrosomia than were fast-ing values (59), and a 1-hour value of 130 mg/dL ormore was found to be an appropriate threshold (60). Arandomized trial compared preprandial with 1-hour post-prandial glucose measurements in 66 women whoseGDM was severe enough to require insulin treatment by30 weeks of gestation (25). Macrosomia, neonatal hypo-glycemia, and cesarean deliveries for shoulder dystociawere significantly lower among those who had postpran-dial monitoring, and their glycohemoglobin levels alsodecreased more markedly than did the levels of the sub-jects who used preprandial monitoring. No studies are

Table 1. Two Diagnostic Criteria for Gestational Diabetes Mellitus

Plasma or Serum Glucose Level Plasma LevelStatus Carpenter/Coustan Conversion National Diabetes Data Group Conversion

mg/dL mmol/L mg/dL mmol/LFasting 95 5.3 105 5.8One hour 180 10.0 190 10.6Two hours 155 8.6 165 9.2Three hours 140 7.8 145 8.0Adapted from Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of DiabetesMellitus. Diab Care 2000;23(suppl 1):S4–S19

!

Figure 5: Two Diagnostic Criteria for GDM9

Source: ACOG Practice Bulletin for GDM 2001.

2012 Srinivasa 6

4. Oral Agents a. Traditionally contraindicated because of risks of crossing the placenta and teratogenic effects b. When compared to insulin, glyburide showed similar glucose control and pregnancy outcomes c. Glyburide was not detected in infants based on cord blood analyses d. No oral agent has been shown to be safe and effective; further study is recommended

B. ADA: Standards of Medical Care in Diabetes (2011, 2012)1,10

1. Does not provide recommendations for treatment. “Additional well-‐designed clinical studies are needed to determine the optimal intensity of monitoring and treatment of women with GDM diagnosed by the new criteria.”

C. Perkins et al. Perspectives in Gestational Diabetes Mellitus: A Review of Screening, Diagnosis, and Treatment (2007)5

1. Diet a. Patients should receive nutrition counseling to count carbohydrates and meal planning b. Women of normal weight: 30-‐32 kcal/kg; carbohydrates should be 40% of calories c. Overweight women: 25 kcal/kg

2. Exercise 3. Pharmacologic Therapy

a. Insulin i. Traditionally, longer acting insulin such as NPH have been used for GDM ii. More data is needed regarding newer insulin formulations iii. If fasting blood glucose > 90 mg/dL, NPH should be started at a dose of 0.2 units/kg QHS iv. If both fasting and preprandial blood glucose is still elevated, a rapid-‐acting insulin analogue

can be added on at mealtimes b. Glyburide

i. Dosing and titration schedule not specified ii. Langer et al. found that an average dose of 10 mg daily brought patients to goal

c. Metformin i. Dosing and titration schedule not specified

VI. Pharmacologic Agents11,12 A. Insulin

1. Mechanism of Action: acts on membrane-‐bound receptors of target tissues to regulate metabolism of carbohydrate, protein, and fats; lowers blood glucose by enhancing glucose transport into adipose tissue and muscle by recruitment of glucose transporters (GLUT 4) from the interior of the cell to the plasma membrane

2. Products Available: see Appendix A 3. Dosing: no specific dosing guidelines recommended 4. Adverse Effects: hypoglycemia, injection site reactions, weight gain

B. Metformin (Glucophage®, Fortamet®, Glumetza®)13

1. Mechanism of Action: decreases hepatic glucose production, decreases intestinal absorption of glucose, improves insulin sensitivity

2. Dosing: initiate at 500 mg PO BID with food; increase to 1 g PO BID after 1 week if tolerated 3. Adverse Effects: GI: diarrhea, N/V, flatulence 4. Pregnancy Category: B

2012 Srinivasa 7

C. Glyburide (DiaBeta®, Glynase®)14 1. Mechanism of Action: stimulates insulin release, increases insulin sensitivity, reduces hepatic

glucose output 2. Dosing: initiate at 2.5 mg PO daily, can increase by 2.5 mg the next week, 5 mg/week thereafter;

maximum dose: 20 mg/day 3. Adverse Effects: hypoglycemia, epigastric fullness, nausea, heartburn 4. Pregnancy Category: B/C (varies among manufacturer)

D. Other Agents

1. See Appendix B

VII. Goals and Monitoring3,5 A. Blood Glucose Goals

1. Before meals < 95 mg/dL 2. 1-‐hour postprandial < 140 mg/dL 3. 2-‐hour postprandial < 120 mg/dL

B. Monitoring5

1. Patients should be taught proper SMBG technique 2. SMBG should be performed 4 times daily (AM fasting and 2-‐hour postmeal) 3. Grams of carbohydrate consumed should be documented as well 4. Values should be brought into each prenatal visit and can be used to guide therapy adjustment

2012 Srinivasa 8

VIII. Literature Review A. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus Insulin for the Treatment of

Gestational Diabetes. N Engl J Med 2008;358:2003-‐15.15 Study Design Randomized, open-‐label trial Study Site(s) New Zealand, Australian urban obstetric hospitals Objective To rule out an increase in neonatal complications in women being treated with metformin vs. insulin Subjects 751 women with gestational diabetes mellitus at 20 to 33 weeks of gestation

Inclusion Criteria • Between 18 and 45 years of age, with a diagnosis of GDM • Met hospital’s criteria for starting insulin treatment, and after lifestyle intervention, had more than one FBG > 97.2 mg/dL or more than one 2-‐hour PPG > 120.6 mg/dL

Exclusion Criteria • Previous diagnosis of DM, contraindication to metformin, a fetal anomaly, gestational HTN, preeclampsia, fetal growth restriction, and ruptured membrane

Methods • Randomization occurred with a block size of four and was stratified according to gestational age • Goal was FBG < 99 mg/dL and PPG < 126 mg/dL • Metformin: started at 500 mg daily or BID with food and increased over 1-‐2 weeks to a max 2500 mg • If targets were not achieved, insulin was added; insulin was prescribed according to usual practice

Statistics • Two-‐tailed tests used to rule out a significant difference in the incidence of composite neonatal complications in the metformin group • Differences between treatment groups were compared using chi-‐square or Fisher’s exact test for categorical variables and two-‐sample t-‐test or Mann–Whitney test for continuous variables • Analyses were performed with SAS software • Relative risks were reported with 95% confidence intervals

Results

• Metformin group: 168 women (46.3%) required supplemental insulin • 76.6% of women in metformin group would choose it again, compared to 27.2% in insulin group (P<0.001)

Outcome Metformin (N=363) Insulin (N=370) RR (95% CI) P value Primary Outcomes Recurrent BG < 46.8 mg/dL Any BG < 28.8 mg/dL

55 (15.2%) 12 (3.3%)

69 (18.6%) 30 (8.1%)

0.81 (0.59-‐1.12) 0.41 (0.21-‐0.78)

0.21 0.008

Respiratory Distress 12 (3.3%) 16 (4.3%) 0.76 (0.37-‐1.59) 0.47 Pre-‐term Birth 44 (12.1%) 28 (7.6%) 1.60 (1.02-‐2.52) 0.04 Neonatal Outcomes P value Gestational age at birth-‐week 38.3 ± 1.4 38.5 ± 1.3 0.02 Birth weight-‐g 3372 ± 572 3413 ± 569 0.33 Maternal Outcomes Glycemic control from randomization until delivery AM Fasting 93.6 ± 10.8 91.8 ± 12.6 0.24 Postprandial 111.6 ± 10.8 115.2 ± 16.2 0.003 Hgb A1c at week 36-‐37 5.6 ± 0.5 5.7 ± 0.6 0.25 Results of 75-‐g OGTT at 6-‐8 week post partum Fasting plasma glucose (mg/dL) 91.8 ± 14.4 91.8 ± 16.2 0.34

Authors’ Conclusions

Metformin, alone or with supplemental insulin, is an effective and safe treatment option for women with GDM. “Metformin is more acceptable to women with gestational diabetes mellitus than is insulin.”

Comments Follow up data showed that at 2 years children exposed to metformin had larger measures of subcutaneous fat, but overall body fat was the same in the children of mothers who were treated with insulin. Weaknesses: -‐ Some patients received combination of metformin and insulin -‐ Study completed in Australia, not generalizable Strengths: + Posthoc inferiority analysis supports conclusion that metformin is noninferior to insulin + Followed standards of practice + Safety measures were monitored

2012 Srinivasa 9

B. Langer O, Conway DL, Berkus MD, Xenakis EM-‐, Gonzales O. A Comparison of Glyburide and Insulin in Women with Gestational Diabetes Mellitus. N Engl J Med 2000;343:1134-‐8.14

Study Design Randomized, open-‐label trial Study Site(s) Maternal health clinics in San Antonio, Texas Objective To establish information on the efficacy of glyburide when used as treatment for gestational diabetes Subjects • 404 women with a diagnosis of gestational diabetes

• Women carrying 1 child with FPG on day of OGTT ≥ 95 mg/dl and < 140 mg/dl at 11-‐33 weeks gestation • If FPG < 95 mg/dl, they were initially treated with diet, but if later they had FPG ≥ 95 mg/dl or their PPG ≥ 120 mg/dl, they were enrolled in the study

Methods • Women randomly assigned to receive glyburide or insulin from a computer-‐generated list • Detailed social, medical history was obtained at first visit • Women were provided with recommendations for 3 meals and 4 snacks daily (25 kcal/kg for obese women and 35 kcal/kg for non-‐obese women. 40-‐45% of calories came from carbohydrates)

• Adherence to diet was assessed at weekly visits • Insulin: started at 0.7 units/kg TID. If necessary, dose was adjusted weekly • Glyburide: started at 2.5 mg QAM. If necessary, dose was increased 2.5 mg the following week, and then by 5 mg weekly. Max dose was 20 mg daily.

• Patients were educated on glucose meter use and instructed to test 7 times daily. This began 1 week before initiation of therapy. Hgb A1c and serum C peptide were also measured at this time. Hgb A1c was repeated in 3rd trimester.

Statistics • Intention to treat analysis • Chi-‐squared tests used to compare data between the treatment groups • Student’s t-‐tests were used to compare numerical data

Results Outcome Glyburide Group (N=201) Insulin Group (N=203) P Value FBG (mg/dL) 98 ± 13 96 ± 16 0.17 Postprandial 113 ± 22 112 ± 15 0.60 Hgb A1c 5.5 ± 0.7 5.4 ± 0.6 0.12 Neonatal Outcomes Large size for gestational age

24 (12%) 26 (13%) 0.76

Birth weight – g 3256 ± 543 3194 ± 598 0.28 Macrosomia 14 (7%) 9 (4%) 0.26 Admission to neonatal ICU

12 (6%) 14 (7%) 0.68

• Glyburide group: 8 women (4%) failed to maintain glycemic control and had to be switched to insulin • BG< 40: glyburide group: 4 women, Insulin group: 41 women P=0.03


In women with gestational diabetes, glycemic control and perinatal outcomes were essentially the same for glyburide and insulin treatment groups.

Comments Weaknesses: -‐ Used 50-‐g OGTT for diagnosis; different screening/diagnosis than current practice Strengths: + One of the first studies to look at glyburide vs. insulin + Patients were provided with nutrition counseling and assessed for adherence with diet + Relatively large population studied

2012 Srinivasa 10

C. Moore LE, Clokey D, Rappaport VJ, Curet LB. Metformin compared with glyburide in gestational diabetes: a randomized controlled trial. Obstet Gynecol 2010;115:55-‐9.16 Study Design

Randomized controlled trial

Study Site(s) University of New Mexico, Albuquerque, New Mexico Objective To compare the efficacy of glyburide and metformin for glycemic control in gestational diabetes Subjects 149 pregnant women receiving prenatal care from the UNM Pregnancy Diabetic group

Inclusion Criteria • Women were screened with 50-‐g glucose load; those with 1-‐hour glucose level ≥ 130 mg/dL were given a 3-‐hour 100-‐g glucose load. GDM was diagnosed if 2 or more abnormal values were found. Those diagnosed were provided diet and exercise education.

• Women who failed to maintain FBG < 105 mg/dL or 2-‐hour PPG < 120 mg/dL were offered participation in the study

Exclusion Criteria • History of renal or hepatic disease, chronic HTN needing medication, substance misuse

Methods • Women were randomized between 11 and 33 weeks and received either glyburide or metformin based on a computer-‐generated random list

• Women advised to eat a diet providing 30 kcal/kg for normal body weight and 25 kcal/kg for obese women. 40% of calories from carbohydrates, 20% from protein, and 30-‐40% from fats

• Exercise was encouraged, and walking 30 minutes per day was recommended • Patients instructed on use of glucometer and told to check AM fasting and 2 hours after each meal • Glyburide: started at 2.5 mg BID, increased as necessary to a max dose of 10 mg BID • Metformin: started at 500 mg daily; increased as necessary to a max dose of 2 grams in divided doses • Oral medications were discontinued if insulin was initiated

Statistics • Powered to have 80% probability of detecting 10 mg/dL difference in blood glucose between the treatment groups with a standard deviation of 20 mg/dL and α of 0.05.

• Fisher exact test used for categorical data, Student t-‐test used for numerical data • Intent to treat analysis was used

Results Outcome Glyburide Group (N=74) Metformin Group (N=75) P Value FBG (mg/dL) 90.9 ± 13 (88.5) 94.3 ± 15 (88.5) 0.23 2-‐hour breakfast 104 ± 17 (104.8) 99 ± 20 (97.7) 0.15 2-‐hour lunch 112 ± 22 (108.6) 107 ± 16 (105.8) 0.28 2-‐hour dinner 119 ± 19 (117) 123 ± 17 (115) 0.32 Neonatal Outcomes Est. Gestational Age 38 ± 1 38 ± 2 0.49 Birth weight – g 3329.6 ± 334 3103 ± 600 0.02 NICU Admission 1 4 0.37 Cesarean Delivery 2 11 0.02 • Failure to meet glycemic goals, requiring insulin: Glyburide group: 12 (16.2%), Metformin group: 26 patients (34.7%) P=0.01


Metformin had a failure rate of achieving glycemic control 2.1 times higher than glyburide.

Comments Results do not completely coincide with results from previous studies. This may be due to difference in patient population, i.e., ethnicity, BMI. Weaknesses: -‐ Study had a very small sample size and was underpowered -‐ Screening/diagnosis did not follow IADPSG recommendations Strengths: + 1 of 2 trials to compare glyburide to metformin + Studied high risk population

2012 Srinivasa 11

IX. Other Considerations for Selecting Treatment A. Provider Preference 1. Comfort level/experience with insulin versus oral agents 2. Insulin use requires extensive training

B. Patient Preference 1. Fears associated with insulin use and injection 2. Side effect profile

C. Accessibility 1. Glyburide and metformin are available at a low cost 2. Oral medications do not require purchase of additional supplies, e.g., syringes

X. Follow-‐up1 A. History of GDM increases risk of developing DM later in life 1. Screen 6 weeks postpartum 2. Women should be screened for diabetes at least every 3 years thereafter

XI. Summary/Conclusions (See Appendix C for Proposed Algorithm for Treating GDM) A. Screening/Diagnosis 1. Patients should be screened for GDM based on risk factors 2. Screen for GDM and undiagnosed DM at first prenatal visit 3. At 24-‐28 weeks gestation, 75-‐g OGTT should be performed to diagnose GDM

B. Treatment 1. Avoid complications that can affect both mother and baby by using aggressive therapy 2. Patient should be given a trial of lifestyle modifications (diet/exercise) for 2 weeks and instructed to

SMBG at home 3. If patient does not meet blood glucose targets, pharmacotherapy should be started 4. More evidence supports insulin as first line, but glyburide has been used widely and can also be

considered first line 5. Metformin should be considered after insulin and glyburide

C. Monitoring and Follow-‐up 1. Patient should continue to SMBG and follow up with provider frequently, so that adjustments to

therapy can be made as necessary 2. After delivery, patient should be screened for diabetes at 6 weeks and then every 3 years thereafter

D. Future Considerations 1. Well-‐designed studies are needed to evaluate safety and efficacy of oral antidiabetic drugs, optimal

insulin regimens, and to establish current treatment guidelines

2012 Srinivasa 12

Appendix A: Available Insulin Products11,12,17,18

Type of Insulin Onset (Hours) Peak (Hours) Duration (Hours) Pregnancy Category

Rapid-‐Acting Aspart (Novolog®) 15-‐30 min 1-‐2 3-‐5 B

Glulisine (Apidra®) 15-‐30 min 1-‐2 3-‐4 C

Lispro (Humalog®) 15-‐30 min 1-‐2 3-‐4 B

Short-‐Acting Regular (Humulin®, Novolin®)

0.5-‐1.0 2-‐3 4-‐6 B

Intermediate-‐Acting NPH (Humulin N®, Novolin N®)

2-‐4 4-‐8 8-‐12 B

Long-‐Acting Detemir (Levemir®) 2 -‐-‐-‐ 14-‐24 C

Glargine (Lantus®) 4-‐5 -‐-‐-‐ 22-‐24 C

2012 Srinivasa 13

Appendix B: Noninsulin Antidiabetic Agents and Pregnancy Category11,12,18

Drug Pregnancy Category

Biguanides Metformin (Glucophage®, Fortamet®, Glumetza®) B

Sulfonylureas

Glimepiride (Amaryl®) C

Glipizide (Glucotrol®) C

Glyburide (DiaBeta®, Glynase®) B/C (varies among manufacturer)

Thiazolidinediones

Pioglitazone (Actos®) C

DPP-‐4 Inhibitors

Sitagliptin (Januvia®) B

Saxagliptin (Onglyza®) B

Linagliptin (Tradjenta®) B

α-‐Glucosidase Inhibitors

Acarbose (Precose®) B

Miglitol (Glyset®) B

Short-‐acting insulin secretagogues

Nateglinide (Starlix®) C

Repaglinide (Prandin®) C

GLP-‐1 Agonists

Exenatide (Byetta®) C

Liraglutide (Victoza®) C

Amylinomimetic

Pramlintide (Symlin®) C

2012 Srinivasa 14

Appendix C: Proposed Algorithm for Management of GDM19

*Risk Factors for GDM Low Risk �< 25 yo

�No prior hx poor obstetric outcomes �Low-‐risk ethnic group �Normal weight before or throughout pregnancy �No hx glucose intolerance

Medium Risk

�Neither low or high risk

High Risk �Obese �DM in 1º relative �Current glycosuria �Hx GDM/glucose intolerance �Prior delivery of macrosomic infant

†Use IADPSG thresholds to diagnose GDM

FBG ≥ 92 mg/dL, 1 hour mm≥ 180 mg/dL, OR 2 hour ≥ 153 mg/dL

Low or Medium Risk Patient*

High Risk Patient*

Screen at 24-‐28 weeks with 75-‐g OGTT

GDM (+)†

GDM (-‐)†

Screen at first prenatal visit

GDM (+)†

GDM (-‐)†

Non-‐pharmacologic

therapy (2-‐week trial)

Does not meet glycemic goals

Meets glycemic goals

FBG < 95, 1-‐HR PP <140 2-‐HR PP <120

Initiate pharmacologic

therapy

Insulin

(Category B Products)

Oral: glyburide OR metformin

Continue to monitor

Follow up with glucose testing postpartum

Adapted from: http://www.uspharmacist.com/CMSImagesContent/2009/9/GestationalFig1.gif

2012 Srinivasa 15

Appendix D: Abbreviations Abbreviation Definition ACOG American Congress of Obstetricians and Gynecologists ADA American Diabetes Association FPG Fasting plasma glucose HAPO Hyperglycemia Adverse Pregnancy Outcomes HCS Human chorionic somatomammotropin IADPSG International Association of Diabetes in Pregnancy Study Group OGTT Oral glucose tolerance test PPG Postprandial glucose PRAMS Pregnancy Risk Assessment Monitoring System SMBG Self-‐monitoring of blood glucose Acknowledgments

• Christy Blanco, WHNP, DNP • Debra Lopez, PharmD, CDE, BCACP • Jeri Sias, PharmD, MPH • Margie Padilla, PharmD, CDE • Tricia Tabor, PharmD, BCPS

2012 Srinivasa 16

References

1. American Diabetes Association. Standards of Medical Care in Diabetes—2012. Diabetes Care 2012;35:S11-‐63.

2. 2011 National Diabetes Fact Sheet." CDC.Web. National Center for Chronic Disease Prevention and Health Promotion, Division of Diabetes Translation. <http://www.cdc.gov/diabetes/pubs/estimates11.htm#8>.

3. Landon MB, Gabbe SG. Gestational diabetes mellitus. Obstet Gynecol 2011;118:1379-‐93. 4. "Prevalence and Outcomes of Pre-‐existing and Gestational Diabetes, 2004-‐2009 Texas Pregnancy Risk

Assessment Monitoring System (PRAMS)." Texas Diabetes (2011): 2-‐3. Texas Department of State Health Services. Web. 11 Jan. 2012. <http://www.dshs.state.tx.us/diabetes/PDF/newsletter/spring11.pdf>.

5. Perkins JM, Dunn JP, Jagasia SM. Perspectives in Gestational Diabetes Mellitus: A Review of Screening, Diagnosis, and Treatment. Clinical Diabetes 2007;25:57-‐62.

6. "Pathophysiology of Diabetes In Pregnancy (Gestational Diabetes)." Diabetes Mellitus Treatments. Web. 12 Jan. 2012. <http://diabetesmellitustreatments.com/pathophysiology-‐of-‐diabetes-‐in-‐pregnancy-‐gestational-‐diabetes/>.

7. Hyperglycemia and adverse pregnancy outcomes. (2008). N Engl J Med, 358(19), 1991-‐2002. 8. International Association of Diabetes and Pregnancy Study Groups Consensus Panel. International

Association of Diabetes and Pregnancy Study Groups Recommendations on the Diagnosis and Classification of Hyperglycemia in Pregnancy. Diabetes Care 2010;33:676-‐82.

9. American College of Obstetricians and Gynecologists. Gestational Diabetes. ACOG Practice Bulletin 30. Washington, DC: ACOG; 2001.

10. American Diabetes Association. Standards of Medical Care in Diabetes—2011. Diabetes Care 2011;34:S11-‐61.

11. Lexi-‐Comp OnlineTM, Hudson, Ohio: Lexi-‐Comp, Inc.; December 29, 2011. 12. Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Reuters

(Healthcare) Inc. Updated periodically. 13. Gandhi P, Bustani R, Madhuvrata P, Farrell T. Introduction of metformin for gestational diabetes mellitus

in clinical practice: has it had an impact? Eur J Obstet Gynecol 2011; 1-‐4. 14. Langer O, Conway DL, Berkus MD, Xenakis EM-‐, Gonzales O. A Comparison of Glyburide and Insulin in

Women with Gestational Diabetes Mellitus. N Engl J Med 2000;343:1134-‐8. 15. Rowan JA, Hague WM, Gao W, Battin MR, Moore MP. Metformin versus Insulin for the Treatment of

Gestational Diabetes. N Engl J Med 2008;358:2003-‐15. 16. Moore LE, Clokey D, Rappaport VJ, Curet LB. Metformin compared with glyburide in gestational diabetes:

a randomized controlled trial. Obstet Gynecol 2010;115:55-‐9. 17. Triplitt CL, Reasner CA. Diabetes Mellitus. In DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey

LM, editors, Pharmacotherapy: A Pathophysiologic Approach. 8th ed. (2011). Retrieved December 29, 2011 from http://www.accesspharmacy.com/content.aspx?aID=7990956.

18. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2011. URL: http://cp.gsm.com. Updated October 2011.

19. Jacobs, TF. "Management of Gestational Diabetes." USPharmacist.com Home. Web. 29 Dec. 2011. <http://www.uspharmacist.com/content/s/165/c/28129/>.

20. Beucher G, Viaris dL, Dreyfus M. [Maternal outcome of gestational diabetes mellitus]. J Gynecol Obstet Biol Reprod (Paris) 2010;39:S171-‐88.

21. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS. Effect of Treatment of Gestational Diabetes Mellitus on Pregnancy Outcomes. N Engl J Med 2005;352:2477-‐86.

22. American Diabetes Association. Gestational Diabetes Mellitus. Diabetes Care 2004;27:s88-‐90. 23. Kimmel B, Inzucchi SE. Oral Agents for Type 2 Diabetes: An Update. Clinical Diabetes 2005;23:64-‐76. 24. Lee-‐Parritz A. Contemporary management of gestational diabetes. Curr Opin Endocrinol Diabetes Obes

2011;18:395-‐400. 25. Moore TR. Glyburide for the Treatment of Gestational Diabetes. Diabetes Care July 2007;30:S209-‐13.

srinivasa02-03-12(1)

Documents

Transcript of srinivasa02-03-12(1)