Volume 8, Issue 2 Gestational Diabetes

Summer 2013 How do we recognize and treat it? Compiled by Danielle Clare Pharm.D. Candidate 2014

Diabetes continues to be a health concern 1 hour value of 180 mg/dL; for Native American communities in the 2 hour value of 152 mg/dL. United States. According to the Center for Patients diagnosed with GDM should Disease Control (CDC) , American Indian receive education regarding appropriate and Alaska Native (AI/AN) adults are 2.6 glucose levels and A1C% goals should be times more likely to have diabetes com- established with the patient. The Fifth pared to whites of the same age. Most International Workshop Conference on cases of diabetes in the AI/AN population Gestational Diabetes recommends glucose are Mellitus (T2DM) , targets of preprandial: < 95 mg/dL; 1-h post- which is associated with risk factors that can meal: < 140 mg/dL; and 2-h postmeal: < 120 be modified, such as obesity and physical mg/dL. inactivity. However, diabetes may present with pregnancy and pose health threats to Targeting blood glucose to stated goals has the mother and child. Diabetes that been investigated with data to support re- develops with a glucose intolerance begin- duced risks with better control. According to ning in pregnancy is considered Gestational the Hyperglycemia and Adverse Pregnancy

Diabetes Mellitus (GDM). GDM is similar to Outcome (HAPO) Study, the risk of adverse

other forms of diabetes and is characterized outcomes increased as a function of mater- by pancreatic beta-cell function that cannot nal glycemic control at 24-28 weeks for the meet the needs of the body. mother, fetus and neonate. The HAPO

According the American Diabetes study, a large scale, multinational epidemi- Association (ADA), it is estimated that GDM ologic study that included approximately affects 18% of pregnancies. 25,000 women demonstrated risk with glucose ranges that were previously Appropriate prenatal care is necessary to considered normal for pregnancy. identify GDM and develop an action plan to Additionally, there was no threshold for risk. adequately control glycemia and minimize Increased risk of adverse outcomes include E S T E A M risk of adverse effects of uncontrolled GDM. neonatal hypoglycemia, hyperbilirubinemia, According to the ADA 2013 guidelines, macrosomia, increased risk of obesity or screening for undiagnosed T2DM should be diabetes for children later in life, and completed at the first prenatal visit in those increased risk for other maternal co- patients with risk factors. However, screen- morbidities. Women with GDM who have ing and diagnosing of GDM should be per- uncontrolled blood sugars have an formed at 24-28 weeks of gestation in increased risk of preeclampsia, preterm women not previously diagnosed with overt delivery and cesarean section. diabetes. The standard to perform the GDM test is to use a 75-g OGTT with a plasma It is well noted that uncontrolled diabetes glucose measurement fasting, at 1-hour, can cause harm to the unborn child. The and at 2-hours. The OGTT should be leading cause of morbidity and mortality in performed in the morning, after an overnight infants born to mothers with Type I or T2DM fast of at least 8 hours. A diagnosis is made is major congenital malformation. Therefore, when any of the following plasma glucose education and interventions are necessary values are exceeded: to improve outcomes in patients with GDM Fasting plasma glucose of 92mg/dL; and their children.

(continued on page 2) ALASKA NATIVE DIABET Objectives: Inside this issue:  Identify appropriate treatment options in Women with Gestational Diabetes 1-3 pregnant women diagnosed with gesta- How do we recognize and treat it? tional diabetes (GDM)  Recognize treatment goals for patients with GDM  Identify how canaglifozin (Invokana®) New Drug Approved: ca- 3-4 works to improve glycemic control in nagliflozin (Invokana®)

diabetes Diabetes Diabetes Dispatch Gestational Diabetes How do we recognize and treat it?

The majority of women with GDM can be managed with lifestyle interventions alone. Primary literature studies stated 80- 90% of the population achieved control with no pharmacotherapy. Appropriate lifestyle interventions include engaging in >150 min/week of moderate-intensity aerobic physical activity, spread over 3 days per week with no more than 2 consecu- tive days without exercise. The American College of Obstetricians and Gynecology (ACOG) advocates exercise in women who have exercised before conception, but not in those who previously had not exercised. Exercise has been shown to improve glycemic control. Diet modification is another appropriate lifestyle intervention that can help to control blood sugar in a patient with GDM, in addition to exercise. A registered dietitian should provide the best recommendation for dietary needs. Pharmacotherapy for the management of GDM when diet and lifestyle interventions cannot achieve glycemic control, may be warranted. Consideration of risk-to-benefit for each patient should be discussed for pharmacotherapy choices available. Published guidelines and primary literature have investigated several agents including insulin, , , and glyburide. Metformin and acarbose are classified as Category B (no evidence of risk in humans). All other oral anti-diabetic agents are Pregnancy Category C. Insulin is the recommended therapy for GDM by ADA and ACOG. Human insulin (NPH and ) is the least immunogenic of all insulin preparations on the market. Lispro and aspart have been effica- cious in clinical trials with minimal placental transfer and no teratogenic effect. Pregnancy Category B include: NPH, regular, aspart, lispro, and detemir. Glulisine and glargine insulin are considered Pregnancy Category C. Metformin is traditionally used as a first-line agent in T2DM. However, with pregnancy, there is risk of drug transfer to the fetus which may have unintended adverse effects. According to Briggs’ Pregnancy and Lactation, metformin has human data which suggests low risk with use. However, the recommendation is that insulin is still the treatment of choice, as it does not cross the placenta. In addition, “carefully prescribed insulin therapy will provide better control, thereby preventing the fetal and neonatal complications that occur with this disease.” According to the Fifth International Workshop Conference on Gestational Diabetes, there is insufficient evidence to recommend metformin for treatment of GDM, except in clinical trials. Other oral agents for glycemic control have been investigated, including glyburide and acarbose. Glyburide, has some evidence for adjunctive therapy to lifestyle interventions. It is the only that has minimal transfer across the placenta. A meta-analysis comparing three randomized controlled trials of insulin and glyburide therapy found no statistically significant differences in maternal outcomes, glycemic control, cesarean section, neonatal outcomes, neonatal hypoglyce- mia or infant birth weight. Cheng et al. found that neonates born to women managed on glyburide for GDM were more likely to be macrosomic and admitted to ICU compared to those treated with insulin. The use of glyburide needs further investiga- tion for effect on the fetus’ glycemia and a report of unexplained still-birth. Acarbose, an alpha-glucosidase inhibitor, has poor absorption from the gastrointestinal tract. Since absorption is poor, there is thought that placental transfer to fetus may be low. There is some preliminary data suggesting efficacy in reduction of postprandial glucose levels in GDM. However, gastrointestinal upset is a common complaint with this medication and may not be well tolerated. Safety and placental drug transfer needs further evaluation with acarbose in the setting of GDM. In the pregnant woman, additional co-morbidities that need attention during pregnancy should also be addressed with clinic visits. Hypertension may present as a new or underlying comorbidity with pregnancy. Patients with diagnosed hypertension should target blood pressure to systolic goal of 110-129 mm Hg and diastolic goal of 65-79 mm Hg. Lower blood pressure levels may be associated with impaired fetal growth. Many of the standard drug classes used to treat hypertension in other populations, are not appropriate for use in the pregnant female. Angiotensin Converting Enzyme (ACE)-inhibitors and Angiotensin Receptor Blockers (ARBs) are contraindicated during pregnancy due to fetal damage. Chronic diuretic use has been associated with restricted plasma volume which may reduce uteroplacetal perfusion. There are some antihypertensive drugs known to be safe and effective in pregnancy. Drugs that have been studied in pregnancy include methyldopa, labeta- lol, diltiazem, clonidine, and prazosin. Risk versus benefit should be considered for all agents and should include the possi- bility of drug transfer across the placenta. The risks of GDM carry beyond the pregnancy. A history of GDM leaves the patient at increased risk of development of dia- betes after the pregnancy has come to term. Monitoring and screening for pre-diabetes or diabetes should be evaluated and reinforcement of lifestyle interventions are appropriate. The Nurse’s Health Study II established that in women with GDM, the risk of diabetes was significantly lower for women who followed healthy eating patterns. These statistics enforce the importance of continued responsibility to provide care to women with history of GDM. ADA suggests screening women with GDM for persistent diabetes at 6-12 weeks postpartum, using OGTT and non-pregnancy diagnostic criteria. Since pre-partum treatment for hyperglycemia may affect A1C%, the use of A1C% for diagnosis of persistent diabetes at the postpartum visit is not recommend. Women with a history of GDM should continue to have lifelong screening of diabetes or pre-diabetes at least every 3 years. An ADA class A recommendation for women with a history of GDM, who have pre-diabetes, should receive lifestyle interventions or metformin to prevent the progression to diabetes. According the CDC, half of all women who have a history of GDM will develop T2DM.

Page 2 DIABETES DISPATCH

Gestational Diabetes How do we recognize and treat it?

To help patients prevent or delay the progression to T2DM later in life encourage:  Reaching pre-pregnancy weight 6 to 12 months after the baby is born  If pre-pregnancy weight has not been achieved, recommend a 5-7% body weight loss goal  Physical activity at least 30 minutes most days of the week  Healthy eating plan including grains, fruits, and vegetables  Breastfeeding. Studies show mother who breastfeed have a lower chance of getting T2DM later in life  Continue follow up with doctor for monitoring of blood sugars every 3 years Informing patients about risks involved with GDM and the possibly of progression towards T2DM should be discussed and patient focused. The appropriate care starts with education and non-pharmacological interventions to improve outcomes and glycemic control.

References: 1. Center for Disease Control. Trends in Diabetes Prevalence Among American Indian and Alaska Native Children, Adolescents, and Young Adults—1990-1999 2. American Diabetes Association. Standards of Medical Care in Diabetes . 2013. 3. Metzger, et al. Summary and Recommendations of the Fifth International Workshop-Conference on Gestational Diabetes Mellitus. Diabetes Care. 2007. 30:S251-S260. 4. Tempe, A., Mayanglambam, R. Glyburide as treatment option for gestational diabetes mellitus. The Journal of Obstetrics and Gynaecology Research. 2013. 39(6): 1147-1152 5. Serlin,, DC. , Lash, RW. Diagnosis and Management of Gestational Diabetes . American Family Physician. 2009. 80 (1): 57-62. 6. Briggs, G., Freeman, R., Yaffe, S. Drugs in Pregnancy and Lactation., 9th edition 2011. Lippincott Williams and Wilkins. 7. Cheng, et al. Treatment of gestational diabetes mellitus: glyburide compared to subcutaneous insulin therapy and associated perinatal outcomes. J Matern Fetal Neonatal Med 2012. 25: 379-384. New Drug Approved: (Invokana®) Will Coleman, Pharm.D. Candidate 2013

The FDA announced canagliflozin’s (Invokana®) approval on March 29, 2013 as the first diabetes treatment approved in a new class of medications, sodium-glucose co-transporter2 (SGLT2) inhibitors. SGLTs are classified as secondary active co-transporters that rely on the established sodium gradient that is maintained by Na/K-ATPase located on the basolateral membrane of cells (Raskin, 2013). While SGLT1 is expressed in the small intestines, skeletal muscles, heart, and mini- mally in the kidneys (mainly in the distal portion of proximal convoluted tubule), SGLT2 is expressed almost exclusively in the early portion of the proximal tubules of the kidneys (See Figures 1 and 2). SGLT2 is responsible for the reabsorption of approximately 90% of the glucose that passes through the glomerulus (Panchapakesan et al. 2013). After entering the proximal tubule cell, the glucose exits across the basolateral membrane via diffusion that is facilitated by the glucose trans- porter (GLUT) family.

According to Stenlöf et al. (2013), “Renal glucose resorptive capacity is increased in Type 2 Diabetes Mellitus (T2DM), con- tributing to the worsening of hyperglycemia” (p 373). Serving as a novel anti-diabetic agent, canagliflozin inhibits SGLT2 and subsequently prevents renal glucose reabsorption and promotes glucose in the urine. Thus, canagliflozin acts through an insulin-independent process and is proposed as an adjunct therapy to diet and exercise to improve glyce- mic control in adults with T2DM. This medication may not only reduce blood glucose levels and A1C%; it is also associ- ated with the reversal of beta-cell dysfunction and insulin resistance (Kurosakii2013). (continued on page 4)

VOLUME 8, ISSUE 2 Page 3 New Drug Approved: Canagliflozin (Invokana) Will Coleman, Pharm.D. Candidate 2013

Figure 2 Canagliflozin can be administered once daily (100mg: half live =10.6 hours; 300mg: half live =13.1 hours) and its onset of action occurs within 24 hours of administration. It is best to administer prior to the first meal of the day to help reduce postprandial hyperglycemia. This medication comes in both 100mg (starting dose) and 300mg (maximum dose) tablet forms. However, even at increasing medication doses, the amount of glu- cose excreted in the urine reaches a plateau at 30 to 40% of the 180g per day filtered in healthy indi- viduals (Kurosaki & Ogasawara 2013). Canagliflozin warrants careful consideration in regards to renal function. In fact, this medication is associated with increases in serum creatinine and blood urea nitrogen (Raskin, 2013). Use is not recommended in patients with an eGFR of 30 to 45mL/min. For patients with an eGFR of 45 to 60mL/min, the max dose is 100mg once daily. Otherwise, for patients with an eGFR greater than 60mL/min, no dosage adjustments are necessary. During clinical trials for canagliflozin’s approval, the most common side effects were vaginal yeast infections and urinary tract infections. Canagliflozin has a diuretic effect resulting from concentrating glucose in the urine, which can reduce intravascular volume and subsequently cause orthostatic or postural hypotension. Canagliflozin has a low potential for hypoglycemia and, contrary to many other anti-diabetic agents, can potentially contribute to weight loss as a result of the caloric loss through urinary glucose excretion (Raskin, 2013). Other beneficial effects of this medication include reduced blood pressure from its diuretic-like activity as well as protecting the proximal tubular cells from glycotoxicity (Panchapakesan et al. 2013). In addition, canagliflozin is associated with increases in HDL-C as well as dose-related increases in LDL-C, but the mechanism for these effects is not well understood (Stenlöf et al., 2013). The FDA is requiring the manufacturer, Janssen, to pursue five post-marketing studies for canagliflozin including: a cardiovascular outcomes trial, an enhanced pharmacovigilence monitoring program, a bone safety study, and two pediatric studies. Thus, as with any newly approved medication, canagliflozin’s long-term safety profile is largely unknown until further studies can be conducted.

References Chao, E. (2011). A paradigm shift in diabetes therapy- and other SGLT2 inhibitors. Discovery Medicine, 88. http://www.discoverymedicine.com/Edward-C-Chao/2011/03/23/a-paradigm- shift-in -diabetes-therapy-dapagliflozin-and-other-sglt2-inhibitors/. Idris I. & Donnelly R. (2009). Sodium-glucose co-transporter-2 inhibitors: an emerging new class of oral antidiabetic drug. Diab Obes & Metab (2009), 11: 79-88. Kurosaki, E. & Ogasawara, H. (2013). Ipragliflozin and other sodium-glucose cotransporter-2 (SGLT2) inhibitors in the treatment of type 2 diabetes: Preclinical and clinical data, Pharmacology and Therapeutics, http://dx.doi.org/10.1016/j.pharmthera.2013.04.003 Panchapakesan, U., Pegg, K., Gross, S., Komala, M., Mudaliar, H., Forbes, J., Polluck, C., and Mather, A. (2013). Effects of SGLT2 inhibition in human kidney proximal tubular cells- Renoprotection in diabetic nephropathy? PLoS ONE, 8 (2): e54442. doi:10.1371/journal.pone.0054442 Raskin, P. (2013). Sodium-glucose cotransporter inhibition: therapeutic potential for the treatment of type II diabetes mellitus. Diabetes Metab Res Rev., doi: 10.1002/dmrr.2403 Stenlöf, K., Cefalu, W., Kim, K., Alba, M., Usiskin, K., Tong, C., Canovatchel, W., and Meininger, G. (2013). Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes, Obesity, and Metabolism, 15; 372-382.

Goal-The goal of the Diabetes Dispatch is to Judy B. Thompson, Pharm.D., BCPS, CDE, BC-ADM increase the reader’s knowledge of diabetes Alaska Native Diabetes Dispatch Reviewers treatments and technologies and to provide the Angela Manderfeld, RD, CDE most current information on new drugs, therapies, Ann Marie Mayer, NP, MPH and devices.

4315 Diplomacy Drive  UAN# 0139-9999-13-014-H01-P/T Anchorage, AK 99508  Release date: August 15, 2013 Phone: 907-729-2164  Expiration Date : August 15, 2016 Fax: 907-729-2119  ANMC HED Activity # 11-30010 Email: [email protected] The speakers/authors disclose that they do not have sig- Diabetes Office Phone: 907-729-1125 nificant financial interests in any product or class of prod- We are on the Web: ucts discussed directly or indirectly in this activity, includ- www.anthc.org/anmc/services/diabetes/ ing research support.

Page 4 DIABETES DISPATCH Continuing Education Quiz Diabetes Dispatch: Summer 2013

1. When should screening for gestational diabetes be performed? 6. What is the mechanism of action for canagliflozin? a. At the first prenatal visit in those patients with risk factors a. It is a sodium-glucose co-transporter II inhibitor, there- b. At the first prenatal visit in all patients fore it prevents renal glucose reabsorption and in- c. At 24-28 weeks of gestation in women not previously creases glucose excretion. diagnosed with diabetes b. It is a sodium-glucose co-transporter II inhibitor, there- d. Both A and C fore decreasing hepatic glucose production. e. All of the above c. It is a DPP-IV inhibitor, therefore it increases postpran- dial active incretin which results in an increase in insulin secretion and a decrease in glucagon secretion. 2. How long must one fast before obtaining a ‘fasting’ blood glu- d. It activates the nuclear transcription factor PPAR- cose level? gamma a. 4 hours b. 6 hours 7. Where is SGLT2 MOST exclusively expressed? c. 8 hours d. 10 hours a. Skeletal muscle b. Small intestine 3. What is the recommended preprandial blood glucose goal in c. Early portion of the proximal tubules of the kidney women with gestational diabetes? d. Distal portion of the proximal convoluted tubule a. < 85 mg/dL b. < 95 mg/dL 8. What percentage of absorbed glucose is SGLT2 responsible c. < 110 mg/dL for? d. < 125 mg/dL a. 75% b. 80% 4. GDM patients are at an increased risk for developing diabetes c. 85% post-term. What preventative measures should be taken? d. 90% a. Continue insulin therapy post-term

b. Reinforcement of lifestyle medications 9. Which of the following is a common adverse drug effect of c. Switch patient from insulin to metformin canagliflozin (Invokana)? d. Both B and C a. Vaginal yeast infections b. Urinary tract infections 5. True or False: Hypertension in those with GDM should be treated with an ACE inhibitor or an ARB. c. Increase in serum creatinine d. Increase in blood urea nitrogen a. True e. All the above b. False

10. True or False: Canagliflozin can cause weight loss. a. True b. False

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