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Anti-Diabetic Agents

Click here for Diagnosis of Hyperglycemia in Pregnancy

The target capillary blood glucose levels recommended by the California Sweet Success Program  [13,19,20] during pregnancy are:

Time Glucose Value
Fasting 60 - 89 mg/dl
1 hour after meals 100 -129 mg/dl

Key components in the management of diabetes are diet and exercise. Click here for diabetic exchange list. If diet and exercise therapy fail to maintain blood glucose levels in the recommended ranges insulin therapy is generally recommended [1]. However, treatment with glyburide appears to be gaining approval as an acceptable  alternative to insulin therapy in some women [16].

Patients with diabetes prior to pregnancy, a history of diabetic ketoacidosis, liver disease, or a fasting blood sugar greater than or equal to 140 mg/dL at diagnosis are treated appropriately with insulin [1-4].

The commonly used types of insulin are regular insulin and NPH. Regular insulin  has a duration of action of 5 to 8 hours. Neutral Protamine Hagedorn , NPH, is named after one of its developers the physician Hans Christian Hagedorn who discovered that combining a suspension of crystalline zinc insulin with protamine could prolong the duration of action of the insulin.

Insulin aspart , insulin lispro, insulin detemir, and insulin glargine are human insulin that have had their chemical composition slightly altered to influence their onset and duration of action. The American Diabetes Association (ADA) recommends that patients with preexisting diabetes who are taking detemir or glargine should be transitioned to NPH insulin twice or three times daily until clinical trials have proven the efficacy and safety of these analogs [32].  For patients who insist on continuing detemir or glargine throughout pregnancy (or are unable to use NPH insulin due to protamine allergy [35,36])   clinicians will have to rely on their knowledge of the pharmacology of the treatments, sporadic case reports, and their own judgment regarding the risks and benefits of continuing to use these analogs in a particular patient [21].

The American Association of Clinical Endocrinologists, (AACE) Diabetes Mellitus Clinical Practice Guidelines Task Force has recommended that continuous subcutaneous insulin infusion (CSII) (insulin pump) therapy is indicated for patients with type 1 diabetes mellitus who are pregnant [22]. However, a systematic review did not show any advantage or disadvantage of using continuous subcutaneous insulin infusion (CSII) over multiple-dose insulin (MDI) in pregnant diabetic women [23] . The authors of the review suggested CSII should perhaps be reserved for special circumstances such as  instances in which normoglycemia is not achieved by conventional means.

The AACE Diabetes Mellitus Clinical Practice Guidelines Task Force suggested  CSII therapy is also indicated for:

  • Patients who are unable to achieve acceptable control using a regimen of multiple daily injections
  • Patients with histories of frequent hypoglycemia and/or hypoglycemia unawareness
  • Patients with extreme insulin sensitivity (pump therapy facilitates better precision than subcutaneous injections)
  • Patients with a history of dawn phenomenon (these patients can program a higher basal rate for the early morning hours to counteract the rise in blood glucose concentration)
  • Patients who require more intensive diabetes management because of complications including neuropathy, nephropathy, and retinopathy
  • Patients taking multiple daily injections who have demonstrated willingness and ability to comply with prescribed diabetes self-care behavior including frequent glucose monitoring, carbohydrate counting, and insulin adjustment

Glyburide appears to be an effective alternative to insulin in the treatment of gestational diabetes for some women. Women with a 1 hour OGTT less than 200 mg/dL, a fasting blood sugar less than 110 mg/dL, or who fail dietary therapy after 30 weeks gestation appear to be good candidates for treatment with glyburide therapy [5-9] if diet fails to control their blood sugar.

Although metformin also appears be a useful adjunct or alternative to insulin during pregnancy metformin has a higher rate of failure in the treatment of gestational diabetes than glyburide [14,15]. Some authors caution that data are needed on the long-term safety of metformin before it can be considered as first-line therapy for women with gestational diabetes [16,17].

Both glyburide and metformin appear to cross the placenta [33,34].


 Insulin

Insulin is a peptide hormone with a  molecular weight of 5808 Da. It is produced in the islets of Langerhans in the pancreas. Synthetic "human" insulin is  manufactured using recombinant DNA technology.

Doses of insulin are measured in units. U-100 insulin contains 100 units/mL. Initial doses for insulin will vary according to trimester and weight.

See Initial Insulin Calculator
For DKA see Diabetic Ketoacidosis Order Set

In general, when a longer-acting insulin (e.g. NPH insulin isophane suspensions) is mixed with short-acting or rapid acting-soluble insulin (e.g., regular), the short-acting or rapid acting insulin should be drawn into the syringe first. Insulin glargine must NOT be diluted or mixed with any other insulin or solution

The subcutaneous tissue of the abdomen is preferred site for injection because absorption of the insulin is more consistent from this location than subcutaneous tissues in other locations.

Among the potential clinical adverse effects associated with the use of all insulins are hypoglycemia and hypokalemia.

Storage

Unopened insulin should be stored in a refrigerator between 2 and 8°C (36 and 46°F); it should not be placed in a freezer. After initial use a vial may be kept at temperatures below 30°C (86°F) for up to 28 days, but should not be exposed to excessive heat or sunlight.  Unused insulin should be thrown away after the expiration date. Insulin in a pump reservoir should be discarded after at least every 48 hours of use or after exposure to temperatures that exceed 37°C (98.6°F).

Syringes

Insulin syringes are available in three barrel sizes 1mL (100 units), ½ mL (50 units) and 3/10 mL (30 units).

BD Micro-Fine™ IV Needle is a 28-gauge, 12.7mm (1/2")
BD Ultra-Fine™ Needle is a 30-gauge, 12.7mm (1/2")
BD Ultra-Fine™ Short Needle  31-gauge, 8mm (5/16")/p>

For information on safe disposal of needles, syringes, and other sharps in the community contact:

 


Rapid-acting Insulins- Onset 15 minutes [21]

Insulin aspart [rDNA origin] injection (NovoLog® )
Insulin lispro, [rDNA origin] injection (Humalog®)
Insulin analogs. Onset 15 minutes , peak of action 30 to 90 minutes, duration of action less than 5 hours [22].

  • Indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia.

    Give calculated dose subcutaneously 15 minutes before a meal.
    The algorithm below may used, but may need to be modified according to the patient population. [25]
     
    Preprandial or Bedtime Blood Glucose average for at least 3 consecutive days (mg/dl) Adjust dose of aspart (Novolog) units
    >180 +3
    160-180 +2
    140-159 +2
    120-139 +1
    100-119 maintain dose
    80-99 -1
    60-79 -2
    <60 -4

(100 Units per mL in 10 mL vials, 3 mL cartridges, or 3 mL Pens)
 


Short-acting Insulins- Onset 30 to 60 minutes

Regular insulin human injection, USP (rDNA origin)
(Humulin
®  -R, Novolin® -R)
Insulin. Onset 30 to 60 minutes , peak of action 2 to 3 hours, duration of action 5 to 8 hours [22].

  • Indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia.

    Give calculated dose subcutaneously 30 minutes before a meal.
     

(100 Units per mL in 10 mL vials)


Regular insulin human injection, USP (rDNA origin)
(
Humulin R (U-500) ® ,Concentrated)

Insulin. Onset 30 to 60 minutes , peak of action 2 to 3 hours, duration of action 5 to 8 hours [22].

  • Indicated in the treatment of diabetic patients with marked insulin resistance (daily requirments more than 200 units)

    Give calculated dose subcutaneously 30 minutes before a meal.

(500 Units per mL in 20 mL vials)


Intermediate-acting, Basal Insulin- Onset 2 to 4 hours

Neutral Protamine Hagedorn (NPH) Human Insulin (rDNA origin) Isophane Suspension 
(Humulin
®  -N , Novolin® N)
Zinc insulin combined with the polypeptide protamine. Onset 2 to 4 hours, peak of action 4 to 10 hours, duration of action 10 to 16 hours [22].

  • Indicated in the treatment of patients with diabetes mellitus for the control of hyperglycemia.

Give calculated dose alone or mixed with short or rapid acting insulin subcutaneously.

(100 Units per mL in 10 mL vials)

 


Insulin Pump

See Calculation of Initial Insulin Pump Requirements

 


Glyburide (Micronase® )
Oral blood-glucose-lowering drug of the sulfonyl- urea class [10].

  • Used as an adjunct to diet to lower the blood glucose in patients with non-insulin-dependent diabetes mellitus [11].

      1.25 mg to 2.5 mg PO daily 60 minutes before meals to control postprandial sugar.
      May give at 10 to 11 PM  to control fasting blood sugar.
      May increase by 1.25 to 2.5 mg every 3 to 7days to a maximum of 20 mg.

(1.25, 2.5, and 5 mg tablets)
Limited data indicate that the levels of glyburide in milk are negligible [12].
 

Use in Breastfeeding Lactmed


Metformin (Glucophage® )
Oral blood-glucose-lowering drug of the biguanide  [18].

  • Used as an adjunct to diet to lower the blood glucose in patients with non-insulin-dependent diabetes mellitus [14,15]

    500 mg once or twice daily given with meals. Usually given with breakfast and dinner. May increase in increments of 500 mg weekly up to a total of 2500 mg per day.

Lactic acidosis is a rare, but serious, metabolic complication that can occur due to metformin accumulation during treatment; when it occurs, it is fatal in approximately 50% of cases. Reported cases have occurred primarily in diabetic patients with significant renal insufficiency.The onset of lactic acidosis often is subtle, and accompanied only by nonspecific symptoms such as malaise, myalgias, respiratory distress, increasing somnolence, and nonspecific abdominal distress.

 

(500, 850, and 1000 mg tablets)

Use in Breastfeeding Lactmed


REFERENCES

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3. Jacobson GF, et al. Comparison of glyburide and insulin for the management of gestational diabetes in a large managed care organization. Am J Obstet Gynecol. 2005 Jul;193(1):118-24. PMID: 16021069
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5. Kahn BF, et al., Predictors of glyburide failure in the treatment of gestational diabetes. Obstet Gynecol.2006;107:1303-9. PMID: 16738156
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10 Micronase® package insert 2002 www.pfizer.com/pfizer/download/uspi_micronase.pdf . Accessed 5/18/2007
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13.Guidelines for Care, California Diabetes and Pregnancy Program,2002
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PMID: 17596473
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18. Glucophage package insert 2008 http://packageinserts.bms.com/pi/pi_glucophage.pdf Accessed 11/30/2008

19. HAPO Study Cooperative Research Group, Metzger BE, et al. Hyperglycemia and adverse pregnancy outcomes.N Engl J Med. 2008 May 8;358(19):1991-2002. PMID: 18463375

20. Combs CA, et al. .Relationship of fetal macrosomia to maternal postprandial glucose control during pregnancy.Diabetes Care. 1992 Oct;15(10):1251-7. PMID: 1425084

21. Jovanovic L, Pettitt DJ.Treatment With Insulin and Its Analogs in Pregnancies Complicated by Diabetes.  Diabetes Care. 2007 Jul;30 Suppl 2:S220-4.  PMID: 17596476

22. AACE Diabetes Mellitus Clinical Practice Guidelines Task Force. AACE diabetes mellitus guidelines. Glycemic management. Endocr Pract 2007 May-Jun;13(Suppl 1):16-34. http://www.aace.com/pub/pdf/guidelines/DMGuidelines2007.pdf

23. Mukhopadhyay A, Farrell T, Fraser RB, Ola B. Continuous subcutaneous insulin infusion vs intensive conventional insulin therapy in pregnant diabetic women: a systematic review and metaanalysis of randomized, controlled trials. Am J Obstet Gynecol. 2007 Nov;197(5):447-56. Epub 2007 Aug 6. Review.PMID: 17678864

24. Gerstein HC, Yale JF, Harris SB, Issa M, Stewart JA, Dempsey E.  A randomized trial of adding insulin glargine vs. avoidance of insulin in people with Type 2 diabetes on either no oral glucose-lowering agents or submaximal doses of metformin and/or sulphonylureas. The Canadian INSIGHT (Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment) Study.Diabet Med. 2006 Jul;23(7):736-42.PMID: 16842477

25. Ambulatory Insulin Titration Form Agency for Healthcare Research and Quality
http://www.ahrq.gov/populations/chroniccaremodel/chronic3a11b.htm Accessed 12/3/08

26. Mooradian AD, Bernbaum M, Albert SG.Narrative review: a rational approach to starting insulin therapy.Ann Intern Med. 2006 Jul 18;145(2):125-34. PMID: 16847295

27. Horvath K, et al., . Long-acting insulin analogues versus NPH insulin (human isophane insulin) for type 2 diabetes mellitus.Cochrane Database Syst Rev. 2007 Apr 18;(2):CD005613. Review. PMID: 17443605

 28. Smith JG, Manuck TA, White J, Merrill DC.Insulin Glargine versus Neutral Protamine Hagedorn Insulin for Treatment of Diabetes in Pregnancy.
Am J Perinatol. 2008 Oct 31. PMID: 18979406

29. Gallen IW, Jaap A, Roland JM, Chirayath HH. Survey of glargine use in 115 pregnant women with Type 1 diabetes.Diabet Med. 2008 Feb;25(2):165-9. Epub 2008 Jan 19. PMID: 18215174


30.  Pöyhönen-Alho M, Rönnemaa T, Saltevo J, Ekblad U, Kaaja RJ. Use of insulin glargine during pregnancy.Acta Obstet Gynecol Scand. 2007 Aug 29:1-4. [Epub ahead of print] PMID: 17851816
 

31. Price N, Bartlett C, Gillmer M. Use of insulin glargine during pregnancy: a case-control pilot study.BJOG. 2007 Apr;114(4):453-7. Epub 2007 Jan 25.  PMID: 17261126

32.  Kitzmiller JL, et al. Managing preexisting diabetes for pregnancy: summary of evidence and consensus recommendations for care.
Diabetes Care. 2008 May;31(5):1060-79.  PMID: 18445730
33. Hebert MF,et al. Obstetric-Fetal Pharmacology Research Unit Network.Are we optimizing gestational diabetes treatment with glyburide? The pharmacologic basis for better clinical practice. Clin Pharmacol Ther. 2009 Jun;85(6):607-14.19295505
34. Vanky E,et al. Placental passage of metformin in women with polycystic ovary syndrome. Fertil Steril. 2005 May;83(5):1575-8. PMID: 15866611
35. Raap U, Delayed-type hypersensitivity to protamine as a complication of insulin therapy.
Contact Dermatitis. 2005 Jul;53(1):57-8. PMID: 15982236

36. Hulshof MM, Granulomatous hypersensitivity to protamine as a complication of insulin therapy.
Br J Dermatol. 1992 Sep;127(3):286-8.PMID: 1390174

37. Pollex EK, Insulin glargine safety in pregnancy: a transplacental transfer study.Diabetes Care. 2010 Jan;33(1):29-33. Epub 2009 Oct 6.
PMID: 19808914

 
   

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