eMedicine Specialties > Endocrinology > Diabetes Mellitus

Glucose Intolerance: Treatment & Medication

Author: Samuel T Olatunbosun, MD, FACP, Chief, Internal Medicine, 56th Medical Group, Luke Air Force Base
Coauthor(s): Samuel Dagogo-Jack, MD, MBBS, MSc, FRCP, Professor of Medicine, Program Director, Division of Endocrinology, Diabetes and Metabolism, University of Tennessee Health Science Center
Contributor Information and Disclosures

Updated: Aug 5, 2009

Treatment

Medical Care

Routine evaluation in an ambulatory setting is feasible for most patients. Patients with acute decompensation due to glucose intolerance or to any of the related disorders may require inpatient care. See Consultations for other specialists who the patient may benefit from consulting.14

A major goal in the management of glucose intolerance is glycemic control.

  • Intensive lifestyle modification has been shown to effectively delay or prevent diabetes in a cost-effective manner.15,16 Nonpharmacologic therapy and lifestyle modification include the following:
    • Diet
    • Exercise
    • Counseling for smoking cessation and counseling regarding alcohol use
    • Reversal of drug-related, iatrogenic causation of glucose intolerance
    • Substitution or addition of an agent or agents that do not adversely affect glucose tolerance or reduction of the dosage of the offending drug
  • Pharmacologic therapy may be required in the following situations:17
    • Fasting glucose level is greater than 126 mg/dL, postprandial glucose level is greater than 160 mg/dL, or glycosylated hemoglobin (HbA1C) level is greater than 7%
    • Hyperglycemia (a significant risk factor in the development of vascular complications)

Consultations

  • Endocrinologist
  • Dietitian
  • Cardiologist, ophthalmologist, and nephrologist, depending on the presence of other related disorders and predominant pathology

Diet

Medical nutrition therapy should be guided by the ADA recommendations and should be individualized based on weight and height, level of physical activity, and requirements for calories and nutrients.18

Activity

A high level of physical activity is desirable, as appropriate to the patient's ability and general health. Most patients benefit from carefully planned exercise programs tailored to individual needs.

Medication

Oral antidiabetic agents can be classified into functional categories, as follows:

  • Secretagogues (eg, sulfonylureas, meglitinides), which stimulate insulin release
  • Insulin sensitizers (eg, biguanides, thiazolidinediones), which reduce insulin resistance
  • Medications that slow the digestive/absorptive process (eg, alpha-glucosidase inhibitors)
  • DPP-4 inhibitors (eg, sitagliptin), which inhibit DPP-4, the enzyme that inactivates incretin hormones GLP-1 and GIP.19,20

Of note is the novel treatment with DPP-4–resistant GLP-1 receptor agonists, such as exenatide and liraglutide, which are incretin mimetics, as well as with the DPP-4 inhibitors sitagliptin (Januvia; Merck & Co) and vildagliptin (LAF237, Norvatis Pharmaceuticals); the latter is in the late stage of clinical development.19,20 Both strategies have been successful in clinical studies. The action mechanisms of incretin mimetics include stimulation of insulin secretion in response to nutrient intake, inhibition of glucagon secretion, delay of gastric emptying, and induction of early satiety. Other benefits include preservation of beta-cell mass and improvement of secretory function. The advantages of the DPP-IV inhibitors include oral availability, good tolerability, and weight neutrality.

Amylin has several glucoregulatory effects that complement those of insulin in postprandial glucose regulation; thus, mealtime amylin administration may be adjunctive to mealtime insulin replacement and may facilitate improvement of postprandial and overall glycemic control in patients with type 1 or type 2 diabetes. However, naturally occurring human amylin is unsuitable for clinical use because of several physicochemical properties; pramlintide acetate contains an amylin analogue without those limitations.21,22,23,24,25,26

All patients with type 1 diabetes are insulin-dependent. Treatment of severe hyperglycemia during acute decompensation in a patient with type 2 diabetes may reverse the state of glucose toxicity, further improving secretory function of beta cells in the pancreas. Type 2 diabetes can be treated effectively with oral hypoglycemic drugs, with or without the addition of insulin. The natural history of type 2 diabetes is that of progressive beta-cell deterioration, secondary failure of oral agents, and the subsequent need for insulin therapy. Gestational diabetes mellitus is treated with insulin and/or with lifestyle change. Oral agents are contraindicated in pregnancy.

With regard to the management of impaired glucose tolerance, the current approach is aggressive lifestyle modifications. The results of the Diabetes Prevention Program (DPP) showed that metformin therapy and intensive lifestyle intervention reduced the risk of developing type diabetes by 31% and 58% respectively, compared with placebo, in individuals with impaired glucose tolerance. The Study to Prevent Non-Insulin–Dependent Diabetes Mellitus (STOP-NIDDM) Trial demonstrated a 25% relative risk reduction in the development of diabetes, and also showed an associated reduction in hypertension (34%) and cardiovascular events (49%). Orlistat may be beneficial in the context of obesity.16

Sulfonylureas

Chlorpropamide and tolbutamide (first-generation), as well as glipizide, glyburide, and glimepiride (second-generation), are secretagogues, that is, medications that stimulate insulin secretion.


Glipizide (Glucotrol)

Second-generation sulfonylurea that stimulates release of insulin from pancreatic beta cells.

Adult

5-40 mg/d PO; not to exceed 15 mg/dose or 40 mg/d

Pediatric

Not established

Beta blockers, phenytoin, corticosteroids, and thiazides decrease hypoglycemic effects; cimetidine may increase hypoglycemic effects; ACE inhibitors enhance hypoglycemic activity

Documented hypersensitivity; ketoacidosis; type 1 diabetes; pregnancy

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Caution in renal or liver dysfunction; trauma, infection, surgery, or stress may require use of insulin

Meglitinides

These agents stimulate insulin secretion from pancreatic cells.


Repaglinide (Prandin)

Meglitinides analogue, a secretagogue that acts on the pancreas to stimulate the release of insulin. Nateglinide (Starlix) is an analogue of D -phenylalanine.

Adult

For oral hypoglycemic-naïve patient or HbA1C <8%: Repaglinide 0.5 mg PO tid ac; nateglinide 120 mg PO tid ac
Previously treated patient or HbA1C >8%: Repaglinide 1-2 mg PO tid ac; not to exceed 16 mg PO

Pediatric

Not established

CYP3A4 inhibitors (eg, clarithromycin, ketoconazole, miconazole, erythromycin) decrease metabolism, thus increasing serum levels and hypoglycemic effects; hypoglycemic activity also enhanced by chloramphenicol, NSAIDs, probenecid, salicylates, and warfarin; hypoglycemic activity decreased by corticosteroids, estrogens, INH, phenytoin, and thiazides; glucose control destabilized by beta blockers, quinolones, and thyroid hormones

Documented hypersensitivity; ketoacidosis; type 1 diabetes

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Hepatic disease; elderly patients

Antidiabetic agents, biguanides

These agents improve peripheral glucose uptake and utilization.


Metformin (Glucophage)

Reduces insulin resistance, ie, metformin is an insulin sensitizer. Hepatic glucose output is decreased; peripheral insulin-stimulated uptake is increased.

Adult

500 mg PO bid or 850 mg PO qd; not to exceed 2500 mg

Pediatric

Not established

Hypoglycemic activity enhanced by ketoconazole, miconazole, erythromycin, chloramphenicol, NSAIDs, probenecid, salicylates, and warfarin; hypoglycemic activity decreased by corticosteroids, estrogens, INH, phenytoin, and thiazides; glucose control destabilized by beta blockers, quinolones, and thyroid hormones

Documented hypersensitivity; renal dysfunction; CHF that requires treatment; concomitant use of parenteral radiographic agents; type 1 diabetes

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Hepatic disease; advanced age; discontinue if lactic acidosis, hypoxemia, or sepsis occurs

Thiazolidinediones

These agents stimulate peripheral use of glucose as stimulated by insulin. Rosiglitazone and pioglitazone are commonly used.

Following the online publication of a meta-analysis, the Food and Drug Administration on May 21, 2007, issued an alert to patients and health care professionals stating that rosiglitazone can potentially cause an increased risk of myocardial infarction (MI) and heart-related deaths. Rosiglitazone is an antidiabetic agent (thiazolidinedione derivative) that improves glycemic control by improving insulin sensitivity.

The drug is highly selective and is a potent agonist for peroxisome proliferator-activated receptor gamma (PPAR gamma). Activation of PPAR-gamma receptors regulates insulin-responsive gene transcription involved in glucose production, transport, and utilization, thereby reducing blood glucose concentrations and reducing hyperinsulinemia. Potent PPAR-gamma agonists have been shown to increase the incidence of edema. A large scale phase III trial (RECORD) is underway that is specifically designed to study cardiovascular outcomes of rosiglitazone.

For more information, see FDA’s Safety Alert on Avandia. The meta-analysis published online, entitled “Effect of Rosiglitazone on the Risk of Myocardial Infarction and Death from Cardiovascular Causes” can be viewed at The New England Journal of Medicine. Additionally, responses to the controversy can be viewed at the Heartwire news (the heart.org from WebMD), including the following articles: 1) Rosiglitazone increases MI and CV death in meta-analysis and 2) The rosiglitazone aftermath: legitimate concerns or hype?


Rosiglitazone (Avandia)

Sensitizes target cells' response to insulin.

Adult

4-8 mg/d PO qd or divided bid

Pediatric

Not established

Hypoglycemic activity decreased by loop diuretics, thiazides, and salicylates; glucose control destabilized by quinolones

Documented hypersensitivity; active liver disease; ketoacidosis; type 1 diabetes

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Monitor transaminases, discontinue if ALT rises to more than 3 times upper limit of normal; edema; CHF

Alpha-glucosidase inhibitors

These agents include acarbose and miglitol, which are medications that slow the digestive and absorptive process.


Acarbose (Precose)

Slows digestive and absorptive process.

Adult

25 mg PO tid with first bite of each meal initially; not to exceed 50 mg PO tid if <60 kg; not to exceed 100 mg PO tid if >60 kg

Pediatric

Not established

Enhances hypoglycemic activity of antidiabetic drugs; decreases digoxin serum levels

Documented hypersensitivity; IBD; colonic ulceration; ileus; cirrhosis; ketoacidosis

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Monitor liver function; use glucose (not sucrose) to treat hypoglycemia

Antidiabetic agents, insulins

Insulin is used as hormone replacement.


Insulin (Humulin, Novolin)

Various preparations based on onset, peak, and duration of action. The exogenous insulin supply is used to overcome insulin deficiency and resistance.

Adult

0.1-2.5 U/kg/d SC; individualized and highly variable
Diabetic ketoacidosis: Regular insulin only, 0.1 U/kg/h IV; use a bolus of 0.1 U/kg if insulin delayed

Pediatric

Administer as in adults

Hypoglycemic effect decreased by thyroid hormone, corticosteroids, estrogen, diltiazem, and thiazide; hypoglycemic effect increased by alcohol, anabolic steroids, salicylates, beta blockers, alpha blockers, and tetracycline

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Instruct patient on proper administration of insulin, blood testing, diet, exercise, and management of hypoglycemia; titrate dosage according to patient's need

Incretin mimetics

This new class of drugs broadens the armamentarium of antidiabetic medications. Exenatide and liraglutide are DPP-4 – resistant GLP-1 receptor agonists or analogues. As incretin mimetics, they enhance insulin secretion, the suppression of glucagon secretion, and the slowing of gastric emptying. Exenatide has been approved by the FDA as adjunctive therapy in patients who have not achieved adequate control with metformin or sulfonylurea; exenatide has been available since June 2005.


Exenatide (Byetta)

A 39-amino acid incretin mimetic peptide derived from Gila monster hormone exendin-4; structurally similar to GLP-1. Enhances glucose-mediated insulin secretion in the beta cell; decreases the pathologic hypersecretion of glucagon in the alpha cell; slows gastric emptying; induces satiety. Improves postprandial hyperglycemia without significant risk of hypoglycemia; produces moderate weight loss. Improvement in islet cell function demonstrated by increased proinsulin-to-insulin ratio.

Adult

5 mcg SC bid within 1 h ac in morning and evening; based on response, may increase to 10 mcg SC bid after 1 mo

Pediatric

Not established

Data limited; coadministration decreases digoxin Cmax and delays Tmax, decreases lovastatin AUC and Cmax, delays lisinopril Tmax, and decreases acetaminophen AUC and Cmax, but these pharmacokinetic alterations do not appear to be clinically significant; may decrease absorption of orally administered drugs (take drugs that require rapid absorption [eg, oral contraceptives, antibiotics] at least 1 h before exenatide)

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Administer in thigh, abdomen, or upper arm; may cause hypoglycemia, nausea, vomiting, diarrhea, jittery feeling, dizziness, headache, or dyspepsia; may develop antibodies to protein contents

Amylin analogue

Pramlintide is an amylinomimetic agent that modulates gastric emptying, prevents postprandial increases in plasma glucagon, and promotes satiety, leading to decreased caloric intake and potential weight loss.21,22,23,24,25,26

Although naturally-occurring human amylin is unsuitable for clinical use because of several physicochemical properties (eg, poor solubility; self-aggregation; formation of b-pleated sheets, amyloid fibrils, amyloid plaques), the selective substitution of the amino acid proline for Ala25, Ser28, and Ser29 addresses the suboptimal physicochemical properties of human amylin while preserving the important metabolic actions. Pramlintide acetate injection, which contains this amylin analogue, is a sterile, clear, colorless, aqueous solution that also contains mannitol for isotonicity and the preservative m-cresol.


Pramlintide (Symlin)

Synthetic analogue of human amylin, a naturally occurring hormone made in pancreas beta cells. Pramlintide slows gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake through centrally mediated appetite modulation. It is indicated to treat type 1 or type 2 diabetes in combination with insulin. Pramlintide is administered before mealtime for patients who have not achieved desired glucose control despite optimal insulin therapy. The drug helps to achieve lower blood glucose levels after meals, less fluctuation of blood glucose levels during the day, and improvement of long-term control of glucose levels (ie, HbA1C levels) compared with insulin alone. Reductions in insulin use and body weight are also observed.

Adult

Type 1 diabetes: 15 mcg SC ac initially; titrate upward in 15-mcg increments (if no significant nausea occurs for 3-7 d) to maintenance dose of 30-60 mcg/dose; insulin dose must be initially decreased during initiation phase; once target pramlintide dose achieved, optimize insulin to maintain glycemic control
Type 2 diabetes: 60 mcg SC ac initially; titrate upward (if no significant nausea occurs for at least 3 d) to maintenance dose of 120 mcg/dose; insulin dose must initially be decreased during initiation phase; once target pramlintide dose achieved, optimize insulin to maintain glycemic control

Pediatric

Not established

Do not use with other drugs that slow gastric emptying (eg, anticholinergic agents, such as atropine) or drugs that slow intestinal nutrient absorption (eg, alpha glucosidase); may delay absorption of concomitantly administered oral drugs (to avoid this effect, administer other drug 1 h before or 2 h after pramlintide)

Documented hypersensitivity to pramlintide or any of its components, metacresol, D-mannitol, acetic acid, or sodium acetate; gastroparesis; hypoglycemia unawareness

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Increases risk of insulin-induced severe hypoglycemia, especially with type 1 diabetes or gastroparesis; reduce insulin dose in all patients (type 2 or type 1) when initiating therapy (monitor blood glucose and adjust insulin dose during initiation phase); common adverse effects include GI symptoms, especially nausea (incidence decreased when dose increased gradually); always use separate insulin syringe to measure and administer; do not mix in same syringe as insulin (it alters their individual pharmacokinetics); may cause local redness, swelling, or itching at injection site; do not administer unless ingesting major meal (ie, >250 calories or 30 g of carbohydrates)
Adverse events include nausea, vomiting, abdominal pain, headache, fatigue, and dizziness
Incidence and severity of nausea is highest at initiation of therapy and may be reduced by a gradual increase to recommended doses

Dipeptidyl Peptidase-4 Inhibitor

The DPP-4 inhibitors are oral agents that inactivate the major enzyme responsible for degrading incretin hormones in vivo.


Sitagliptin (Januvia)

First of a new class of antidiabetic agents known as dipeptidyl peptidase – IV (DPP-4) inhibitors. Sitagliptin blocks the enzyme DPP-4, which is known to degrade incretin hormones. Sitagliptin increases concentrations of active intact incretin hormones (GLP-1 and GIP). The hormones stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Sitagliptin is indicated for diabetes type 2 as monotherapy or in combination with metformin or with a peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonist (eg, thiazolidinediones).

Adult

100 mg PO qd
CrCl >30 to <50 mL/min: 50 mg PO qd
CrCl <30 mL/min: 25 mg PO qd

Pediatric

Not established

Data limited; caution with other drugs that decrease glucose

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Common adverse effects include upper respiratory tract infection, nasopharyngitis, and headache; assess renal function before initiating therapy and periodically thereafter; decrease dose with moderate or severe renal insufficiency


Saxagliptin (Onglyza)

Dipeptidyl peptidase IV (DPP-4) inhibitor. Blocks the enzyme DPP-4, which is known to degrade incretin hormones. Increases concentrations of active intact incretin hormones (GLP-1 and GIP). The hormones stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Adult

2.5-5 mg PO qd
CrCl <50 mL/min: 2.5 mg PO qd
Coadministration with strong CYP450 3A4/5 inhibitors: 2.5 mg PO qd

Pediatric

<18 years: Not established

Coadministration with strong CYP3A4/5 inhibitors (eg, ketoconazole, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin) significantly increases serum concentration (do not exceed 2.5 mg/d with concurrent use of these drugs); concurrent use with CYP3A4/5 inducers (eg, rifampin) significantly decreases exposure, but not active metabolite AUC (dose adjustment not needed); coadministration with sulfonylureas increases risk of hypoglycemia (decrease dose of sulfonylurea); coadministration with thiazolidinedione (eg, rosiglitazone, pioglitazone) increases risk for peripheral edema

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Common adverse effects include upper respiratory tract infection, urinary tract infection, and headache; may cause peripheral edema (especially when coadministered with thiazolidinedione); hypoglycemia reported more often when coadministered with sulfonylurea; may cause hypersensitivity-related events (eg, urticaria, facial edema)

More on Glucose Intolerance

Overview: Glucose Intolerance
Differential Diagnoses & Workup: Glucose Intolerance
Treatment & Medication: Glucose Intolerance
Follow-up: Glucose Intolerance
Multimedia: Glucose Intolerance
References
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Further Reading

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Keywords

glucose intolerance, abnormal glucose tolerance, abnormal glucose homeostasis, disorders of glucose tolerance, disorders of glycemia, glucose tolerance, type 1 diabetes mellitus, type 2 diabetes mellitus, gestational diabetes mellitus, GDM, impaired glucose tolerance, IGT, impaired fasting glucose, IFG, insulin resistance, hyperglycemia, normoglycemia, ketoacidosis, dysmetabolic syndrome, central adiposity, pancreas, pancreatic function, hypoglycemia, pancreatic beta cells

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Contributor Information and Disclosures

Author

Samuel T Olatunbosun, MD, FACP, Chief, Internal Medicine, 56th Medical Group, Luke Air Force Base
Samuel T Olatunbosun, MD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, and American Diabetes Association
Disclosure: Nothing to disclose.

Coauthor(s)

Samuel Dagogo-Jack, MD, MBBS, MSc, FRCP, Professor of Medicine, Program Director, Division of Endocrinology, Diabetes and Metabolism, University of Tennessee Health Science Center
Samuel Dagogo-Jack, MD, MBBS, MSc, FRCP is a member of the following medical societies: American College of Physicians, American Diabetes Association, American Federation for Medical Research, Endocrine Society, and Royal College of Physicians
Disclosure: Eli Lilly None Speaking and teaching; GlaxoSmithKline None Speaking and teaching; Merck None Speaking and teaching

Medical Editor

David S Schade, MD, Chief, Division of Endocrinology and Metabolism, Professor, Department of Internal Medicine, University of New Mexico School of Medicine and Health Sciences Center
David S Schade, MD is a member of the following medical societies: American College of Physicians, American Diabetes Association, American Federation for Medical Research, Endocrine Society, New Mexico Medical Society, New York Academy of Sciences, and Society for Experimental Biology and Medicine
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Don S Schalch, MD, Professor Emeritus, Department of Internal Medicine, Division of Endocrinology, University of Wisconsin Hospitals and Clinics
Don S Schalch, MD is a member of the following medical societies: American Diabetes Association, American Federation for Medical Research, Central Society for Clinical Research, and Endocrine Society
Disclosure: Nothing to disclose.

CME Editor

Mark Cooper, MBBS, PhD, FRACP, Head, Diabetes & Metabolism Division, Baker Heart Research Institute, Professor of Medicine, Monash University
Disclosure: Nothing to disclose.

Chief Editor

George T Griffing, MD, Professor of Medicine, St Louis University School of Medicine
George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation
Disclosure: Nothing to disclose.

 
 
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