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SCIENTIFIC REVIEW CLINICIANS CORNER

AND CLINICAL APPLICATIONS

Oral Antihyperglycemic Therapyfor Type 2 DiabetesClinical ApplicationsEric S. Holmboe, MD

SEVERAL CLINICALPRACTICEGUIDE-lines for type 2 diabetes are now

available. All advocate a hemo-globin A1clevel of less than 7%,and at least 1 organization has adopteda target of 6.5%.1-3 Despite the numberofagentsto choose from,Inzucchi4 notesthat theonly ones evaluatedin random-ized controlled trialswith regardto clini-cally important outcomes are insulin,metformin,andthesulfonylureas.5-7 Twoimportant clinical trials have demon-strated that more aggressive glycemiccontrol in type 2 diabetic patients re-duced microvascular complications.Questions remain about the effect of all

the oral agents and insulin on reducingmacrovascular complications.6,7

Primary care physicians providemuch of the care for patients with type2 diabetes.8 Although this article dis-cusses primarily drug treatment, edu-cation on self-management, nutrition,and exercise is essential to help pa-tients achieve glycemic control. Self-management training is effective intype 2 diabetes and should be recom-mended for all patients.9

Recommendations for the use of oral

agents for each clinical situation arebasedon thebest evidence available andaccepted clinical guidelines. Informeddecision making about therapy, how-ever, must involve the patient and in-clude a clear explanation of therapeutic-

choice rationale, an assessment of hisor her understanding, preferences, andbarriers to care, and a discussion of therisks and benefits of each therapy.10-12

An active patient-physician partner-ship facilitates treatment of this com-plex, multifaceted disease.13 The TABLEprovides a brief summary of the avail-able oral agents and their relative costs.Th e BOX provides additional re-sources.

CLINICAL CONTEXT

Patient 1

A moderately obese 49-year-old woman(body mass index, 29 kg/m2) com-plains of increased thirst, polyuria, andfatigue. Her family history is pertinentfor diabetes in her mother and an olderbrother. A random plasma glucose se-rum test shows a level of 480 mg/dL

(26.6 mmol/L). Her serum electrolyteand anion gap levels are normal.

At this visit,the patient meets Ameri-can DiabetesAssociation criteria for hav-ing diabetes.14 Given her symptoms andhigh blood glucose level, the question iswhether to start an oral agent or insulintherapy. Guidelines are not prescrip-tive regarding the choice of the initialagent.1-3,15 One consideration in decid-ingwhether to initiate insulin therapyoran oral agent is glucose toxicity.16,17 High

Author Affiliations: Department of Medicine, YaleUniversity School of Medicine, NewHaven,Conn, andQualidigm (Connecticut Peer Review Organization),Middletown, Conn.Corresponding Author and Reprints: Eric S. Holm-boe, MD,Yale Primary Care ResidencyProgram, Wa-terburyHospital, 64 RobbinsSt, Waterbury, CT 06721(e-mail: [email protected] or [email protected]).Scientific Review: Clinical ApplicationsSection Editor:Wendy Levinson, MD, Contributing Editor.

Oral agents are the mainstay of pharmacologic treatment for type 2 diabe-

tes, and physicians now have a number of agents to choose from. However,

more choices translate into more complex decision making. Many patients

with diabetes have associated comorbidities, and most diabetic patients will

require more than 1 agent to achieve good glycemic control. This article il-

lustrates several of the pharmacologic approaches to type 2 diabetes through

4 situations that use principles of evidence-based medicine. The scenarios

also highlight some of the difficulties in choosing the optimal pharmaco-

logic treatment regimen for individual patients. Physicians should also rec-

ognize that type 2 diabetes is a multisystem disorder that requires multidis-

ciplinary care, including education and ongoing counseling for effective patient

self-management of the disease. Finally, patient preferences are a vital com-

ponent of informed decision making for pharmacologic treatment of diabetes.

JAMA. 2002;287:373-376 www.jama.com

See also pp 360 and 379.

2002 American Medical Association. All rights reserved. (Reprinted) JAMA, January 16, 2002Vol 287, No. 3 373

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levels of glucose are toxic to pancreaticbetacells, impairing insulin secretion intheface of relative insulin deficiency. Al-thoughnot studied in a randomized con-trolled trial, initial treatment with insu-lin has been suggested to allow more

rapid control of plasma glucose, recov-ery of beta cell function,and better sub-sequent response to oral agents.17,18 Ad-ditionally,insulin dosage canbe adjustedquickly, facilitating more rapid controlof hyperglycemia and associatedsymp-toms.15-17 Once a stable target glucoselevel hasbeen achieved, thepatient maybe able to begin receiving an oral agent.However, insulin therapy does requireimmediate patient education on injec-tion techniques, use of a home glucosemeter, and identification and treat-ment of hypoglycemicreactions. If avail-

able locally, certifieddiabetes nurse edu-catorscan be particularly helpful in thisprocess. Deciding whether to start in-sulin therapy also requires assessmentof the patients understanding andwishes.10

Whenthepatientis switchedto anoralagent or an oral agent is used as initialtherapy, guidelines suggest that eithera sulfonylurea or metformin agent isappropriate. However, given that thispatient is moderately obese, metforminwould be the recommended initialagent.4,7,15 Ittendstopromote weightlossandisequallyeffectiveinloweringhemo-globin A1ccompared with sulfonylureaand thiazolidinedione (TZD) agents.4

Given her degree of hyperglycemia, thispatient may eventually need 2 oral agentsto achieve adequate control.

Patient 2

A 57-year-old man with type 2 diabe-tes treated for 9 years is currently re-ceiving glyburide at a dosage of 10mg/d. His hemoglobin A1c level a weekago was 8.5%. You suggest adding met-

formin, butthe patient wonders whyhecannot increase his glyburide dose be-cause his hemoglobin A1clevel was al-ways controlled well by this medica-tion and he has been toldthat 10mg isonly half the maximal dose.

Although daily doses of up to 20 mgof glyburide and 40 mg of glipizide areapproved and can be used, data haveclearly shown that, above 10 to 12 mg/d,the additional gain in glycemic controlis marginal.19 In addition,the failure rateof sulfonylureatherapyis 5% yearly, andthis patient has been receiving gly-

buridetherapy for9 years.4,6,7,15 Thus, in-creasing his sulfonylurea dose is highlyunlikelyto helphim reachthetarget levelof hemoglobin A1c. Likewise, switchingto another single oral agentsuch as met-formin, TZD, or meglitinide or anothernonsulfonylurea secretagogue is un-likely to lead to adequate glycemic con-trol, given the duration of his diabetes.Therefore, addition of another agentshould be considered. The UnitedKingdom Prospective Diabetes Study(UKPDS) andother trials foundthatadd-

ing metformin to sulfonylurea therapyloweredhemoglobinA1c levels.

4,7,20,21 TheUKPDS, however, found an unex-pected increase in diabetes-relatedmor-tality with this combination, althoughwhen all patients who were actuallytreatedwithmetformin according to pro-tocol analysis were investigated, a 19%reduction in diabetes-related end pointswasobserved.7,22 Another optionistoadda TZD; this combination hasalso shownsubstantial reductionsin hemoglobin A1clevels.4 Although no definite evidence

exists of severe hepatotoxicity with rosi-glitazone and pioglitazone, frequentmonitoring of liver enzymes is still re-quired becauseof troglitazones associa-tion with hepatotoxicity.

Patient 3

A 55-year-old woman was diagnosedwith diabetes almost 10 years ago andis

Table.Summary of Available Oral Agents and Costs

MonthlyRetail Cost, $*

ComparativeCost, $/d

SulfonylureasMicronase (glyburide), 5mg, ii bid #120 112 3-4

Diabeta (glyburide), 5 mg, ii bid #120 101 3-4

Generic glyburide, 5 mg, ii bid #120 52 2

Glynase (micronized glyburide), 6 mg, i bid #60 86 2-3

Generic micronized glyburide, 6mg, i bid #60 58 2

Glucotrol (glipizide), 10 mg, ii bid #120 111 3-4

Generic glipizide, 10 mg, ii bid #120 46 2

Glucotrol XL (glipizide GITS), 10 mg/d, ii #60 50 2

Amaryl (glimepiride), 4 mg/d, ii #60 60 2-3

BiguanidesGlucophage (metformin), 500 mg, ii bid #120 102 3-4

Glucophage XR (metformin, extended release),500 mg/d, iiii #120

88 2-3

-Glucosidase inhibitorsPrecose, 100 mg, i tid #90 78 2-3

Glyset, 50 mg, i tid #90 73 2-3

ThiazolidinedionesAvandia, 4 mg, i bid #60 175 4

Actos, 45 mg/d, i #30 169 4

Nonsulfonylurea secretagoguesPrandin (repaglinide), 2 mg, ii tid #180 165 4

Starlix (nateglinide), 120 mg, i tid #90 103 3-4

Fixed combinationsGlucovance (glyburide/metformin), 5 mg/500 mg, i i b id #120 105 3-4

Insulins (1 vial, 100 U)Novolin or Humulin NPH 24 2

Lantus 44 2-3

Humalog 45 2-3

Humalog 75/25 46 2-3

*Cost is based on the mean of retail costs in 2001 at 3 New Haven County, Connecticut, national chain pharmaciesand is adapted from Inzucchis Yale Diabetes Center Facts and Guidelines 2001, available from Takeda Pharma-ceuticalsAmerica;bid indicates2 times daily;tid, 3 times daily;romannumerals, thenumber of tablets in each dose;and numbers following a pound sign, the number of tablets in a months supply.

Add approximately $5 to $15 monthly for insulin syringes and alcohol wipes for 1 to 2 injections daily.

ORAL ANTIHYPERGLYCEMIC THERAPY FOR TYPE 2 DIABETES

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receiving 20 mg of glipizide daily and1000 mg of metformin twice daily. Herhemoglobin A1c level is 8.5%. She is ada-mant about not starting insulin therapybecauseshe believesitsignalsthe last stepbefore dying from diabetes. What are

your options?Before embarking on a discussionabout therapy, thephysicianshouldfirstacknowledge and discuss the patientsconcerns about insulintherapy. Regard-ing drug treatment, will any of the re-maining available oral agents lower he-moglobin A1c levels in this patient?Because of its relative decreased effi-cacy in lowering hemoglobin A1c levels,acarbose wouldnot be a good therapeu-tic option.4,23 The meglitinidesare insu-lin secretagogues and therefore wouldnot be effective in a patient already re-

ceiving a sulfonylurea agent.4 The onlyfeasible additional oral agent to usewould be rosiglitazone or pioglitazone,both of which are approved for use incombinationwithmetformin or a sulfo-nylurea agent. A recent study found that43% of patients receiving triple oraltherapy (sulfonylurea, metformin, andtroglitazone) achieved a targethemoglo-binA1c value(8%)compared with only6% of patients taking the metformin-sulfonylurea combination.24

Regardless of approach, the main goal

for this relatively young patient re-mains optimal glycemic control with ahemoglobin A1c level below 6.5%. Insu-lin therapy is another reasonable op-tion and is less expensive than addinga TZD(Table).1,4,15 If rosiglitazone or pio-glitazone is added, the full effect of theTZD therapy may not be apparent for 4to 12 weeks, but a hemoglobin A1c levelshould be assessed at 3 months. Al-though this patient is resistant to start-ing insulin therapy, better glycemic con-trol through insulin therapy in the

UKPDS

6

and the Kumomato Trial

5

ledto a reduction in microvascular compli-cations. If thetarget hemoglobin A1c levelis not attained with the addition of aTZD, then insulin therapy isthebestop-tion. Many patients will eventually re-quire insulin therapy for adequate gly-cemic control. In the UKPDS, forexample, approximately 10% of pa-

tients initially assigned to receive a sul-

fonylurea agent hadto start receiving in-sulin therapy during the trial.6 Talkingto thepatient mayhelpherovercome herreluctance to start insulin therapy.25

Patient 4

A 72-year-old man with a history of hy-pertension, myocardial infarction, andNew York Heart Association class IIcongestive heart failure comes to theclinic for a routine follow-up visit. Athis last visit 6 months ago, his randomblood glucose level was 180 mg/dL

(10.0 mmol/L). He was not subse-quently tested for a fasting blood glu-cose level but was encouraged to loseweight and maintain a proper diet. Henow complains of having had poly-uria and constant thirst for the past 2months. Hisrandomblood glucose levelis tested in your office and is 260 mg/dL(14.4 mmol/L). His creatinine level was

1.7 mg/dL (129.63 mol/L) 6 months

ago. The patient weighs 83.3 kg. He isreceiving spironolactone, furosemidefor his hypertension, and an angioten-sin-converting enzyme inhibitor forcongestive heart failure. What are yourtherapeutic options?

Although determining a fasting glu-cose level and a baseline hemoglobinA1c level will be helpful, thepatient nowhas symptomatic diabetes and war-rants pharmacologic treatment. Al-though it appears that diet did not con-trol his blood glucose level, reinforcing

the importance of diet and lifestyleshouldstill be attempted.26 Evidence ex-ists that suggests consulting a nutri-tionist or diabetes educator improvesglycemic control.27,28

Regardingdrugtherapy, there aresev-eralimportant issues to consider for thisolder diabetic patient. First, what shouldthe target hemoglobin A1clevel be? No

Box. Resources for Primary Care Physicians and Patients

Guidelines

American Diabetes Association. Standards of medical care for patients with dia-betes mellitus. Diabetes Care. 2001;24(suppl 1):S33-S43. Web site available at: http://www.diabetes.org.

Institute for Clinical Systems Improvement (ICSI). Web site available at: http://www.icsi.org. Printed copies can be obtained from ICSI, 800934th Ave S, Suite1200, Bloomington, MN 55425.

American Associationof Clinical Endocrinologists. Web site available at: http://www.aace.com/clin/guides/diabetes.

All guidelines listed above are also available at: http://www.guideline.gov (Na-tional Guideline Clearinghouse).

Organizations

American Diabetes Association, 1701 N Beauregard St, Alexandria, VA 22311.Phone: (800) 842-6323. Information and educational brochures are available forpatients. The association has offices across the United States.

American Dietetic Association. Diabetes Care & Educational Practice Group,216 W Jackson Blvd, Suite 800, Chicago, IL 60606. Phone: (800) 366-1655. Website available at: http://www.eatright.org. Good source for information about nu-

tritional therapy in diabetes.Centers for Medicare and Medicaid Services (CMS).Web site available at: http://www.hcfa.gov. The CMS concentrates on diabetes improvement efforts for Medi-care patients. Quality of care programs for the CMS are managedacrossthe UnitedStates by peer-review organizations, all of which have educational material andongoing projects designed to help the primary care provider care for Medicare pa-tients with type 2 diabetes.

Centers for Disease Control and Prevention. Web site available at: http://www.cdc.gov/nccdphp/ddt/ddthome.htm.

National Diabetes Education Program. Web site available at: http://www.ndep.nih.gov.


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outcome data for elderly diabetics ex-ist.However, several studies havefoundthat lower hemoglobin A1c levels are as-sociated with lower costs for patients inallage groups, especially those with car-diovascular disease,29-31 and better con-

trol of diabetes improves the quality oflife for older diabetic patients.32-34 Sec-ond, what aretheappropriate oral agentsforthis patient?Givenhisunderlyingcar-diovascular disease,metformin would bean idealagent, but hishistory of conges-tive heart failure andelevated serum cre-atinine levels are absolute contraindica-tions. Remaining agents to lower bloodglucose levelsarea sulfonylurea, a rapid-acting secretagogue, or a TZD. A majorconcernabout startingsulfonylurea treat-ment in older patients is hypoglycemiathat canbe profound andprolongedbe-

cause of the long half-lifeof the second-generation agents. If a long-acting sul-fonylurea is chosen, the lowest possiblestarting dose (eg, 2.5 mg of glipizide)should be initiated and the patient fullyeducated about hypoglycemic reac-tionsand treatment.4,34 Hismildrenal in-sufficiency also places him at increasedrisk for hypoglycemia. If hypoglycemiais a major concern related to other un-derlying health issues (eg, the patient isat significantrisk for falls or lives alone),a rapid-acting secretagogue taken with

meals may be saferbecause of its shorterhalf-life.4 The disadvantage is the fre-quent dosing schedule required withthese agents.Acarbose could be tried, butthe magnitude of glucose-level reduc-tion is less than that with other agents,the adverse gastrointestinal effects maybedifficult forthisolder patientwith con-gestive heart failure, and again the drugmust be taken several times a day.4 ATZD may be prescribed but should beused only cautiously in this patient withclass II congestive heart failure. Be-

cause of their propensity to expandplasma volume, TZDs are clearly con-traindicatedfor patientswithclass IIIandIV congestive heartfailure.Therefore, forthis patient an oral agent may not bethebest treatment and in fact may increasethe risk of adverse events because of hismultiple comorbidities.Despite the milddegree of hyperglycemia, insulin maybe

the best choice as an initial agent in thispatient. It has several advantages: flex-ibility with regardto dose anddosingad-justmentsand multiplepreparations thatallow physicians to tailor a treatmentregimen that best meets the needs and

goals of the patient.CONCLUSIONS

Decisions about treatment with oralagents require a number of importantconsiderations, including drug efficacyand adverse effects, strength of evi-dence, patient preferences, cost, and ef-fective use of nonpharmacologic thera-pies such as diet and exercise. Patientinvolvement in self-managementis criti-cal to successful glycemic control, andall therapeutic choices must involve acomprehensive dialogue and negotia-

tion between patient andphysician. Or-ganizations to obtain resources for car-ing for diabetic patients are provided inthe Box. For themajority of patients, theoverarching goal is to lower the hemo-globinA1c level to as close to normal andas safely as possible.

REFERENCES

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Managed Care Q . 1999;7:56-66.14. Expert Committee on the Diagnosis and Classi-ficationof DiabetesMellitus.Report ofthe ExpertCom-mittee on the Diagnosis and Classification of Diabe-tes Mellitus.Diabetes Care. 2001;24(suppl):S5-S20.15. DeFronzo RA. Pharmacologic therapy for type 2diabetes.Ann Intern Med. 1999;131:281-303.16. Yki-Jarvinen H. Acute and chronic effects of hy-perglycaemia on glucose metabolism. Diabet Med.1997;14(suppl 3):S32-S37.17. Rossetti L, Giaccari A, DeFronzoRA. Glucose tox-icity.Diabetes Care. 1990;13:610-630.18. Kayashima T, Yamaguchi K, Konno Y, Nani-matsu H, Aragaki S, Shichiri M. Effects of early intro-duction of intensiveinsulin therapy on the clinical coursein non-obeseNIDDM patients. Diabetes Res ClinPract.1995;28:119-125.19. Stenman S, Melander A, Groop PH, Groop LC.What is thebenefitof increasing thesulfonylurea dose?

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Obes Relat Metab Disord. 2000;24(suppl):S12-S20.26. Maazuca SA, Moorman NH, Wheeler ML, et al.The diabetes education study. Diabetes Care. 1986;9:1-10.27. PeyrotM, Rubin RR.Modelingthe effects of dia-betes education on glycemic control. Diabetes Educ.1994;20:143-148.28. Franz MJ, Monk A, Barry B, et al. Effectivenessof medical nutrition therapy provided by dietitians inthe management of non-insulin diabetes mellitus.J Am Diet Assoc. 1995;95:1009-1017.29. Gilmer TP,OConnor PJ,Manning WG, Rush WA.Thecost to health plans of poor glycemiccontrol. Dia-betes Care. 1997;20:1847-1853.30. Wagner EH, Sandhu N, Newton KM, et al. Ef-fects of glycemic control on healthcare costs and uti-lization.JAMA. 2001;285:182-189.31. Testa MA, Simonson DC. Health economic ben-efitsand quality of life during improved glycemic con-

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