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Scientific Review and Clinical Applications | Clinician's Corner

Oral Antihyperglycemic Therapy for Type 2 Diabetes:  Clinical Applications FREE

Eric S. Holmboe, MD
[+] Author Affiliations

Author Affiliations: Department of Medicine, Yale University School of Medicine, New Haven, Conn, and Qualidigm (Connecticut Peer Review Organization), Middletown, Conn.


Scientific Review: Clinical Applications Section Editor: Wendy Levinson, MD, Contributing Editor.


JAMA. 2002;287(3):373-376. doi:10.1001/jama.287.3.373.
Text Size: A A A
Published online

Oral agents are the mainstay of pharmacologic treatment for type 2 diabetes, 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 illustrates 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 pharmacologic treatment regimen for individual patients. Physicians should also recognize that type 2 diabetes is a multisystem disorder that requires multidisciplinary care, including education and ongoing counseling for effective patient self-management of the disease. Finally, patient preferences are a vital component of informed decision making for pharmacologic treatment of diabetes.

Several clinical practice guidelines for type 2 diabetes are now available. All advocate a hemoglobin A1c level of less than 7%, and at least 1 organization has adopted a target of 6.5%.13 Despite the number of agents to choose from, Inzucchi4 notes that the only ones evaluated in randomized controlled trials with regard to clinically important outcomes are insulin, metformin, and the sulfonylureas.57 Two important clinical trials have demonstrated that more aggressive glycemic control in type 2 diabetic patients reduced microvascular complications. Questions remain about the effect of all the oral agents and insulin on reducing macrovascular complications.6,7

Primary care physicians provide much of the care for patients with type 2 diabetes.8 Although this article discusses primarily drug treatment, education on self-management, nutrition, and exercise is essential to help patients achieve glycemic control. Self-management training is effective in type 2 diabetes and should be recommended for all patients.9

Recommendations for the use of oral agents for each clinical situation are based on the best evidence available and accepted clinical guidelines. Informed decision making about therapy, however, must involve the patient and include a clear explanation of therapeutic-choice rationale, an assessment of his or her understanding, preferences, and barriers to care, and a discussion of the risks and benefits of each therapy.1012 An active patient-physician partnership facilitates treatment of this complex, multifaceted disease.13Table 1 provides a brief summary of the available oral agents and their relative costs. The BOX provides additional resources.

Guidelines

American Diabetes Association. Standards of medical care for patients with diabetes 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, 8009 34th Ave S, Suite 1200, Bloomington, MN 55425.

American Association of Clinical Endocrinologists. Web site available at: http://www.aace.com/clin/guidelines/diabetes_2000.pdf.

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

Organizations

American Diabetes Association, 1701 N Beauregard St, Alexandria, VA 22311. Phone: (800) 842-6323. Information and educational brochures are available for patients. 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. Web site available at: http://www.eatright.org. Good source for information about nutritional 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 Medicare patients. Quality of care programs for the CMS are managed across the United States by peer-review organizations, all of which have educational material and ongoing projects designed to help the primary care provider care for Medicare patients 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.

Table Graphic Jump LocationTable. Summary of Available Oral Agents and Costs
Patient 1

A moderately obese 49-year-old woman (body mass index, 29 kg/m2) complains of increased thirst, polyuria, and fatigue. Her family history is pertinent for diabetes in her mother and an older brother. A random plasma glucose serum test shows a level of 480 mg/dL (26.6 mmol/L). Her serum electrolyte and anion gap levels are normal.

At this visit, the patient meets American Diabetes Association criteria for having diabetes.14 Given her symptoms and high blood glucose level, the question is whether to start an oral agent or insulin therapy. Guidelines are not prescriptive regarding the choice of the initial agent.13,15 One consideration in deciding whether to initiate insulin therapy or an oral agent is glucose toxicity.16,17 High levels of glucose are toxic to pancreatic beta cells, impairing insulin secretion in the face of relative insulin deficiency. Although not studied in a randomized controlled trial, initial treatment with insulin has been suggested to allow more rapid control of plasma glucose, recovery of beta cell function, and better subsequent response to oral agents.17,18 Additionally, insulin dosage can be adjusted quickly, facilitating more rapid control of hyperglycemia and associated symptoms.1517 Once a stable target glucose level has been achieved, the patient may be able to begin receiving an oral agent. However, insulin therapy does require immediate patient education on injection techniques, use of a home glucose meter, and identification and treatment of hypoglycemic reactions. If available locally, certified diabetes nurse educators can be particularly helpful in this process. Deciding whether to start insulin therapy also requires assessment of the patient's understanding and wishes.10

When the patient is switched to an oral agent or an oral agent is used as initial therapy, guidelines suggest that either a sulfonylurea or metformin agent is appropriate. However, given that this patient is moderately obese, metformin would be the recommended initial agent.4,7,15 It tends to promote weight loss and is equally effective in lowering hemoglobin A1c compared with sulfonylurea and thiazolidinedione (TZD) agents.4 Given her degree of hyperglycemia, this patient may eventually need 2 oral agents to achieve adequate control.

Patient 2

A 57-year-old man with type 2 diabetes treated for 9 years is currently receiving glyburide at a dosage of 10 mg/d. His hemoglobin A1c level a week ago was 8.5%. You suggest adding metformin, but the patient wonders why he cannot increase his glyburide dose because his hemoglobin A1c level was always controlled well by this medication and he has been told that 10 mg is only half the maximal dose.

Although daily doses of up to 20 mg of glyburide and 40 mg of glipizide are approved and can be used, data have clearly shown that, above 10 to 12 mg/d, the additional gain in glycemic control is marginal.19 In addition, the failure rate of sulfonylurea therapy is 5% yearly, and this patient has been receiving glyburide therapy for 9 years.4,6,7,15 Thus, increasing his sulfonylurea dose is highly unlikely to help him reach the target level of hemoglobin A1c. Likewise, switching to another single oral agent such as metformin, TZD, or meglitinide or another nonsulfonylurea secretagogue is unlikely to lead to adequate glycemic control, given the duration of his diabetes. Therefore, addition of another agent should be considered. The United Kingdom Prospective Diabetes Study (UKPDS) and other trials found that adding metformin to sulfonylurea therapy lowered hemoglobin A1c levels.4,7,20,21 The UKPDS, however, found an unexpected increase in diabetes-related mortality with this combination, although when all patients who were actually treated with metformin according to protocol analysis were investigated, a 19% reduction in diabetes-related end points was observed.7,22 Another option is to add a TZD; this combination has also shown substantial reductions in hemoglobin A1c levels.4 Although no definite evidence exists of severe hepatotoxicity with rosiglitazone and pioglitazone, frequent monitoring of liver enzymes is still required because of troglitazone's association with hepatotoxicity.

Patient 3

A 55-year-old woman was diagnosed with diabetes almost 10 years ago and is receiving 20 mg of glipizide daily and 1000 mg of metformin twice daily. Her hemoglobin A1c level is 8.5%. She is adamant about not starting insulin therapy because she believes it signals the last step before dying from diabetes. What are your options?

Before embarking on a discussion about therapy, the physician should first acknowledge and discuss the patient's concerns about insulin therapy. Regarding drug treatment, will any of the remaining available oral agents lower hemoglobin A1c levels in this patient? Because of its relative decreased efficacy in lowering hemoglobin A1c levels, acarbose would not be a good therapeutic option.4,23 The meglitinides are insulin secretagogues and therefore would not be effective in a patient already receiving a sulfonylurea agent.4 The only feasible additional oral agent to use would be rosiglitazone or pioglitazone, both of which are approved for use in combination with metformin or a sulfonylurea agent. A recent study found that 43% of patients receiving triple oral therapy (sulfonylurea, metformin, and troglitazone) achieved a target hemoglobin A1c value (<8%) compared with only 6% of patients taking the metformin-sulfonylurea combination.24

Regardless of approach, the main goal for this relatively young patient remains optimal glycemic control with a hemoglobin A1c level below 6.5%. Insulin therapy is another reasonable option and is less expensive than adding a TZD (Table 1).1,4,15 If rosiglitazone or pioglitazone is added, the full effect of the TZD therapy may not be apparent for 4 to 12 weeks, but a hemoglobin A1c level should be assessed at 3 months. Although this patient is resistant to starting insulin therapy, better glycemic control through insulin therapy in the UKPDS6 and the Kumomato Trial5 led to a reduction in microvascular complications. If the target hemoglobin A1c level is not attained with the addition of a TZD, then insulin therapy is the best option. Many patients will eventually require insulin therapy for adequate glycemic control. In the UKPDS, for example, approximately 10% of patients initially assigned to receive a sulfonylurea agent had to start receiving insulin therapy during the trial.6 Talking to the patient may help her overcome her reluctance to start insulin therapy.25

Patient 4

A 72-year-old man with a history of hypertension, myocardial infarction, and New York Heart Association class II congestive heart failure comes to the clinic for a routine follow-up visit. At his last visit 6 months ago, his random blood glucose level was 180 mg/dL (10.0 mmol/L). He was not subsequently tested for a fasting blood glucose level but was encouraged to lose weight and maintain a proper diet. He now complains of having had polyuria and constant thirst for the past 2 months. His random blood glucose level is tested in your office and is 260 mg/dL (14.4 mmol/L). His creatinine level was 1.7 mg/dL (129.63 µmol/L) 6 months ago. The patient weighs 83.3 kg. He is receiving spironolactone, furosemide for his hypertension, and an angiotensin-converting enzyme inhibitor for congestive heart failure. What are your therapeutic options?

Although determining a fasting glucose level and a baseline hemoglobin A1c level will be helpful, the patient now has symptomatic diabetes and warrants pharmacologic treatment. Although it appears that diet did not control his blood glucose level, reinforcing the importance of diet and lifestyle should still be attempted.26 Evidence exists that suggests consulting a nutritionist or diabetes educator improves glycemic control.27,28

Regarding drug therapy, there are several important issues to consider for this older diabetic patient. First, what should the target hemoglobin A1c level be? No outcome data for elderly diabetics exist. However, several studies have found that lower hemoglobin A1c levels are associated with lower costs for patients in all age groups, especially those with cardiovascular disease,2931 and better control of diabetes improves the quality of life for older diabetic patients.3234 Second, what are the appropriate oral agents for this patient? Given his underlying cardiovascular disease, metformin would be an ideal agent, but his history of congestive heart failure and elevated serum creatinine levels are absolute contraindications. Remaining agents to lower blood glucose levels are a sulfonylurea, a rapid-acting secretagogue, or a TZD. A major concern about starting sulfonylurea treatment in older patients is hypoglycemia that can be profound and prolonged because of the long half-life of the second-generation agents. If a long-acting sulfonylurea is chosen, the lowest possible starting dose (eg, 2.5 mg of glipizide) should be initiated and the patient fully educated about hypoglycemic reactions and treatment.4,34 His mild renal insufficiency also places him at increased risk for hypoglycemia. If hypoglycemia is a major concern related to other underlying health issues (eg, the patient is at significant risk for falls or lives alone), a rapid-acting secretagogue taken with meals may be safer because of its shorter half-life.4 The disadvantage is the frequent dosing schedule required with these agents. Acarbose could be tried, but the magnitude of glucose-level reduction is less than that with other agents, the adverse gastrointestinal effects may be difficult for this older patient with congestive heart failure, and again the drug must be taken several times a day.4 A TZD may be prescribed but should be used only cautiously in this patient with class II congestive heart failure. Because of their propensity to expand plasma volume, TZDs are clearly contraindicated for patients with class III and IV congestive heart failure. Therefore, for this patient an oral agent may not be the best treatment and in fact may increase the risk of adverse events because of his multiple comorbidities. Despite the mild degree of hyperglycemia, insulin may be the best choice as an initial agent in this patient. It has several advantages: flexibility with regard to dose and dosing adjustments and multiple preparations that allow physicians to tailor a treatment regimen that best meets the needs and goals of the patient.

Decisions about treatment with oral agents require a number of important considerations, including drug efficacy and adverse effects, strength of evidence, patient preferences, cost, and effective use of nonpharmacologic therapies such as diet and exercise. Patient involvement in self-management is critical to successful glycemic control, and all therapeutic choices must involve a comprehensive dialogue and negotiation between patient and physician. Organizations to obtain resources for caring for diabetic patients are provided in the BOX. For the majority of patients, the overarching goal is to lower the hemoglobin A1c level to as close to normal and as safely as possible.

American Diabetes Association.  Standards of medical care for patients with diabetes mellitus.  Diabetes Care.2001;24(suppl 1):S33-S43.
American Association of Clinical Endocrinologists.  The AACE medical guidelines for the management of diabetes mellitus.  Endocr Pract.2000;6:1-5.
 Management of Type 2 Diabetes Mellitus. Bloomington, Minn: Institute for Clinical Systems Improvement; 2000. ICSI guideline GOH07.
Inzucchi S. Oral antihyperglycemic therapy for type 2 diabetes: scientific review.  JAMA.2002;287:360-372.
Ohkubo Y, Kishikawa H, Araki E.  et al.  Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus.  Diabetes Res Clin Pract.1995;28:103-117.
UK Prospective Diabetes Study Group.  Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).  Lancet.1998;352:837-853.
UK Prospective Diabetes Study Group.  Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).  Lancet.1998;352:854-865.
Griffin S, Kinmonth AL. Systems for routine surveillance for people with diabetes mellitus [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2000;issue 4.
Norris SL, Engelgau MM, Venkat Narayan KMV. Effectiveness of self-management training in type 2 diabetes.  Diabetes Care.2001;24:561-587.
Braddock CH, Edwards KA, Hasenberg NM.  et al.  Informed decision making in outpatient practice.  JAMA.1999;282:2313-2320.
Guyatt GH, Sackett DL, Cook DJ.for the Evidence-Based Medicine Working Group.  Users' guides to the medical literature, II: how to use an article about therapy or prevention, B: what were the results and will they help me in caring for my patients?  JAMA.1994;271:59-63.
Deber RB, Kraetschmer N, Irvine J. What role do patients wish to play in treatment decision making?  Arch Intern Med.1996;156:1414-1420.
Wagner EH, Davis C, Schaefer J.  et al.  A survey of leading chronic disease management programs: are they consistent with the literature?  Manag Care Q.1999;7:56-66.
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Diabetes Care.2001;24(suppl):S5-S20.
DeFronzo RA. Pharmacologic therapy for type 2 diabetes.  Ann Intern Med.1999;131:281-303.
Yki-Jarvinen H. Acute and chronic effects of hyperglycaemia on glucose metabolism.  Diabet Med.1997;14(suppl 3):S32-S37.
Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity.  Diabetes Care.1990;13:610-630.
Kayashima T, Yamaguchi K, Konno Y, Nanimatsu H, Aragaki S, Shichiri M. Effects of early introduction of intensive insulin therapy on the clinical course in non-obese NIDDM patients.  Diabetes Res Clin Pract.1995;28:119-125.
Stenman S, Melander A, Groop PH, Groop LC. What is the benefit of increasing the sulfonylurea dose?  Ann Intern Med.1993;118:169-172.
Hermann LS. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations.  Diabetes Care.1994;17:1100-1109.
Erle G, Lovise S, Stocchiero C.  et al.  A comparison of preconstituted, fixed combinations of low-dose glyburide plus metformin versus high-dose glyburide alone in the treatment of type 2 diabetic patients.  Acta Diabetol.1999;36:61-65.
Palumbo PJ. Editorial.  Endocr Pract.1998;4:428-429.
Scheen AJ. Clinical efficacy of acarbose in diabetes mellitus.  Diabetes Metab.1998;24:311-320.
Yale J-F, Valiquett TR, Ghazzi MN.  et al.  The effect of a thiazolidinedione drug, troglitazone, on glycemia in patients with type 2 diabetes mellitus poorly controlled with sulfonylurea and metformin.  Ann Intern Med.2001;134:737-745.
Snoek FJ. Barriers to good glycemic control.  Int J Obes Relat Metab Disord.2000;24(suppl):S12-S20.
Maazuca SA, Moorman NH, Wheeler ML.  et al.  The diabetes education study.  Diabetes Care.1986;9:1-10.
Peyrot M, Rubin RR. Modeling the effects of diabetes education on glycemic control.  Diabetes Educ.1994;20:143-148.
Franz MJ, Monk A, Barry B.  et al.  Effectiveness of medical nutrition therapy provided by dietitians in the management of non-insulin diabetes mellitus.  J Am Diet Assoc.1995;95:1009-1017.
Gilmer TP, O'Connor PJ, Manning WG, Rush WA. The cost to health plans of poor glycemic control.  Diabetes Care.1997;20:1847-1853.
Wagner EH, Sandhu N, Newton KM.  et al.  Effects of glycemic control on healthcare costs and utilization.  JAMA.2001;285:182-189.
Testa MA, Simonson DC. Health economic benefits and quality of life during improved glycemic control in patients with type 2 diabetes mellitus.  JAMA.1998;280:1490-1496.
Wandell PE, Tovi J. The quality of life of elderly diabetics.  J Diabetes Complications.2000;14:25-30.
Goddijn PP, Bilo HJ, Feskens EJ.  et al.  Longitudinal study on glycemic control and quality of life in patients with type 2 diabetes mellitus referred for intensive control.  Diabet Med.1999;16:23-30.
Jennings PE. Oral antihyperglycaemics: considerations in older patients with non-insulin-dependent diabetes mellitus.  Drugs Aging.1997;10:323-331.

Figures

Tables

Table Graphic Jump LocationTable. Summary of Available Oral Agents and Costs

References

American Diabetes Association.  Standards of medical care for patients with diabetes mellitus.  Diabetes Care.2001;24(suppl 1):S33-S43.
American Association of Clinical Endocrinologists.  The AACE medical guidelines for the management of diabetes mellitus.  Endocr Pract.2000;6:1-5.
 Management of Type 2 Diabetes Mellitus. Bloomington, Minn: Institute for Clinical Systems Improvement; 2000. ICSI guideline GOH07.
Inzucchi S. Oral antihyperglycemic therapy for type 2 diabetes: scientific review.  JAMA.2002;287:360-372.
Ohkubo Y, Kishikawa H, Araki E.  et al.  Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus.  Diabetes Res Clin Pract.1995;28:103-117.
UK Prospective Diabetes Study Group.  Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).  Lancet.1998;352:837-853.
UK Prospective Diabetes Study Group.  Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).  Lancet.1998;352:854-865.
Griffin S, Kinmonth AL. Systems for routine surveillance for people with diabetes mellitus [Cochrane Review on CD-ROM]. Oxford, England: Cochrane Library, Update Software; 2000;issue 4.
Norris SL, Engelgau MM, Venkat Narayan KMV. Effectiveness of self-management training in type 2 diabetes.  Diabetes Care.2001;24:561-587.
Braddock CH, Edwards KA, Hasenberg NM.  et al.  Informed decision making in outpatient practice.  JAMA.1999;282:2313-2320.
Guyatt GH, Sackett DL, Cook DJ.for the Evidence-Based Medicine Working Group.  Users' guides to the medical literature, II: how to use an article about therapy or prevention, B: what were the results and will they help me in caring for my patients?  JAMA.1994;271:59-63.
Deber RB, Kraetschmer N, Irvine J. What role do patients wish to play in treatment decision making?  Arch Intern Med.1996;156:1414-1420.
Wagner EH, Davis C, Schaefer J.  et al.  A survey of leading chronic disease management programs: are they consistent with the literature?  Manag Care Q.1999;7:56-66.
Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Diabetes Care.2001;24(suppl):S5-S20.
DeFronzo RA. Pharmacologic therapy for type 2 diabetes.  Ann Intern Med.1999;131:281-303.
Yki-Jarvinen H. Acute and chronic effects of hyperglycaemia on glucose metabolism.  Diabet Med.1997;14(suppl 3):S32-S37.
Rossetti L, Giaccari A, DeFronzo RA. Glucose toxicity.  Diabetes Care.1990;13:610-630.
Kayashima T, Yamaguchi K, Konno Y, Nanimatsu H, Aragaki S, Shichiri M. Effects of early introduction of intensive insulin therapy on the clinical course in non-obese NIDDM patients.  Diabetes Res Clin Pract.1995;28:119-125.
Stenman S, Melander A, Groop PH, Groop LC. What is the benefit of increasing the sulfonylurea dose?  Ann Intern Med.1993;118:169-172.
Hermann LS. Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations.  Diabetes Care.1994;17:1100-1109.
Erle G, Lovise S, Stocchiero C.  et al.  A comparison of preconstituted, fixed combinations of low-dose glyburide plus metformin versus high-dose glyburide alone in the treatment of type 2 diabetic patients.  Acta Diabetol.1999;36:61-65.
Palumbo PJ. Editorial.  Endocr Pract.1998;4:428-429.
Scheen AJ. Clinical efficacy of acarbose in diabetes mellitus.  Diabetes Metab.1998;24:311-320.
Yale J-F, Valiquett TR, Ghazzi MN.  et al.  The effect of a thiazolidinedione drug, troglitazone, on glycemia in patients with type 2 diabetes mellitus poorly controlled with sulfonylurea and metformin.  Ann Intern Med.2001;134:737-745.
Snoek FJ. Barriers to good glycemic control.  Int J Obes Relat Metab Disord.2000;24(suppl):S12-S20.
Maazuca SA, Moorman NH, Wheeler ML.  et al.  The diabetes education study.  Diabetes Care.1986;9:1-10.
Peyrot M, Rubin RR. Modeling the effects of diabetes education on glycemic control.  Diabetes Educ.1994;20:143-148.
Franz MJ, Monk A, Barry B.  et al.  Effectiveness of medical nutrition therapy provided by dietitians in the management of non-insulin diabetes mellitus.  J Am Diet Assoc.1995;95:1009-1017.
Gilmer TP, O'Connor PJ, Manning WG, Rush WA. The cost to health plans of poor glycemic control.  Diabetes Care.1997;20:1847-1853.
Wagner EH, Sandhu N, Newton KM.  et al.  Effects of glycemic control on healthcare costs and utilization.  JAMA.2001;285:182-189.
Testa MA, Simonson DC. Health economic benefits and quality of life during improved glycemic control in patients with type 2 diabetes mellitus.  JAMA.1998;280:1490-1496.
Wandell PE, Tovi J. The quality of life of elderly diabetics.  J Diabetes Complications.2000;14:25-30.
Goddijn PP, Bilo HJ, Feskens EJ.  et al.  Longitudinal study on glycemic control and quality of life in patients with type 2 diabetes mellitus referred for intensive control.  Diabet Med.1999;16:23-30.
Jennings PE. Oral antihyperglycaemics: considerations in older patients with non-insulin-dependent diabetes mellitus.  Drugs Aging.1997;10:323-331.

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