`MELLITUS: AN UPDATE OF CURRENT
`ORAL ANTIDIABETIC THERAPY
`Darwin L. Brown, MD, and David Brillon, MD
`New York, NY
`
`This article reviewed the relevant literature including published clinical trials and reviews on
`currently available oral hypoglycemic agents. Results showed that the benefits of glycemic con-
`trol have been established through multiple clinical trials. Long-term control of blood glucose
`levels in type 1 and type 2 diabetic patients will decrease the incidence and prolong the time
`until progression of diabetic retinopathy, nephropathy, and neuropathy. Our increased under-
`standing of the pathophysiology behind type 2 diabetes has led to the development of many
`new agents that are aimed at treating the underlying insulin resistance and relative insulinope-
`nia. The sulfonylureas as a group have been used for many years and act by stimulating insulin
`secretion. They are useful alone or as combination therapy with insulin or another oral hypo-
`glycemic agent. The biguanides act by decreasing hepatic glucose production and by increas-
`ing peripheral insulin sensitivity. The alpha-glucosidase inhibitors act nonsystemically by block-
`ing the metabolism of digested polysaccharides and therefore lowering the amount of carbo-
`hydrate absorbed in a meal. Benzoic acid derivatives act in a manner similar to that of sul-
`fonylureas by enhancing pancreatic insulin production. They offer a shorter duration of action,
`lowering the risk of hypoglycemia. The thiazolidinediones increase peripheral insulin sensitivi-
`ty and are effective as both monotherapy and combination therapy. Oral hypoglycemic agents,
`when properly administered, are very effective in controlling type 2 diabetes and preventing
`long-term complications. (J Natl Med Assoc. 1999;91 :389-395.)
`
`Key words: diabetes mellitus
`* hypoglycemic agents
`
`Diabetes mellitus is a disorder of abnormal glu-
`cose homeostasis, often resulting in acute and chron-
`ic complications of hyperglycemia. Obesity, physical
`inactivity, and a genetic predisposition are risk fac-
`tors for the development of glucose intolerance and
`
`From the Division of Diabetes, Endocrinology and Metabolism,
`Weill Medical College of Cornell University, New York, NY.
`Requests for reprints should be addressed to Dr Darwin l. Brown,
`Diabetes and Endocrinology Associates, PC, 2665 N Decatur Rd,
`Ste 520, Decatur, GA 30033 .
`
`type 2 diabetes in all ethnic groups. It is unclear why
`these risk factors are more prevalent in the black
`community and how these factors lead to a dispro-
`portionately higher prevalence of the disease and a
`higher incidence of its complications in African
`Americans. It is estimated that 5% of Americans
`have diabetes and that 95% of these people have
`type 2 diabetes. At least three million African
`Americans have diabetes mellitus, with the disease
`affecting 8.5% of black men and 12% of black
`women."3 This can be compared with the 2.5%-8%
`of whites who suffer from the disease. In addition,
`African Americans historically have had a dispro-
`portionately higher prevalence of diabetic complica-
`tions such as nephropathy and retinopathy.2 Today
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`ORAL ANTIDIABETIC THERAPY UPDATE
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`Table 1. Type 2 Diabetes: A Summary of Oral Therapy
`
`Toxicity/Side Effects
`Hypoglycemia
`Glyburide must be used
`with caution in the elderly
`or renally impaired patient;
`glipizide is safer in the
`elderly patient
`
`Risk of lactic acidosis; contra-
`indicated in patients with
`renal, hepatic or cardiores-
`piratory compromise;
`gastrointestinal irritation
`
`Effects
`Increases insulin
`secretion; reduces
`HgbA1C 1%-2%
`as monotherapy;
`glimepiride may
`have peripheral
`insulin-sensitizing
`effects
`Decreases hepatic
`glucose output; can
`cause mild weight
`loss & reduce trigly-
`cerides; reduces
`HgbA1C 1.5%-2%
`as monotherapy
`Increases peripheral
`Hepatotoxicity LFTs must be
`insulin sensitivity;
`monitored during therapy;
`reduces HgbA1C
`peripheral edema, weight
`.9% alone and 1.5% gain
`on average in
`combination with
`insulin; may need
`3-4 weeks prior to
`seeing effects
`Increases insulin
`secretion with meals
`
`Hypoglycemia if tablet is
`not taken with meals
`
`Combination Therapy
`Biguanide or
`thiazolidinediones
`
`Thiazolidinediones,
`sulfonylurea, benzoic
`acid derivative
`
`Originally approved for
`combination therapy
`with insulin
`biguanide, sulfonylurea,
`nylurea, or benzoic
`acid derivative
`
`Biguanide or
`thiazolidinediones
`
`Class of Drug
`Sulfonylurea
`
`Chemical
`Structure
`Sulfonic acid-urea
`nucleus
`
`Biguanide
`
`Structurally distinct
`from sulfonylureas;
`dimethylimidodicar-
`bonic compound
`
`Thiazoli-
`dinediones
`
`Thiazolidinedione-a
`tocopherol
`compound
`
`Benzoic acid
`derivatives
`
`Alpha-gluco-
`sidase inhib-
`itors
`
`Benzoic acid
`compound; some
`sequence homology
`to the nonsulfonyl-
`urea moiety of
`glyburide
`Oligosaccharide
`inhibitor of intest-
`inal hydrolases
`
`Blocks intestinal
`carbohydrate
`absorption
`
`Gastrointestinal irritation
`and flatus
`
`Biguanide or
`thiazolidinediones
`
`the country is in the midst of a nationwide initiative
`to improve the care of individuals with diabetes and
`to reduce the severity of complications among all
`Americans, especially African Americans.
`The pathophysiology of type 2 diabetes is multi-
`factorial in nature. Insulin resistance and impaired
`insulin secretion both lead to the development of
`the disease. This is in contrast to type 1 diabetes in
`which the disease is caused by an autoimmune-
`mediated destruction of pancreatic islets and resul-
`
`tant absolute insulin deficiency. Normally, in the
`fasting state, insulin is essential in regulating hepatic
`glucose output. In the fed state, insulin secretion in
`response to an ingested meal increases cellular glu-
`cose uptake and maintains normal circulating glu-
`cose concentrations. When insulin sensitivity is
`impaired, hyperinsulinemia and glucose intolerance
`develop. This leads to increased basal and postpran-
`dial glucose concentrations. Over time, the beta cell
`gradually loses its ability to secrete adequate
`
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`amounts of insulin and increased glucose concentra-
`tions further retard insulin secretion. Patients with
`type 2 diabetes have defects in both insulin sensitiv-
`ity and insulin secretion. However, the relative con-
`tributions of these factors may vary in different
`patients. Identifying the major factors that have led
`to diabetes can guide the physician in developing a
`treatment plan.
`Therapies are now available to enhance insulin
`secretion, decrease hepatic glucose output, and
`increase peripheral insulin sensitivity. Once the
`underlying factors have been identified that led to
`the development of diabetes in an individual, the
`physician can choose the most appropriate medica-
`tion(s) for the patient. Several studies have unequiv-
`ocally demonstrated that intensive therapy of type 1
`and type 2 diabetes results in a decreased incidence
`of complications and improved overall morbidity.4-6
`This article summarizes the indications, efficacy,
`and potential dangers of the oral agents currently
`available for treatment of type 2 diabetes. With
`effective use of these medications, the control of
`type 2 diabetes in African Americans will improve
`and the incidence of its complications will decrease.
`
`SULFONYLUREAS
`These agents are derivatives of sulfonic acid and
`urea, and produce their effects by binding to receptors
`on the surface of pancreatic beta cells. The binding of
`sulfonylureas results in depolarization of the cell mem-
`brane, the influx of calcium ions, and subsequent
`release of insulin. The sulfonylureas were developed
`in 1954 and continue to be the most widely prescribed
`oral agents for the treatment of type 2 diabetes. Early
`evidence of associated increased cardiovascular mor-
`bidity has not been reproduced, and today sulfony-
`lureas are considered relatively safe agents that have
`proven effective over long-term use.4'7
`First-Generation
`Sulfonylureas consists of two groups or genera-
`tions of agents. The first-generation agents are now
`less commonly used because second-generation
`agents are as effective and have fewer side effects.
`Two first-generation agents, chlorpropamide and
`tolbutamide are still popular with some physicians.
`This group also contains tolazamide and acetohexa-
`mide; both are rarely used today.
`Chlorpropamide. Chlorpropamide is adminis-
`tered once daily in a 100 mg or 250 mg tablet. Its
`half-life is extremely long, with effects lasting up to
`
`ORAL ANTIDIABETIC THERAPY UPDATE
`
`>48 hours. The principal disadvantage of this agent
`is excreted almost entirely renally.
`is that it
`Therefore, the risk of hypoglycemia makes this drug
`relatively contraindicated in the elderly and abso-
`lutely contraindicated in those with renal insuffi-
`ciency. Chlorpropamide also enhances the effects of
`vasopressin, at times resulting in the syndrome of
`inappropriate antidiuretic hormone (SIADH). With
`the introduction of more potent agents that have a
`much shorter half-life and fewer side effects, today
`there is little reason to use chlorpropamide.
`Tolbutamide. Tolbutamide has a much shorter
`duration of action (6-10 hours) and is metabolized
`primarily by the liver. It is a safer agent than chlor-
`propamide; however, it is relatively weak in its
`antidiabetic activity.
`Second-Generation
`Second-generation sulfonylureas are the most
`commonly prescribed agents for treating type 2 dia-
`betes. As a group, they are at least 100 times more
`potent than tolbutamide. They include glyburide,
`glipizide, and the newest agent, glimepiride. Glybur-
`ide and glipizide, when used as monotherapy, have
`proven effective in lowering HgbAIC 1% to 2% in
`most studies.
`Glyburide. Glyburide is metabolized in the liver
`to metabolites with reduced hypoglycemic activity.
`These metabolites are then excreted renally.
`Therefore, in the elderly and patients with compro-
`mised renal function, glyburide is relatively con-
`traindicated because of the risk of hypoglycemia.
`Even in normal subjects it is not unusual to see per-
`sistence of glyburide's effects for up to 24 hours. In
`the United Kingdom Prospective Diabetes Study
`(UKPDS), a multicenter trial of >5000 patients with
`type 2 diabetes mellitus, the incidence of hypo-
`glycemia with glyburide was similar to that seen
`with chlorpropamide.4 Patients usually are started
`on a 2.5-mg or 5-mg tablet in the morning before the
`first meal of the day. The dose can be escalated grad-
`ually to a maximum of 20 mg/day. However, it is
`rare to see further improvement in efficacy with
`doses > 10 mg/day. Again, this agent should be used
`with caution in the elderly population and in those
`with renal insufficiency.
`There also is a micronized form of glyburide.
`However, it has been difficult to find exactly equiv-
`alent dosages between the two forms, which can
`lead to confusion for the patient and physician. The
`micronized agents have not been shown to have a
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`ORAL ANTIDIABETIC THERAPY UPDATE
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`higher bioavailability or greater efficacy than regu-
`lar glyburide.
`Glipizide. Glipizide is completely metabolized in
`the liver and excreted primarily by the kidneys.
`However, it is not as potent as glyburide at raising
`basal insulin levels and therefore is the preferred sul-
`fonylurea in elderly patients or those with renal
`insufficiency. It usually is started with 5 mg orally 30
`minutes prior to breakfast. If the dose exceeds 15
`mg/day, then it is best to divide the doses by giving
`it before breakfast and before dinner. The maximum
`recommended dose is 40 mg/day, although it is rare
`to see additional efficacy with doses >20 mg/day.
`There is also an extended release form of glipizide,
`which allows for once a day dosing.
`Glimepiride. In 1996, a new sulfonylurea, glime-
`piride, was approved for use in the treatment of type
`2 diabetes. It is the most potent of the sulfonylureas
`to date, requiring a 1-, 2-, or 4-mg dose once daily.
`It is completely metabolized in the liver, making it
`safe in the elderly and in those with renal insuffi-
`ciency. The maximal recommended dose is 6
`mg/day, and this agent is of equal efficacy whether
`given once or twice daily.8 Like the other sulfony-
`lureas, glimepiride acts as an insulin secretagogue,9
`but in comparative trials, it caused fewer episodes of
`hypoglycemia.10 Other data from comparative trials
`show that glimepiride provides greater postprandial
`insulin secretion, but fasting glucose control and
`HgbA1C lowering is similar to that of glyburide.11
`Glimepiride has been shown to have extrapancreat-
`ic in vitro effects on glucose uptake, but the clinical
`still to be deter-
`significance of these effects is
`mined. 1
`
`BIGUANIDES
`Metformin
`Metformin is the only biguanide currently
`approved for the treatment of type 2 diabetes melli-
`It was originally developed in the 1950s in
`tus.
`Europe and has been used there for many years. This
`agent was approved for use in the United States in
`1995. While the mechanism of action is not com-
`pletely clear at the present time, we do know that
`metformin is not an insulin secretagogue. It is effec-
`tive in reducing hepatic and renal gluconeogenesis,
`thereby lowering fasting blood glucose values.12
`Metformin also is effective in reducing postprandial
`blood glucose by a mechanism that is thought to
`involve retardation of gastrointestinal absorption.'3
`There also are some data that metformin improves
`
`peripheral insulin sensitivity by increasing the expres-
`sion of glucose transporters and by increasing
`non-oxidative glucose metabolism.13
`Metformin usually is given initially as one 500-
`mg tablet once daily with a meal. One week later,
`the dose should be increased to 500 mg twice daily
`and can eventually reach a maximum of 2500
`mg/day. Most studies show maximum effect with
`2000 mg/day, with no additional efficacy at 2500
`mg/day.13 There also are 850-mg tablets, allowing
`for convenient twice-daily dosing. Most studies ana-
`lyzing the effects of metformin show that patients
`will on average lower HgbA,C by 1.5%-1.9% when
`it is used as monotherapy.13
`This agent can be added to a sulfonylurea or
`insulin therapy (Table 1), in which case a further
`decrease in HgbA,C of 1.5% can be expected.'4
`Metformin alone is not associated with hypo-
`glycemia, but this can occur when combined with
`insulin or sulfonylurea therapy. Metformin has the
`added benefit of reducing triglycerides and inducing
`mild weight loss in some overweight patients.'5 The
`use of metformin to achieve glycemic control was
`studied in a subset of 342 obese diabetic patients in
`the UKPDS.5 Although reduction in myocardial
`infarction endpoints did not quite reach statistical
`significance (P<.052) in the insulin- and sulfony-
`lurea-intensively treated groups, the obese diabetic
`patients treated with metformin had significant
`reductions in myocardial infarction, nonfatal stroke,
`and all cause mortality.5 The increased effect of met-
`formin on prevention of macrovascular disease may
`be related to its known effects on decreasing low-
`density lipoprotein and triglyceride levels. More
`information should be available with the release of
`the UKPDS results concerning lipid profiles.
`The main potential complication of metformin
`use is the risk of lactic acidosis. Unlike its predeces-
`sor phenformin, metformin does not strongly inhib-
`it oxidative metabolism of glucose. Due to the
`absence of this effect, the risk of lactic acidosis is pre-
`sent, but much lower. The incidence of lactic acido-
`sis is quite rare; however, it is recommended to
`avoid using metformin in patients who are predis-
`posed to lactic acidosis or cannot metabolize lactate.
`Therefore, patients with a history of hepatic insuffi-
`ciency, renal insufficiency, severe cardiac or respira-
`tory disease, chronic metabolic acidosis, or alcohol
`abuse should not take metformin. It also is recom-
`mended that metformin should be stopped at the
`time of any interventional procedures, particularly
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`surgical procedures or those requiring contrast dye.
`This will prevent a rise in metformin levels should
`acute renal failure occur. Metformin also should be
`used with caution in elderly patients secondary to
`their diminished renal function.
`There are no known drug interactions and the
`most commonly seen side effect from metformin use
`is gastrointestinal irritation. Administering the tablet
`with food and beginning with the 500-mg dose usu-
`ally prevents or ameliorates this side effect. Less
`than 5% of individuals will actually require cessation
`of metformin due to gastrointestinal side effects.
`
`ALPHA-GLUCOSIDASE INHIBITORS
`Alpha-glucosidase inhibitors also were popular in
`Europe prior to their introduction into the American
`market. At this time, they remain one of the most fre-
`quently prescribed antidiabetic agents in Europe.
`Acarbose was the first agent in this class widely avail-
`the United States.
`able
`Alpha-glucosidase
`in
`inhibitors act by blocking the absorption of carbohy-
`drate from the gastrointestinal tract and are most
`effective in decreasing postprandial glucose elevation.
`The main advantage of these agents is that they act
`locally in the gut and are not systemic in their activi-
`ty. Due to their nonsystemic activity, hypoglycemia is
`not associated with alpha-glucosidase inhibitors. The
`disadvantages, however, are greater in number.
`Acarbose
`Acarbose and the other agents of this class have
`relatively weak antidiabetic activity, only reducing
`HgbAjC by .5%-1% in most patients.14"6 Diarrhea
`and flatulence are the most common side effects,
`occurring in up to 40% of patients in most trials.
`Secondary to the high incidence of gastrointestinal
`distress, acarbose should be initiated slowly. It comes
`in 50-mg and 100-mg tablets, and it is currently rec-
`ommended that patients begin with 25 mg daily
`taken with a meal. Afterward, it can be advanced to
`25 mg with two meals and slowly increased to a max-
`imum of 300 mg/day. Acarbose should be taken with
`the first bite of the meal and the most benefit is
`achieved with doses > 150 mg/day. It is at these high-
`er dosages that a recent study has shown reduction of
`HgbA1C of l/-2%/Y Unfortunately, the incidence of
`gastrointestinal side effects often precludes reaching
`these doses.
`Miglitol
`Recently, miglitol, a new alpha-glucosidase inhibi-
`
`ORAL ANTIDIABETIC THERAPY UPDATE
`
`tor, was approved by the Food and Drug Admini-
`stration. It reportedly has many of the gastrointestinal
`side effects that limit acarbose use. However, in pre-
`liminary studies, miglitol effectively lowered post-
`prandial blood glucose and glycosylated hemoglobin
`levels. 18
`
`THIAZOLIDINEDIONES
`Thiazolidinediones were developed inJapan and
`have been available in the United States since
`March 1997. Today, more than 600,000 people in
`the United States are being treated with troglitazone.
`Until recently, troglitazone was the only available
`member of this group.
`Troglitazone
`Troglitazone has been shown to improve periph-
`eral insulin sensitivity (ie, increase peripheral glu-
`cose disposal) by an as yet undetermined mecha-
`nism. We do know that the drug binds to an intranu-
`clear receptor (PPARgamma), and this complex has
`been found to function as a transcriptional activa-
`tor.19 How PPARgamma activation by troglitazone
`results in improved insulin sensitivity is not clear.
`Troglitazone comes in 200-mg and 400-mg tablets,
`and patients are started at 200 mg in the morning
`with food to aid in rapid absorption. Thereafter, the
`dose can be increased to 400 mg/day and eventually
`to the maximum of 600 mg/day. The tablets should
`be given once in the morning, as there is no advan-
`tage to dividing the dose.
`Troglitazone was initially proven effective in type
`2 diabetic patients who already were being treated
`with insulin. In 1998, troglitazone was approved by
`the FDA for use as monotherapy in the treatment of
`type 2 diabetes. Studies in patients already receiving
`insulin therapy have shown a significant improve-
`ment in HgbAIC and a reduction in insulin require-
`ments. A 1.5% reduction in HgbAIC has been report-
`ed when troglitazone is added to conventional insulin
`therapy.'4 Monotherapy has been less effective, with
`an average decrease in HgbA1C of .9%. Whether
`used as single or combination therapy, there is a lag
`time of several weeks for troglitazone to have a glu-
`cose-lowering effect and a delay of several months for
`maximum glucose lowering effect. The drug is not
`effective in those patients with relative insulinopenia.
`It is important to use clinical judgment in determin-
`ing which patients with type 2 diabetes have signifi-
`cant insulin resistance with hyperinsulinemia and
`therefore are better candidates for troglitazone thera-
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`py. Significant reduction in HgbA1C recently has
`been shown when troglitazone is used in combination
`therapy with glyburide or metformin.20
`Adverse effects range from mild peripheral edema
`and weight gain to recently reported cases of florid
`hepatic failure. Weight gain can be seen in many
`patients, likely secondary to increased insulin sensi-
`tivity and improved glycemic control. The cases of
`hepatotoxicity are more concerning and recently
`were detailed in Annals ofInternal Medicine.21'22 In the
`initial clinical studies, troglitazone was associated with
`mild increases in liver function tests (1.9% compared
`with .6% for placebo) and reversible jaundice.2'
`However, there have been at least five cases of trogli-
`tazone-induced hepatotoxicity and death in the
`United States since the drug's release in 1997.21,22
`Despite these events, the incidence of liver disease
`is rare, and troglitazone remains a useful weapon
`against type 2 diabetes, particularly in those with sig-
`nificant insulin resistance. The FDA now recom-
`mends that patients undergo monitoring of their liver
`function tests (LFTs) on a monthly basis for the first
`eight months of use. Over the next four months, LFTs
`can be monitored every other month and then peri-
`odically thereafter. Troglitazone should be stopped
`with any evidence of significant hepatic impairment
`or a threefold rise in alanine aminotransferase
`(ALT)/aspartate aminotransferase (AST) levels.
`Recently, two additional thiazolidinediones have
`become available. It is hoped that rosiglitazone and
`pioglitazone will have many of the same insulin-sen-
`as troglitazone without the risk of
`sitizing effects
`hepatic injury.
`
`BENZOIC ACID DERIVATIVES
`Repaglinide
`Benzoic acid derivatives are the most recent addi-
`tion to the list of treatment options for type 2 diabetes.
`In 1998, the FDA approved the first agent in this
`class, repaglinide. Benzoic acid derivatives are similar
`to sulfonylureas in that they are insulin secreta-
`gogues.23 However, they differ in that they bind to a
`different receptor on the beta cell membrane. Also, in
`contrast to sulfonylureas, benzoic acid derivatives do
`not cause direct exocytic insulin release in the
`absence of glucose stimulation.
`The true benefit of these agents stems from the fact
`that they have a short duration of action. Repaglinide
`is administered just before the start of the meal and
`stimulates insulin secretion. However, the duration of
`action is much shorter than the sulfonylureas, and the
`
`main effect is to reduce postprandial hyperglycemia.
`Due to the short half-life, repaglinide is useful in
`patients who have erratic meal schedules.
`The main advantage of repaglinide is the poten-
`tial for decreased incidence of hypoglycemia, mak-
`ing it an effective agent in elderly patients and those
`with renal insufficiency or other predisposition to
`hypoglycemia. It is given only at the meal time in 1-
`mg and 2-mg tablets. Most patients are started on
`0.5 mg prior to meals. It often is useful to initially
`monitor pre- and one-hour postprandial fingerstick
`glucoses to assess the effects of this agent.
`
`CONCLUSION
`Much of the benefit from tight control in patients
`with type 1 diabetes has now been extrapolated to the
`much larger group of patients with type 2 diabetes.
`Recent data have shown that tight control of type 2
`diabetes is strongly associated with a decreased inci-
`dence and rate of progression of microvascular com-
`plications. Multiple new oral agents recently have
`been developed for the treatment of this disorder.
`Effective use of these agents by physicians is impera-
`tive in controlling this disease and preventing or
`delaying acute and chronic complications in African
`Americans. It is important to remember that these
`new agents are relatively ineffective without proper
`dietary counseling and increased physical activity. In
`addition to glycemic control, treatment of hyperten-
`sion and hyperlipidemia will also result in significant
`decreases in micro- and macrovascular disease in
`individuals with type 2 diabetes.24'25
`Comprehensive screening also is essential as it is
`estimated that 50% of Americans with the disease are
`unaware of their illness. The ADA now recommends
`testing of fasting glucose every three years for all
`adults >45 years.26 For higher risk groups, such as
`African Americans and those with a history of gesta-
`tional diabetes, screening is recommended on a year-
`ly basis. Those patients with a fasting glucose > 126
`mg/dL must receive proper dietary and exercise
`instruction as well as diabetic teaching about the
`importance of foot care and home glucose monitor-
`ing. These measures combined with the effective use
`of pharmacologic agents in those who fail conserva-
`tive therapy will improve the control of the type 2
`diabetes epidemic in the black community.
`
`Literature Cited
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`1997;9:66-75.
`2. Smith-Veal Y. African Americans and diabetes: reasons,
`rationale, and research.JNatl Med Assoc. 1996;88:203-204.
`3. Agrawal L, Emanuele NV, Abraira C, et al. Ethnic dif-
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`Intensive blood-glucose control with sulfonylureas or
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`Effect of intensive blood-glucose control with metformin
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`(UKPDS 34). Lancet. 1998;352:854-865.
`6. The Diabetes Control and Complications Trial Research
`Group. The effect of intensive treatment of diabetes on the devel-
`opment and progression of long term complications in insulin
`dependent diabetes mellitus. NEnglJMed. 1993;329:977-1036.
`7. University Group Diabetes Program: a study of the effects
`of hypoglycemia agents on vascular complication in patients with
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