REVIEW
`
`Pharmacologic Therapy for Type 2 Diabetes Mellitus
`Ralph A. DeFronzo, MD
`
`Type 2 diabetes mellitus is a chronic metabolic disorder
`that results from defects in both insulin secretion and
`insulin action. An elevated rate of basal hepatic glucose
`production in the presence of hyperinsulinemia is the pri-
`mary cause of fasting hyperglycemia; after a meal, im-
`paired suppression of hepatic glucose production by insu-
`lin and decreased insulin-mediated glucose uptake by
`muscle contribute almost equally to postprandial hyper-
`glycemia. In the United States, five classes of oral agents,
`each of which works through a different mechanism of
`action, are currently available to improve glycemic control
`in patients with type 2 diabetes. The recently completed
`United Kingdom Prospective Diabetes Study (UKPDS) has
`shown that type 2 diabetes mellitus is a progressive disor-
`der that can be treated initially with oral agent mono-
`therapy but will eventually require the addition of other
`oral agents, and that in many patients, insulin therapy will
`be needed to achieve targeted glycemic levels. In the
`UKPDS, improved glycemic control, irrespective of the
`agent used (sulfonylureas, metformin, or insulin), de-
`creased the incidence of microvascular complications (ret-
`inopathy, neuropathy, and nephropathy). This review ex-
`amines the goals of antihyperglycemic therapy and
`reviews the mechanism of action, efficacy, nonglycemic
`benefits, cost, and safety profile of each of the five ap-
`proved classes of oral agents. A rationale for the use of
`these oral agents as monotherapy, in combination with
`each other, and in combination with insulin is provided.
`
`Ann Intern Med. 1999;131:281-303.
`
`For the author affiliation and current author address, see end
`of text.
`
`In the United States, approximately 15.6 million
`
`persons have type 2 diabetes mellitus, and about
`13.4 million have impaired glucose tolerance (1).
`Throughout the world, the prevalence of type 2
`diabetes mellitus has increased dramatically in the
`past two decades (1). Decreased physical activity,
`increasing obesity, and changes in food consumption
`have been implicated in this epidemic (2).
`Patients with diabetes experience significant mor-
`bidity and mortality from microvascular (retinopa-
`thy, nephropathy, and neuropathy) and macrovascu-
`lar (heart attacks, stroke, and peripheral vascular
`disease)
`complications. Proliferative retinopathy,
`macular edema, or both occur in 40% to 50% of
`patients with type 2 diabetes, and diabetes is the
`leading cause of blindness in the United States (3).
`The prevalence of renal disease varies considerably
`among ethnic populations,
`from 5% to 10% in
`
`white persons to 50% in Native Americans (4). Di-
`abetes is the leading cause of end-stage renal fail-
`ure, accounting for one of every three patients who
`enter dialysis or transplantation programs (4). Pe-
`ripheral and autonomic neuropathy occur in 50% to
`60% of patients with type 2 diabetes, whereas heart
`attacks and stroke occur two to four times more
`frequently in persons with diabetes than in those
`without the disease (5). The cost of treating diabe-
`tes and associated microvascular and macrovascular
`complications exceeds $100 billion per year (6).
`I briefly review the pathogenesis of type 2 diabe-
`tes mellitus; provide a rationale for the importance
`of good glycemic control in this disease; and provide
`a therapeutic strategy, with a focus on oral agents
`alone and in combination with each other and with
`insulin. Indications for insulin are discussed briefly,
`but the major emphasis is on therapy with oral
`agents.
`This review primarily relies on evidence-based
`medicine. Wherever possible, the results of large,
`prospective, double-blind, placebo-controlled studies
`published in peer-reviewed journals have been used.
`For several of the recently approved oral agents, I
`used information filed by the drug company with
`the U.S. Food and Drug Administration (FDA).
`Where controversy exists, I delineate both points of
`view and offer commentary that attempts to synthe-
`size and reconcile published results. Statements that
`are not founded on evidence-based medicine are
`clearly indicated.
`
`Pathogenesis of Type 2 Diabetes Mellitus
`
`The appropriate treatment of any disease is
`based on an understanding of its pathophysiology
`(7). The mechanisms responsible for impaired glu-
`cose homeostasis in type 2 diabetes mellitus (Figure
`1) are discussed briefly to provide the foundation
`for discussion of currently available oral agents, in-
`cluding their mechanism of action, efficacy, and side
`effects.
`After ingestion of glucose, maintenance of nor-
`mal glucose tolerance depends on three events that
`must occur in a tightly coordinated fashion: 1) stim-
`ulation of insulin secretion; 2) insulin-mediated sup-
`pression of endogenous (primarily hepatic) glucose
`production by the resultant hyperinsulinemia; and
`
`©1999 American College of Physicians–American Society of Internal Medicine
`
`281
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`AstraZeneca Exhibit 2063
`Mylan v. AstraZeneca
`IPR2015-01340
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`ing the excessive increase in plasma glucose level
`after carbohydrate ingestion (Figure 1).
`From a quantitative standpoint, however, in dia-
`betic patients with established fasting hyperglycemia
`(glucose level . 7.8 mmol/L [.140 mg/dL]), the ex-
`cessive increase in the plasma glucose level above
`baseline after a meal plays a much smaller role in
`determining the mean day-long plasma glucose con-
`centration than does the elevated fasting plasma
`glucose level. This is clear from studies that have
`examined the mean day-long glycemic excursions in
`diabetic patients who consume typical mixed meals.
`For example, in a study by Jeppesen and colleagues
`(14), the fasting glucose level in diabetic patients
`was (10.6 mmol/L [190 mg/dL]), indicating an in-
`crease in basal glucose level of 5.6 mmol/L (100
`mg/dL) above that
`in nondiabetic
`controls
`(5
`mmol/L [90 mg/dL]). This increase above baseline
`was present 24 hours per day, giving a hyperglyce-
`mic index of 2400 (100 mg/dL 3 24 hours). After
`each of three daily meals, the increase in plasma
`glucose concentration was greater in diabetic pa-
`tients than in controls by about 1.9 mmol/L (35
`mg/dL) but returned to the baseline value by 4 to 6
`hours. The hyperglycemic index accounted for by
`the excessive increase in plasma glucose level during
`each meal is 525 (35 mg/dL 3 3 meals 3 5 hours).
`Thus, the contribution of postprandial hyperglyce-
`mia to day-long hyperglycemia is only 22% (525/
`2400).
`Impaired insulin secretion also plays a major role
`in the pathogenesis of glucose intolerance in pa-
`tients with type 2 diabetes (15). Although debate
`still continues about which defect—insulin resis-
`tance or impaired insulin secretion—initiates the
`cascade of events leading to overt diabetes mellitus,
`essentially all patients who have type 2 diabetes with
`elevated fasting plasma glucose levels have a defect
`in insulin secretion (15). In diabetic patients with
`mild fasting hyperglycemia (glucose level , 7.8
`mmol/L [,140 mg/dL]), plasma insulin levels during
`an oral glucose tolerance test or a mixed meal usu-
`ally are elevated in absolute terms (16). However,
`relative to the severity of
`insulin resistance and
`prevailing hyperglycemia,
`even these
`elevated
`plasma insulin levels are deficient (16, 17). As the
`fasting plasma glucose level increases to more than
`7.8 mmol/L (.140 mg/dL),
`insulin secretion de-
`creases progressively, and essentially all diabetic pa-
`tients with a fasting plasma glucose level that ex-
`ceeds 10.0 to 11.1 mmol/L (180 to 200 mg/dL) have
`a plasma insulin response that is deficient in abso-
`lute terms (16, 17). It follows, therefore, that drugs
`that improve insulin secretion will be effective in
`treating type 2 diabetes (Figure 1).
`In summary, patients with type 2 diabetes melli-
`tus are characterized by defects in both insulin se-
`
`Figure 1. Pathogenesis of type 2 diabetes mellitus. Sites of action of
`oral agents are indicated. A negative sign indicates inhibition; a positive sign
`indicates stimulation.
`
`3) insulin-mediated stimulation of glucose uptake by
`peripheral tissues, primarily muscle. Hyperglycemia
`also has its own independent effect of suppressing
`hepatic glucose production and enhancing muscle
`glucose uptake, but these effects are modest com-
`pared to those of insulin.
`In patients with type 2 diabetes and established
`fasting hyperglycemia, the rate of basal hepatic glu-
`cose production is excessive, despite plasma insulin
`concentrations that are increased twofold to four-
`fold (8) (Figure 1). These findings provide unequiv-
`ocal evidence for hepatic resistance to insulin, and
`this evidence is substantiated by an impaired ability
`of insulin to suppress hepatic glucose production
`(9). Accelerated gluconeogenesis is the major ab-
`normality responsible for the increased rate of basal
`hepatic glucose production (10). The increased rate
`of basal hepatic glucose production is closely corre-
`lated with the increase in fasting plasma glucose
`level (7–10). Because the fasting plasma glucose
`level is the major determinant of the mean day-long
`blood glucose level (which clinically is reflected by
`the hemoglobin A1c [HbA1c] value), it follows that
`agents that reduce the elevated basal rate of hepatic
`glucose production will be especially effective in
`improving glycemic control (Figure 1).
`Muscle tissue in patients with type 2 diabetes is
`resistant to insulin (7, 9, 11) (Figure 1). Defects in
`insulin receptor
`function,
`insulin receptor-signal
`transduction pathway, glucose transport and phos-
`phorylation, glycogen synthesis, and glucose oxida-
`tion contribute to muscle insulin resistance (7). In
`response to a meal, the ability of endogenously se-
`creted insulin to augment muscle glucose uptake is
`markedly impaired (12, 13), and muscle insulin re-
`sistance and impaired suppression of hepatic glu-
`cose production contribute approximately equally to
`the excessive postprandial
`increase in the plasma
`glucose level (13). It follows that drugs that improve
`muscle insulin sensitivity will be effective in decreas-
`
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`cretion and insulin action. A recent extensive review
`(7) provides more detailed discussion about
`the
`pathogenesis of type 2 diabetes mellitus.
`
`Glycemic Control and Complications
`
`The Diabetes Control and Complications Trial
`(DCCT) (18) established that in type 1 diabetes
`mellitus, the risk for microvascular complications
`could be reduced by maintaining near-normal blood
`glucose levels with intensive insulin therapy. No gly-
`cemic threshold for the development of long-term
`microvascular complications was observed in the
`DCCT (19). As the HbA1c value was reduced to less
`than 8.0%, the risk for microvascular complications
`continued to decrease (19). Until recently, no large
`prospective long-term study had demonstrated that
`improved glycemic control in patients with type 2
`diabetes can prevent microvascular complications.
`Nonetheless, convincing arguments suggested that
`the DCCT results could be extrapolated to type 2
`diabetes. First, retinal, renal, and neurologic ana-
`tomical lesions seem to be identical in type 1 and
`type 2 diabetes mellitus (3, 20, 21). Second, epide-
`miologic studies have shown a close association be-
`tween glycemic control and microvascular complica-
`tions (3, 22–24). Third, a randomized clinical trial in
`Japanese patients with type 2 diabetes (15) showed
`that attainment of near-normal glycemia with inten-
`sive insulin therapy resulted in improvements in
`retinopathy, nephropathy, and neuropathy similar to
`those observed in the DCCT. Finally, short-term
`prospective studies (25, 26) have shown that reduc-
`tion of the plasma glucose level reduces microalbu-
`minuria and improves nerve conduction velocity in
`patients with type 2 diabetes. On the basis of these
`arguments, most diabetes experts have concluded
`that the DCCT results are applicable to type 2
`diabetes mellitus (27).
`More definitive information on the relation be-
`tween improved glycemic control and prevention of
`complications was recently provided by the United
`
`Kingdom Prospective Diabetes Study (UKPDS)
`(28, 29). In the main randomization group of the
`UKPDS (28), after a dietary run-in period of 3
`months, 3867 patients with newly diagnosed type 2
`diabetes were randomly assigned to intensive ther-
`apy with a sulfonylurea or insulin (n 5 2729) or to
`conventional diet therapy (n 5 1138). In the inten-
`sive group, the aim was to achieve a fasting plasma
`glucose level less than 6 mmol/L (108 mg/dL). In
`the sulfonylurea group, patients were switched to
`insulin therapy or metformin was added if the ther-
`apeutic goal was not achieved after maximum titra-
`tion of the drug dose. In patients assigned to insulin
`treatment in whom the therapeutic goal was not
`met, the dose of ultralente insulin was increased
`progressively and regular insulin was added. In pa-
`tients assigned to conventional diet treatment, the
`aim was to maintain a fasting plasma glucose level
`less than 15 mmol/L (270 mg/dL) without symp-
`toms. If the fasting plasma glucose level exceeded
`15 mmol/L (270 mg/dL) or symptoms occurred, pa-
`tients were randomly assigned to receive therapy
`with a sulfonylurea or insulin. The median follow-up
`was 10.0 years; during this period, a difference in
`HbA1c values of 0.9 percentage points (7.0% com-
`pared with 7.9%; P , 0.001) was maintained be-
`tween the group assigned to intensive therapy and
`the group assigned to conventional therapy (Figure
`2). This difference was associated with a significant
`25% risk reduction (P 5 0.009) in combined micro-
`vascular end points (eye, kidney, and nerve) com-
`pared with the conventionally treated group. No
`difference in combined macrovascular end points
`between the two groups was observed, although
`there was a tendency toward fewer myocardial in-
`farctions in the group assigned to intensive therapy.
`In addition to the 2729 patients with type 2 dia-
`betes assigned to intensive therapy and the 1138
`patients assigned to conventional therapy, 342 over-
`weight patients were randomly assigned to intensive
`treatment with metformin (29). These 342 patients
`
`Figure 2. Time-related change
`in
`median fasting plasma glucose level
`(left) and median hemoglobin A1c
`(HbA1c) (right) in patients with type 2
`diabetes treated with sulfonylureas
`(triangles), metformin (diamonds), in-
`sulin (squares), or conventional (diet)
`therapy (circles). The number of pa-
`tients followed for more than 11 years
`drops off markedly. The curves for chlor-
`propamide and glibenclamide have been
`combined into one sulfonylurea curve for
`ease of presentation. Redrawn from refer-
`ences 28 and 29.
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`were compared with 411 overweight diabetic pa-
`tients receiving conventional therapy and with 951
`overweight diabetic patients receiving intensive ther-
`apy (of whom 542 were receiving sulfonylureas and
`409 were receiving insulin). The median follow-up
`in this group was 10.7 years; during this time, a
`difference in the HbA1c value of 0.6 percentage
`points (7.4% compared with 8.0%; P , 0.001) was
`maintained between the group assigned to metformin
`therapy and the group assigned to conventional ther-
`apy (Figure 2). The magnitude of reduction (29%)
`in the risk for microvascular complications in the
`metformin-treated group was similar to that in pa-
`tients treated intensively with insulin or sulfonyl-
`ureas, but it did not reach statistical significance
`(Figure 3). Patients assigned to intensive blood glu-
`cose control with metformin had a 32% lower risk
`(P 5 0.002) for any diabetes-related end point, a
`36% lower risk (P 5 0.021) for death from any
`cause, a 42% reduction in diabetes-related death
`(P 5 0.11), a 39% lower risk (P 5 0.010) for myo-
`cardial infarction, and a 41% lower risk (P 5 0.032)
`for stroke compared with patients who received
`conventional treatment (Figure 3). The risk reduc-
`
`tion for any diabetes-related end point (P 5 0.003)
`and death from any cause (P 5 0.021) in the met-
`formin group was significantly greater than that in
`the group assigned to intensive therapy with insulin
`or sulfonylureas (Figure 3).
`In summary, the results of the UKPDS show that
`1) the development of microvascular complications
`was similarly reduced in patients with type 2 diabe-
`tes treated with sulfonylureas, insulin, or metformin;
`2) there was no threshold for the reduction in
`HbA1c value and the development of microvascular
`complications; 3) in patients with type 2 diabetes
`assigned to intensive therapy with sulfonylureas or
`insulin, the incidence of macrovascular complica-
`tions was not increased compared with the group
`assigned to conventional therapy; and 4) a decrease
`in macrovascular complications was seen only in
`patients with type 2 diabetes assigned to intensive
`therapy with metformin. Thus, the findings of the
`UKPDS are consistent with those of the DCCT (17)
`and the study by Ohkubo and associates (30).
`it
`On the basis of the results reviewed above,
`seems most prudent to reduce blood glucose levels
`in patients with type 2 diabetes to as close to nor-
`
`Figure 3. Effect of conventional treatment with diet (bold solid line), intensive treatment with sulfonylureas or insulin (solid line), and
`metformin therapy (dashed line) on any diabetes-related end point (top left), diabetes-related death (bottom left), microvascular complica-
`tions (top right), and myocardial infarction (bottom right). P values represent differences between metformin and other therapies. Redrawn from
`references 28 and 29.
`
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`
`mal as possible while avoiding symptomatic hypo-
`glycemia. Effective treatment will require the com-
`bined use of diet, exercise, oral agents, and insulin.
`
`Diagnostic Criteria and Therapeutic Goals
`
`On the basis of results from long-term prospec-
`tive epidemiologic studies showing that 10% to 15%
`of persons with a fasting plasma glucose level of 7
`mmol/L or more ($126 mg/dL) develop diabetic
`retinopathy within 10 years of follow-up, an expert
`committee convened by the American Diabetes As-
`sociation recommended that diabetes be diagnosed
`when the fasting plasma glucose level is 7 mmol/L
`or more (126 mg/dL) (24). This fasting plasma glu-
`cose level is consistent with a 2-hour plasma glucose
`level of 11.1 mmol/L or more ($200 mg/dL) during
`an oral glucose tolerance test and corresponds to an
`HbA1c value of about 6.9% (24). A random plasma
`glucose level of at least 11 mmol/L ($200 mg/dL)
`with symptoms also establishes the diagnosis of type
`2 diabetes mellitus. To definitively establish the di-
`agnosis, one of the three previous diagnostic criteria
`must be confirmed.
`Because hyperglycemia is believed to play an im-
`portant role in the pathogenesis of microvascular
`complications, the American Diabetes Association
`has established acceptable and ideal goals for treat-
`ment of type 2 diabetes (31). Pharmacologic action
`is indicated if the fasting glucose level exceeds 7.8
`mmol/L (.140 mg/dL), if the postprandial glucose
`level exceeds 8.9 mmol/L (160 mg/dL), or if the
`HbA1c value exceeds 8.0%. On the basis of the
`results of the UKPDS (27, 28) and the DCCT (19),
`I believe that treatment should be initiated if the
`HbA1c value is 7.0%, not 8.0% (Figure 2), because
`both the UKPDS and DCCT (8, 28) showed that
`treatment of diabetic patients with HbA1c values in
`the range of 6% to 7% is associated with a signif-
`icant reduction in microvascular complications.
`
`Treatment Strategy
`
`In developing a treatment strategy for patients
`with type 2 diabetes, it must be remembered that
`glucose intolerance occurs not in isolation but as
`part of a complex metabolic–cardiovascular syn-
`drome that
`includes dyslipidemia, hypertension,
`obesity, clotting abnormalities, microalbuminuria,
`and accelerated atherosclerosis (32, 33), although
`not every one of these disorders occurs in every
`diabetic patient. Although hyperglycemia has been
`implicated as a risk factor for coronary artery dis-
`ease (34), dyslipidemia far outweighs all other risk
`factors (35). Therefore, treatment of concomitant
`lipid abnormalities, hypertension, and other known
`risk factors for coronary artery disease is essential
`
`(5, 35). Long-term prospective studies have shown
`that treatment of hypertension (36) and dyslipide-
`mia (37) reduces cardiac events in patients with
`type 2 diabetes. Most recently, the UKPDS (38)
`showed that improved control of blood pressure
`reduced not only macrovascular
`complications
`(heart attacks, strokes, and death) but also the risk
`for microvascular end points by 37% (P 5 0.009). In
`this context, it is important that pharmacologic ther-
`apy does not aggravate associated cardiovascular
`risk factors and, preferably, leads to their improve-
`ment. Because obesity and physical
`inactivity are
`risk factors for coronary artery disease as well as for
`diabetes, the need for weight loss and exercise must
`be stressed when diabetes initially is diagnosed and
`must be reinforced throughout the natural history of
`the disease. Many excellent reviews on diet and
`exercise have been published (39, 40). If diet and
`exercise fail to achieve the desired level of glycemic
`control, pharmacologic intervention is indicated.
`The UKPDS showed that type 2 diabetes mellitus
`is a progressive disorder (28, 29) (Figure 2). Al-
`though it was hoped that treatment with sulfonyl-
`ureas, metformin, or insulin would halt the progres-
`sive deterioration of glycemic control, this has not
`turned out to be the case. After an initial and
`similar decrease in the HbA1c value with metformin,
`sulfonylureas, or insulin, the rate of increase in the
`to that
`in the group
`HbA1c value was identical
`treated with diet therapy. These results indicate that
`once overt fasting hyperglycemia has developed, the
`decline in glycemic control
`is relentless. In the
`UKPDS, this decline was related to deterioration of
`b-cell function (28). The results of the University
`Group Diabetes Program study (41, 42) also docu-
`mented the progressive nature of type 2 diabetes
`mellitus. This important observation emphasizes the
`need for constant reassessment of the diabetic pa-
`tient and appropriate adjustment of the therapeutic
`regimen in order to maintain the desired level of
`glycemic control.
`From these observations about the natural his-
`tory of type 2 diabetes mellitus, the following treat-
`ment strategy can be proposed for diabetic patients
`whose disease is inadequately controlled with diet
`and exercise (Figure 4).
`1. Initiate pharmacologic therapy with an oral
`agent or insulin.
`2. Quickly increase the dose of oral agent or
`insulin until adequate glycemic control is achieved. I
`recommend that patients be seen at 2- to 4-week
`intervals or more frequently during this titration
`phase.
`3. In diabetic patients treated with an oral agent,
`choose a drug with glucose-lowering potency that
`can achieve the desired level of glycemic control
`when used as monotherapy. Because most patients
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`with type 2 diabetes are overweight and have asso-
`ciated cardiovascular risk factors, drugs that im-
`prove these abnormalities are preferred.
`4. In diabetic patients whose disease is inade-
`quately controlled with a single oral agent, I favor
`addition of a second oral agent with rapid dose
`titration until the desired level of glycemic control is
`achieved or the maximum dose is reached. Alter-
`nately, bedtime long-acting insulin can be added to
`oral agent monotherapy, or the patient can be
`switched to a mixed-split insulin regimen.
`5. In diabetic patients in whom glycemic control
`is not achieved with combined oral agent therapy,
`several options are available: addition of bedtime
`insulin, switching to a mixed-split insulin regimen,
`or addition of a third oral agent.
`It is important to recognize that, ultimately, most
`patients with type 2 diabetes will require treatment
`with insulin, either alone or in combination with an
`oral agent.
`
`Insulin Therapy
`
`Although the primary focus of this review is oral
`agents, comment about insulin is indicated because
`some diabetologists prefer to initiate therapy with
`insulin in patients with newly diagnosed type 2 di-
`abetes. Edelman and Henry (43) published a com-
`prehensive review of insulin therapy in type 2 dia-
`betes mellitus. Numerous studies have shown that
`excellent glycemic control can be achieved with in-
`tensive insulin therapy in patients with type 2 dia-
`betes (44, 45). An educated, compliant patient with
`an experienced physician can achieve excellent gly-
`cemic control with insulin therapy. However, most
`studies of intensive insulin therapy have been car-
`
`ried out in academic settings, using strict research
`protocols with specialty teams devoted to patient
`care. In such settings, one can expect decreases in
`HbA1c value of about 2 percentage points. How-
`ever, most primary care physicians do not have spe-
`cialized training in insulin use and management of
`its complications, do not have sufficient
`time to
`follow up patients at frequent intervals to ensure
`appropriate adjustment of the insulin dose, and do
`not have diabetes specialty teams to assist them.
`Hayward and coworkers (46) examined insulin
`therapy prescribed by general practice physicians in
`a large staff-model health maintenance organization.
`In 1738 insulin-treated patients with type 2 diabetes,
`the mean decrease in HbA1c value was 0.9 percent-
`age points, and 60% of patients had a HbA1c value
`that exceeded 8.0% at 2 years. In a parallel cohort,
`43% of patients with type 2 diabetes who were
`taking sulfonylureas had an HbA1c value that ex-
`ceeded 8.0%. Although one can raise criticisms
`about this study (46), the results do not indicate any
`superiority of
`insulin over sulfonylureas or vice
`versa in the general practice setting. The UKPDS
`(28, 29) also failed to show any advantage of insulin
`over oral agents or vice versa (Figure 2). The most
`commonly used insulin regimen in general practice
`is a single dose of long-acting insulin in the morn-
`ing; dosages in excess of 80 U/d are rarely given
`(47). Because most patients with type 2 diabetes
`require an insulin dosage of at least 80 to 100 U/d
`and a multiple, split-dose regimen (44, 45), it is not
`surprising that blood glucose levels are inadequately
`controlled in most of these patients (46).
`Weight gain and hypoglycemia are common side
`effects of insulin therapy (28, 29, 45, 48–50). Weight
`gain results from increased truncal fat (49) and is
`
`Figure 4. Pharmacologic algorithm for treatment of patients in whom type 2 diabetes is inadequately controlled with diet and exercise.
`*Goals and therapies must be individualized. †Preferred if the patient is obese or dyslipidemic. FPG 5 fasting plasma glucose level; HbA1c 5 hemoglobin A1c
`value; HBGM 5 home blood glucose monitoring.
`
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`closely related to the mean day-long plasma insulin
`level and daily insulin dose (45). In the UKPDS,
`insulin-treated obese patients with type 2 diabetes
`gained 4.0 kg more after 10 years than patients
`assigned to diet therapy (P , 0.001) (28). Patients
`assigned to sulfonylurea therapy (chlorpropamide or
`glibenclamide) gained 2.2 kg more, while those as-
`signed to metformin therapy gained weight in an
`amount similar to that in patients assigned to diet
`therapy (28, 29). Because obesity is a known cause
`of insulin resistance (51, 52) and represents an in-
`dependent risk factor for coronary artery disease,
`hypertension, and dyslipidemia (5, 53), weight gain
`is an undesirable effect of any therapy.
`Hypoglycemia is another potential side effect of
`insulin therapy in patients with type 2 diabetes (28,
`29, 45, 48–50). In the UKPDS (28, 29), after 10
`years, percentages of diabetic patients with one or
`more major (requiring third-party assistance or hos-
`pitalization) hypoglycemic episodes were 0.5% in
`the sulfonylurea group, 2.3% in the insulin group
`(P , 0.001 for
`insulin compared with all other
`groups), 0% in the metformin group, and 0.1% in
`the diet group. The corresponding rates for any
`hypoglycemic reaction were 14% in the sulfonylurea
`group, 36% in the insulin group, 4% in the met-
`formin group, and 1% in the diet group.
`The authors of the 6-year summary of the UKPDS
`(50) stated that “In patients with primary diet fail-
`ure, it may not be advantageous to proceed directly
`to insulin therapy. It is reasonable to initiate ther-
`apy with oral agents and proceed to insulin if the
`goal is not achieved.” The 10-year summary of the
`UKPDS (29) concluded that metformin is appropri-
`ate first-line therapy in overweight diabetic patients
`because compared with insulin or sulfonylurea treat-
`ment, metformin therapy seems to decrease the risk
`for diabetes-related end points and results in less
`weight gain and fewer hypoglycemic attacks.
`On the basis of the preceding discussion, I rec-
`ommend initiating pharmacologic therapy with an
`oral agent in patients with newly diagnosed type 2
`diabetes. However,
`insulin is indicated as initial
`therapy in specific patients, as follows.
`1. Any patient who has type 2 diabetes, with a
`markedly elevated fasting plasma glucose level
`(.15.6 to 16.7 mmol/L [.280 to 300 mg/dL]), and
`ketonuria or ketonemia.
`2. Symptomatic patients who have type 2 diabetes
`with a markedly elevated fasting plasma glucose
`level (.15.6 to 16.7 mmol/L [.280 to 300 mg/dL]).
`After 6 to 8 weeks of good glycemic control, these
`patients can be switched to an oral agent, or they
`can continue insulin therapy. A benefit of intensive
`insulin therapy with tight glycemic control
`is the
`reversal of glucose toxicity (54). This will improve
`both insulin sensitivity and insulin secretion (54)
`
`and will enhance the subsequent response to oral
`agent therapy (55, 56).
`3. Any patient with type 2 diabetes who, after
`discussing the options with the primary care physi-
`cian, wishes to receive insulin as initial therapy.
`4. Women with gestational diabetes mellitus
`whose disease is not controlled with diet alone. All
`oral agents are contraindicated during pregnancy.
`
`Therapeutic Algorithm for Initiation
`of Oral Therapy
`
`In patients with newly diagnosed type 2 diabetes
`in whom insulin therapy is not indicated, I recom-
`mend that pharmacologic therapy with either a sul-
`fonylurea or metformin be initiated as mono-
`therapy, as long as no contraindications are present
`(Figure 4). This view, which is based on proven
`efficacy of, safety of, and long-term clinical experi-
`ence with oral agents,
`is shared by other leading
`authorities on diabetes (28, 29, 50, 57–59), is the
`approach used in the UKPDS (28, 29, 59), and is
`consistent with the guidelines of the American Dia-
`betes Association (60). When used as monotherapy,
`sulfonylureas and metformin are equally effective in
`decreasing plasma glucose levels, and both are more
`potent than other available oral agents (Table 1).
`Because metformin promotes weight loss and re-
`duces lipid levels, it is preferred in overweight pa-
`tients with type 2 diabetes and dyslipidemia. In lean
`patients with type 2 diabetes, therapy with either a
`sulfonylurea or metformin can be initiated. These
`recommendations are consistent with the findings of
`the UKPDS (28, 29). The dose of metformin or
`sulfonylureas can be increased over a 4- to 8-week
`period until the therapeutic goal (fasting plasma
`glucose level , 7.0 mmol/L [,126 mg/dL] and
`HbA1c value , 7%) is achieved or the maximum
`dose is reached. Diet and exercise must be empha-
`sized even after pharmacologic therapy has begun.
`If monotherapy with a sulfonylurea or metformin
`fails to achieve the desired level of glycemic control,
`a second oral agent should be added, with dose
`escalation over 4 to 8 weeks to the maximum. Some
`diabetologists choose to add bedtime insulin to oral
`agent monotherapy rather than add a second oral
`agent. If combination therapy with two oral agents
`does not achieve the desired goal, three options are
`available: 1) Add bedtime insulin while maintaining
`therapy with one or both oral agents, 2) switch the
`patient to a mixed-split (short-acting plus long-acting
`insulin given in 2 to 4 daily injections) insulin reg-
`imen, or 3) add a third oral agent (Figure 4). It is
`important to individualize therapy on the basis of
`patient and physician preferences.
`Specific insulin regimens to treat type 2 diabetes
`
`17 August 1999 • Annals of Internal Medicine • Volume 131 • Number 4
`
`287
`
`Page 7 of 23
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`

`
`Table 1. Comparison of Sulfonylureas, Repaglinide, Metformin, Troglitazone, and Acarbose When Used as Monotherapy*
`
`Effect
`
`Mechanism of action
`
`D