The Prevention of Type 2 Diabetes Mellitus

Endocrinol Metab Clin N Am 34 (2005) 199–219

The Prevention of Type 2 Diabetes Mellitus Silvio E. Inzucchi, MD*, Robert S. Sherwin, MD* Section of Endocrinology/LCI-101, Department of Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8020, USA

The scope of the problem Concurrent with the disturbing increase in the prevalence of obesity in the United States has been a marked increase in the incidence of type 2 diabetes mellitus (T2DM). When last estimated, more than 17 million Americans had diabetes; more than 90% of those had T2DM [1]. The ramifications for our health care system are profound, given the frequent metabolic and vascular complications of this disease which significantly increase mortality and health care–related costs and erode the quality and life expectancy for patients. Although several, randomized clinical trials definitively related improved glycemic control to a decrease in complication rates [2,3], such reductions are only relative. In addition, the impact of glycemic control on the more common cardiovascular complications remains controversial; the bulk of the evidence suggests that glucose control is insufficient for substantive macrovascular risk reduction [3]. Several intermediate metabolic targets are now published and promoted by professional organizations [4], including those for glycemic, lipid, and blood pressure management. Because of a variety of factors, including systematic issues that are related to current health care delivery in this country, our ability to achieve consistent and sustained glycemic targets outside of clinical trials has been disappointing. Finally, many patients who have newly diagnosed T2DM already have established vascular complications. Diabetes, therefore, is a morbid and costly disease whose frequency is increasing at an alarming rate. Despite increasingly complex approaches that are available for its management, our * Corresponding authors. E-mail addresses: [email protected] (S.E. Inzucchi); [email protected] (R.S. Sherwin). 0889-8529/05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ecl.2004.11.008 endo.theclinics.com

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ability to meet the challenge of optimal control remains, at the least, uncertain. To compound these concerns, such epidemiologic and societal changes are not restricted to the United States. Obesity and T2DM are now global concerns; recent estimates predict that by 2030, 366 million patients will have T2DM, many of whom will live in developing countries [5]. In contrast to these generally discouraging reports, however, have been notable achievements in our understanding of the pathogenesis of this disease over the past several decades. Through a series of elegant investigations, it is now clear that T2DM is the culmination of two key pathophysiologic processes—insulin resistance and relative insulin deficiency (Fig. 1) [6]. Insulin resistance, believed to be a fundamental event by most investigators [7], is manifested initially in skeletal muscle as a reduction in insulin-mediated glucose uptake [8]; in liver by an inadequate suppression of hepatic glucose production; and in the vasculature, by abnormal endothelial function and altered production of inflammatory markers that are believed to be mediators of atherosclerosis [9,10]. In most individuals who are affected, the initial pancreatic b-cell response is to produce more insulin. The resultant hyperinsulinemia serves to maintain glucose levels within the normal range for years to decades. Relative insulin deficiency in a genetically determined subset of the population that is insulin resistant plays a major role in the progression toward diabetes when the pancreatic b cell can no longer compensate adequately for increased peripheral insulin demands [11,12]. As a result, hyperglycemia ensues with progressive insulin deficiency. It is now understood that inherited and environmental factors take part in this complex process.

Abnormal β-cell function

Insulin resistance

Compensated; hyperinsulinemia with normal glucose tolerance

Decompensated; relative insulin deficiency “Pre-Diabetes” (IGT or IFG) prevention Type 2 Diabetes Fig. 1. The dual defects of type 2 diabetes: insulin resistance and b-cell dysfunction. The target for most diabetes prevention trials have been those patients at greatest risk for developing diabetes (ie, those who have ‘‘prediabetes’’). IFG, impaired fasting glucose; IGT, impaired glucose tolerance.

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As b-cell function falters, glucose levels initially increase slightly above the normal, although not into the diabetic range. A fasting plasma glucose (FPG) of between 100 mg/dL and 125 mg/dL now is defined as ‘‘impaired fasting glucose’’ (IFG) [13]. During a 75-g oral glucose tolerance test (OGTT), a 2-hour plasma glucose of 140 mg/dL to 199 mg/dL defines ‘‘impaired glucose tolerance’’ (IGT). Patients who have IFG need not have IGT and vice versa. Both, however, represent stages of ‘‘prediabetes’’; the progression of patients who have these criteria to a diagnosis of T2DM ranges from 5% to 10% per year, depending on the genetic predisposition. In the third National Health and Nutrition Examination Survey, it was estimated that 15.6 million people have IGT and 13.4 million people have IFG (using the older FPG criterion of 110–125 mg/dL) (Fig. 2) [1]. In a more recent analysis that used the same database, it was estimated that 11.9 million overweight adults, aged 45 to 74 years, have prediabetes and could benefit from diabetes prevention strategies [14]. The number would be substantially higher if the estimation extended to those who are older than 75 years and younger than 45 years and the newer criteria for IFG were used. Given our understanding of the pathogenesis of T2DM and the significant ‘‘incubation phase’’ between development of the earliest metabolic defects and manifestation of the full expression of the disease, the concept of diabetes prevention emerged. As a result, investigators

20

Impaired fasting glucose

Diabetes

Impaired glucose tolerance

15.6 15.6

Percent of population

15

14.3 12.3 11.4

10

9.7 8.9 6.5

5

0

1976-80 1988-94

1976-80 1988-94

ADA criteria

1976-80 1988-94

1976-80 1988-94

WHO criteria

Fig. 2. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in the U.S. population 40 to 74 years of age, according to National Health and Nutrition Examination Survey (NHANES) II and NHANES III. (From Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose and impaired glucose tolerance in U.S. adults. Diabetes Care 1998;21:523; with permission.)

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proposed that lifestyle modification or pharmacologic interventions that reduce mild forms of hyperglycemia by improved insulin sensitivity or improved or preserved b-cell function might have a long-term impact upon the ultimate development of T2DM (either prevention or delay) in at-risk patients (Box 1). Logically, all of the diabetes prevention studies targeted their efforts on patients who had prediabetes (see Fig. 1). Preventing type 2 diabetes: results of randomized trials The first published diabetes prevention study was by Sartor and colleagues in 1980 [15]. This nonrandomized investigation suggested that T2DM could be prevented by diet, and to a greater extent, by diet and a sulfonylurea (tolbutamide.) This study’s findings were limited by, among other things, its nonrandomized design; however, it deserves mention as a hypothesis-generating work. The Malmo Feasibility Study The first randomized study to address the issue of diabetes prevention came from Malmo, Sweden [16]. Eligibility criteria and characteristics of the actual participants are listed in Table 1. This small feasibility study demonstrated normalization of glucose tolerance in 50% of the 181 male Box 1. Risk factors for type 2 diabetes mellitus Age of at least 45 years Overweight (body mass index
25 kg/m2)a First-degree relative who has diabetes Habitual physical inactivity Member of a high-risk ethnic population (eg, African American, Latino, Native American, Asian American, Pacific Islander) Previously identified prediabetes (IFG or IGT) History of gestational diabetes mellitus or delivery of a baby that weighed more than 4.1 kg Hypertension (
140/90 mm Hg) High-density lipoprotein level of up to 35 mg/dL or a triglyceride level of at least 250 mg/dl Polycystic ovarian syndrome History of vascular disease a May not be correct for all ethnic groups. Adapted from Sherwin RS, Anderson RM, Buse JB, et al for the American Diabetes Association. The prevention or delay of type 2 diabetes. Diabetes Care 2003;26(Suppl 1):S62.

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Table 1 Diabetes prevention trails: eligibility criteria and baseline characteristics of study subjects Eligibility criteria

Actual participants (mean)

Study [Ref.]

Age (y)

BMI

FPG (mg/dL)

Age (y)

BMI

FPG (mg/dL)

Malmo [16] Da Qing [17] FDPS [18] DPP [19] TRIPOD [20] STOP-NIDDM [21]

47–49 NS 40–65
25 NS 40–70

NS NS
25
24 NS 25–40

NS NS NS 95–125 NS 101–139

47–49 44 55 51 35 55

[ 25 [ 25 31 34 30 [ 31

NG NG 110 106 94 101–139

Abbreviations: NG, not given; NS, not specified or relevant to eligibility. Adapted from Sherwin RS, Anderson RM, Buse JB, et al, for the American Diabetes Association. The prevention or delay of type 2 diabetes. Diabetes Care 2003;26(Suppl 1):S49.

subjects who had IGT after dietary treatment or increase in physical exercise over 6 years. A protective effect on the development of diabetes also was suggested, compared with a group of patients in whom no intervention occurred. Several aspects of this study’s design were suboptimal, although the notion of lifestyle intervention to prevent diabetes in high-risk individuals was further supported. The Da Qing Study Pan and colleagues [17] in 1997 reported the results of the Da Qing IGT and Diabetes Study. In this multicenter Chinese investigation, 577 patients who had IGT from an industrial city in northern China were randomized to a control group or to one of three active treatment groups that consisted of changes in diet only, exercise only, or diet and exercise. Follow-up was conducted every 3 months for 6 years; 530 subjects were followed systematically until end points had been reached or until study completion at 6 years. During the follow-up visits, a 2-hour postprandial plasma glucose level was measured; patients who had readings of 200 mg/dL or greater were referred for a formal 2-hour OGTT. The diagnosis of diabetes was made on the basis of the OGTT result, or if repeated FPG reached or exceeded 140 mg/dL (using the 1985 World Health Organization [WHO] criteria) or if a ‘‘casual’’ (irrespective of meals) plasma glucose reached or exceeded 200 mg/dl. Thirty-three local health clinics participated the study, with group randomization by clinic rather than by patient. Eligibility criteria and baseline characteristics of the Da Qing subjects are shown (see Table 1). For the intervention group, a diet of 25 to 30 calories per kg body weight, which consisted of 55% to 65% carbohydrates, 10% to 15% protein, and 25% to 30% fat was designed. Participants were encouraged to increase their daily intake of vegetables, to reduce the consumption of simple sugars, and to control alcohol intake. Those with a body mass index (BMI) of at least 25 kg/m2 were encouraged to reduce their caloric intake to lose approximately

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0.5 kg to 1 kg per month until a BMI of 23 kg/m2 had been achieved. Patients received individual dietary counseling once weekly for 1 month then monthly for 3 months. For the exercise component of the Da Qing Study [17], participants were asked to increase their leisure activity by one ‘‘unit’’ per day. A ‘‘unit’’ was defined as 30 minutes of mild activity (eg, slow walking), 20 minutes of moderate activity (eg, faster walking), 10 minutes of strenuous activity (eg, slow running), or 5 minutes of very strenuous activity (eg, jumping rope, swimming). Those who were younger than age 50 and no cardiac history were encouraged to increase activity by two units per day. The control group was exposed to general information about diet and exercise but with neither individual recommendations nor counseling sessions. The cumulative incidence of diabetes at 6 years was 67.7% (95% confidence interval [CI], 59.8%–75.2%) in the control group, and 43.8% (95% CI, 35.5%–52.3%) in the diet group, 41.1% (95% CI, 33.4%–49.4%) in the exercise group, and 46% (95% CI, 37.3%–54.7%) in the diet plus exercise group. In a proportional hazards analysis that was adjusted for differences in baseline BMI and fasting glucose, the diet group experienced a relative risk reduction (RRR) of 31% (P \ .03); the exercise group experienced a RRR of 46% (P \ .0005); and the combined group experienced a RRR of 42% (P \ .005) in the development of diabetes (Fig. 3). The benefits of the interventions did not correlate with changes in body weight. Although the randomization by clinic in the Da Qing Study [17] may have introduced certain bias, this investigation was the first large, randomized trial to show the impact of diet and exercise on the development of diabetes in high-risk individuals.

% at 6-year followup

90

70

50

30

10 Control

Diet

Exercise

Diet + Exercise

Fig. 3. The Da Qing Study. Mean rates ( SD) of diabetes for each clinic at 6-year follow-up, by intervention group: control, 66%  10%; diet, 47%  11%; exercise, 45%  9%; and diet plus exercise, 44%  17%. (From Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997;20:537; with permission.)

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The Finnish Diabetes Prevention Study Tuomilehto and colleagues [18] randomly assigned 522 middle-aged, overweight Finnish patients who had IGT to a lifestyle intervention group (n = 265) or to a control group (n = 257) (see Table 1 for eligibility criteria and baseline characteristics) in the Finnish Diabetes Prevention Study (FDPS). Subjects in the intervention group received individualized counseling that targeted five elements: weight reduction (at least 5% of body weight); daily intake of total fat (\ 30% of total calories), saturated fat (\ 10% of total calories), and dietary fiber (at least 15 g/1000 calories); and the amount of physical activity (at least 30 min/d of moderate exercise). Frequent intake of whole-grain products, fruits, vegetables, low-fat milk and meat products, and vegetable oils that were rich in monounsaturated fats was recommended. Dietary advice was tailored by trained nutritionists for each subject based on 3-day food diaries that were completed quarterly. Each subject in the intervention group underwent dietary counseling seven times during the first year, and then every 3 months for the duration of the study. They also received individualized recommendations on increasing physical activity, and were offered supervised, progressive resistancetraining sessions. OGTTs were performed annually, with the diagnosis of diabetes made by conventional fasting or postchallenge criteria (based on the 1985 WHO criteria), and confirmed on repeat testing. During the first year of the study, the mean body weight decreased in the intervention group by 4.2  5.1 kg, with minimal change (0.8  3.7 kg) in the control group. Waist circumference, fasting, and 2-hour postchallenge plasma glucose also decreased significantly in the intervention group as compared with controls. At the end of follow-up (mean, 3.2 years), the cumulative incidence of diabetes was lower in the intervention group (11% [95% CI, 6%–15%]) than in the control group (23% [95% CI, 17%–29%]); a statistical difference was apparent by the end of 2 years. According to Cox regression analysis, the cumulative incidence of diabetes was reduced by 58% with intervention (hazard ratio [HR], 0.4; 95% CI, 0.3–0.7; P \ .001); the benefit was slightly greater in men (63%) than in women (54%) (Fig. 4). When ranked according to their success in achieving the five prespecified goals, a strong relationship emerged between ‘‘success score’’ and the incidence of diabetes; those subjects in either group who had achieved the greater number of lifestyle goals experienced the greatest protection against diabetes. The FDPS [18], therefore, was the first optimally randomized study to confirm that lifestyle intervention is highly effective in the prevention of deterioration to diabetes in overweight, middle-aged patients who have IGT. In addition, the relationship between achieving various lifestyle goals and the impact on diabetes risk provides convincing evidence that these individual targets are important alone or in concert. Clearly, the FDPS is notable as a ‘‘proof of concept’’ investigation; however, implementation of

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1.0 Intervention group

Cumulative Probability of Remaining Free of Diabetes

0.9

0.8

0.7

Control group

0.6

0.5

0.4 0

1

2

3 Study Year

507

471

5 16

15 37

4

5

6

374

167

53

27

22 51

24 53

27 57

27 59

SUBJECTS AT RISK Total no. Cumulative no. with diabetes: Intervention group Control group

Fig. 4. Proportion of subjects who did not have diabetes during the FDPS. (From Tuomilehto J, Lindstrom J, Eriksson JG, et al. Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001;344:1347; with permission.)

its lifestyle strategy in practice (ie, outside of the clinical trial setting) will be challenging. The Diabetes Prevention Program Soon after the publication of the FDPS [18] results, the results of the largest diabetes prevention trial, the Diabetes Prevention Program (DPP), became available [19]. In this 3-year U.S. study, 3234 patients who had IGT were randomly assigned to one of three groups: lifestyle modification; metformin, 850 mg, twice a day; and placebo. The study initially included a fourth arm that used troglitazone, 400 mg/d. This was discontinued in 1998 because of hepatotoxicity that resulted in liver failure and the death of one DPP participant. Eligibility criteria and baseline characteristics of patients are shown (see Table 1). Patients in the lifestyle intervention group were asked to achieve and maintain a reduction of at least 7% in body weight through a healthy, low-calorie, low-fat diet and to engage in physical activity of moderate intensity (eg, brisk walking) for at least 150 minutes per week. To assist the study participants in achieving these goals, intensive support was

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required—efforts that are not available to most of our patients in practice. They were provided a flexible, culturally sensitive, and individualized 16lesson curriculum that covered diet, exercise, and behavior modification [22]. The lessons were conducted on a one-to-one basis by case managers during the first 24 weeks. Subsequently, individual sessions occurred monthly and group sessions were used to reinforce behavioral changes. The end point of diabetes was assessed with semiannual FPG (using 1997 American Diabetes Association [ADA] fasting criteria of FPG
126 mg/dL) and annual OGTTs. Subjects who were assigned to the lifestyle group experienced much greater weight loss (5.6 kg) and a greater increase in physical activity than other participants (Fig. 5). The crude prevalence of diabetes was 11.0, 7.8, and 4.8 cases per 100 person-years for the placebo, metformin, and lifestyle groups, respectively. The estimated respective cumulative prevalence of diabetes at 3 years were 28.9%, 21.7%, and 14.4%, respectively (Fig. 6). The prevalence of diabetes was reduced by 58% with lifestyle change (95% CI, 48%–66%) and by 31% in the metformin group (95% CI, 17%–43%). When the two intervention groups were compared, the incidence of diabetes was 39% lower (95% CI, 24%–51%) in the lifestyle group than in the metformin group. Translating these findings for potential clinical applications and based on these rates, the estimated number of patients who have prediabetes needed to treat to prevent one case of diabetes during this period was calculated to be approximately 7 using lifestyle changes and 14 using metformin. On subgroup analysis, several interesting trends were noted. The treatment effects did not differ according to gender or racial or ethnic group. Lifestyle intervention was effective in all subgroups, although it was significantly more effective in those who had lower 2-hour plasma glucose levels during the baseline OGTT. The effect of metformin was reduced in those who had lower BMI and those who had lower FPG levels. The benefit of lifestyle over metformin was more apparent in older individuals and those who had lower BMI. The effect of metformin was insignificant in those who were older than 60 years of age or had a BMI of less than 30 kg/m2, whereas its effectiveness was essentially equal to lifestyle change in those who were between 25 and 44 years of age or had a BMI of greater than 35 kg/m2. One important finding that was reported in a follow-up analysis is that when patients from the DPP who took metformin were reassessed with a repeat OGTT 1 to 2 weeks (average, 11 days) upon discontinuation of the drug, a sizable minority had developed diabetes. This resulted in an overall reduction of the diabetes-preventing effect of metformin from 31% to 25% [23]. This ‘‘washout’’ study suggests that metformin, at least in some patients, may have been ‘‘masking’’ the diabetes and not preventing it. Whether this is a meaningful distinction in patients who are on long-term preventive therapy is not clear. Adverse effects were greater in the metformin group, particularly gastrointestinal symptoms; however, overall, mortality and hospitalizations were the same in all groups. The study was not powered to assess for

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Change in Weight (kg)

A

+4 +2 Placebo

0 –2 Metformin

–4

Lifestyle

–6 –8 0

Change in Physical Activity (MET-hr/wk)

B

0.5

1.0

1.5

2.0

2.5

3.0

Lifestyle

6 4 Metformin

2

Placebo

0

Medication Adherence (%)

4.0

8

0

C

3.5

0.5

1.0

1.5

2.0

2.5

3.0

3.5

4.0

2.5

3.0

3.5

4.0

85 80

Placebo

75 70

Metformin

65 60 0

0.5

1.0

1.5

2.0 Year

Fig. 5. Changes in body weight (A), leisure physical activity (B), and adherence to medication regimen (C) according to study group in the DPP. Changes in weight and leisure physical activity over time differed significantly among the treatment groups (P \ .001 for each comparison). (From Knowler WC, Barrett-Connor E, Fowler SE, et al. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:396; with permission.)

cardiovascular events, although mild reductions in plasma lipids and blood pressure occurred in the lifestyle change group. The DPP Research Group has also presented, in abstract form only at the time of this writing, provocative results from the study’s troglitazone arm, which was aborted because of hepatotoxicity [24]. Three hundred and eighty-seven participants initially were randomized to this thiazolidinedione. When the drug was discontinued, only 10 patients had developed diabetes

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Cumulative Incidence of Diabetes (%)

40

Placebo

30 Metformin Lifestyle 20

10

0 0

0.5 1.0

1.5 2.0 2.5

3.0 3.5 4.0

Year Fig. 6. Cumulative incidence of diabetes according to study group in the DPP. The incidence of diabetes differed significantly among the three groups (P \ .001 for each comparison). (From Knowler WC, Barrett-Connor E, Fowler SE, et al. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:397; with permission.)

during their follow-up assessment visits, after a mean of 0.9 years (range, 0.5 to 1.5 years) of therapy. The prevalence was indistinguishable from that seen with lifestyle changes, but was significantly less than that seen with metformin (P = .02) and placebo (P \ .001). The investigators concluded that troglitazone reduced the prevalence of diabetes; however, the short period of use limits the interpretation of these findings. In a later publication, the DPP Research Group estimated that the costs to the health system from lifestyle and metformin interventions were approximately $750/y per participant [25]. These costs were believed to be modest, and might be reduced with generic metformin and by improving the efficiency of lifestyle intervention staff with the use of group visits. The ultimate determination of the value of these interventions to health systems and society requires a formal assessment of the costs relative to the actual long-term health benefits that were achieved in the DPP, which may be difficult to quantify. The Study to Prevent Non Insulin Dependent Diabetes Trial a-Glucosidase inhibitors, such as acarbose, exert their antihyperglycemic effect by decreasing postprandial glucose concentrations. Therefore, it is logical to assume that this may result in decreased stimulation of pancreatic islets, potentially resulting in ‘‘b-cell rest’’ and a decrease in the conversion to diabetes. The Study to Prevent Non Insulin Dependent Diabetes (STOPNIDDM) Trial was designed to assess the potential for acarbose to prevent

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INZUCCHI & SHERWIN

1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 0.40

Acarbose Placebo

0 20 0 30 0 40 0 50 0 60 0 70 0 80 0 90 0 10 00 11 00 12 00 13 00

0

p=0.0022

10

Cumulative probability

diabetes in patients who had IGT [21]. The study was conducted in several European countries, Israel, and Canada. Entry criteria and baseline characteristics are noted (see Table 1). STOP-NIDDM initially was designed before the change in diagnostic criteria by the ADA and WHO that reclassified the FPG cut-point for the diagnosis of diabetes to 126 mg/dL. In total, 714 patients were assigned randomly to therapy with acarbose, 100 mg, three times a day with meals, and 715 patients were assigned randomly to placebo. Patients were evaluated every 6 months with a measurement of FPG. OGTTs annually or sooner if the FPG increased to greater than 126 mg/dL. The mean daily dosage of acarbose during the study was 194 mg; many patients did not achieve the recommended dosage because of side effects. Twenty-five percent of subjects discontinued their participation early as a result of adverse events that predominantly were gastrointestinal in origin. The mean follow-up was 3.3 years. Patients who were randomized to acarbose were 25% (HR = 0.75) less likely to develop diabetes than those who were randomized to placebo (Fig. 7). The effect was noted as early as 1 year. Subgroup analysis revealed that the benefit of acarbose applied to all patients, irrespective of age, gender, and BMI. Because the definition of diabetes changed during the trial, the data were reanalyzed to include a diagnosis of diabetes if the FPG reached or exceeded 126 mg/dL on two consecutive visits. Using this criterion, the HR decreased further to 0.68 (RRR = 32%). Using an end

Days after randomisation Patients at risk Acarbose 682 655 628 612 531 523 515 497 463 447 432 349 268 212 Placebo 686 671 655 640 512 505 497 470 434 427 414 331 255 208

Fig. 7. Effect of acarbose and placebo on the cumulative probability of remaining free of diabetes during the STOP-NIDDM trial. (From Chiasson JL, Josse RG, Gomis R, et al. STOPNIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOPNIDDM randomised trial. Lancet 2002;359:2072; with permission.)

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point of diabetes that was diagnosed by any two positive OGTTs, the HR was 0.64 (RRR = 36%). The probability of reverting to normal glucose tolerance over time also was improved significantly with acarbose. Analogous to findings after metformin therapy in the DPP, during a 3-month washout at the conclusion of the study, the conversion to diabetes was greater (15%) in patients who were treated previously with acarbose than in the group that was randomized first to placebo (11%). This suggests some ‘‘masking’’ effect of this pharmacologic approach to diabetes prevention. In a subsequent report, the development of major cardiovascular events (coronary heart disease, cardiovascular death, congestive heart failure, cerebrovascular event, peripheral vascular disease) and hypertension (
140/90 mm Hg) also were assessed by the investigators [26]. Acarbose therapy was associated with an RRR of 49% (2.5% absolute risk reduction) in the development of cardiovascular events (HR, 0.51; 95% CI, 0.28–0.95; P = .03). The risk of myocardial infarction was reduced by an impressive 91% (HR, 0.09; 95% CI, 0.01–0.72; P = .02). Acarbose also was associated with a 34% RRR in the prevalence of new cases of hypertension (HR, 0.66; 95% CI, 0.49–0.89; P = .006). Even after adjusting for other known cardiovascular risk factors, the reduction in the risk of cardiovascular events (HR, 0.47; 95% CI, 0.24–0.90; P = .02) and hypertension (HR, 0.62; 95% CI, 0.45–0.86; P = .004) associated with acarbose treatment remained statistically significant. Although impressive, these data need to be approached with caution and require confirmation because the study was not designed and powered to assess for cardiovascular outcomes. The Troglitazone in Prevention of Diabetes Study Another diabetes prevention study that used a pharmacologic agent was published by Buchanan and colleagues [20] who tested the thiazolidinedione, troglitazone, in a group of predominately Hispanic woman who had a recent history of gestational diabetes. This group of collaborators previously showed that these women convert to diabetes at a rate in excess of 50% over 5 years [27]. They theorized that by improving insulin sensitivity, b-cell function would be preserved, resulting in diabetes prevention. In all, 266 women were enrolled in the Troglitazone in Prevention of Diabetes (TRIPOD) Study and randomized to placebo or troglitazone, 400 mg/d [20]. FPG was measured every 3 months and an OGTT was performed annually. In contrast to other studies, intravenous glucose tolerance tests (IVGTTs) also were performed at baseline and after 3 months of therapy to assess for changes in insulin sensitivity and b-cell response as associated with the risk for diabetes. In addition, 8 months after the conclusion of the trial, those women who did not develop diabetes during TRIPOD returned for OGTT and IVGTT while off study medication.

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Baseline characteristics of TRIPOD subjects are listed (see Table 1). With a median follow-up of 30 months, the mean annual prevalence of diabetes was 12.1% and 5.4% in those who were taking placebo or troglitazone (P \ .01), respectively. This resulted in a 55% RRR with drug therapy (Fig. 8). Protection from diabetes in those women who were randomized to troglitazone seemed to be mediated by a reduction in secretory demands that were placed on the b cell by insulin resistance because it correlated with the degree of reduction in endogenous insulin production during the IVGTT at 3 months. Thus, diabetes prevention seemed to be associated with preservation of b-cell secretion to compensate for insulin resistance. In contrast to the observations after metformin in the DPP and acarbose in STOP-NIDDM, protection persisted 8 months after the cessation of study medication. This continued apparent effect of troglitazone on the development of diabetes suggests a more fundamental effect on the natural history of deterioration to diabetes than the simple masking of hyperglycemia. Other studies

Cumulative incidence of diabetes (%)

Additional preliminary reports of apparent diabetes prevention associated with the use of pharmacologic agents have emerged, each involved posthoc secondary analyses of a separate investigation. Heymsfield and colleagues [28] pooled data from 675 obese subjects who were enrolled in three randomized, double-blind, placebo-controlled clinical trials to compare the effects of placebo with the intestinal lipase inhibitor, orlistat; both groups also followed low calorie diets. OGTTs were performed at study initiation and termination. Mean follow-up was 582 days. Subjects

60

40 Placebo 20 Troglitazone 0

0

12

24

36

48

60

Months on trial Fig. 8. Cumulative incidence rates of type 2 diabetes in women who were enrolled in TRIPOD study. The rate in the troglitazone group was significantly less than the rate in the placebo group (P = .009). (From Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic betacell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002;51:2798; with permission.)

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who received orlistat lost 6.7 kg compared with 3.8 kg in those who took placebo. Of the 120 subjects who had IGT at baseline, fewer subjects who were treated with orlistat (3.0% versus 7.6% with placebo) progressed to diabetes at the study’s conclusion. Of the 67 subjects who had IGT at baseline and were treated with orlistat, 48 (72%) had normal glucose tolerance by the end of the study. Of the 53 patients who were treated with placebo who had IGT at baseline, only 49% had normalized. Yusuf et al [29] reported a posthoc secondary analysis of the Heart Outcomes Prevention Evaluation trial of 5720 subjects who were older than age 55 and did not have diabetes but had known vascular disease at study entry. The patients were followed for a mean of 4.5 years. Patients were assigned randomly to receive ramipril, up to 10 mg/d, or placebo. A diagnosis of diabetes was determined from self-reports at follow-up visits every 6 months. One hundred and fifty-five individuals (5.4%) who took placebo developed diabetes in contrast to 102 subjects (3.6%) who took ramipril (HR, 0.66; 95% CI, 0.51–0.95). In the Losartan Intervention for Endpoint Reduction trial, Dahlof and colleagues [30] randomized 9193 subjects who were aged 55 to 80 years and had essential hypertension and left ventricular hypertrophy to a losartanbased or an atenolol-based regimen. After 4 years, despite equal blood pressure control, the losartan group experienced a 13% RRR in the primary end points of death, myocardial infarction, and stroke. Secondary analysis demonstrated that new-onset diabetes also was less frequent with losartan (6%) than with placebo (9%); this represents a 24% risk reduction (95% CI, 12%–36%) that may reflect a mild insulin sensitizing effect of modulation of the renin-angiotensin axis. In the West of Scotland Coronary Prevention Study, 6595 hypercholesterolemic men, aged 45 to 64 years were randomized to pravastatin or placebo [31]. After 5 years of follow-up, pravastatin decreased low-density lipoprotein cholesterol levels by 26% and definite coronary events (nonfatal myocardial infarction and coronary death) were reduced by 31%. Pravastatin therapy also was associated with a 30% risk reduction in the development of diabetes (95% CI, 1%–50%). The investigators suggested that this might have been the result of a reduction in circulating triglyceride concentrations or the anti-inflammatory effects or endothelial effects of the drug. Of note, however, no other statin trial, including the large Cholesterol and Recurrent Events study, Scandinavian Simvastatin Survival Study, and the Heart Protection Study, have reported similar posthoc findings. Several other T2DM prevention trials are underway, including Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR), Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM), Actos Now for the Prevention of Type 2 Diabetes (ACT NOW; pioglitazone) and Outcome Reduction with Initial Glargine Intervention (ORIGIN; insulin glargine) [32], although results will not be available for several more years.

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Questions that remain Based on the human and financial costs that are associated with the myriad complications of T2DM, disease prevention is a logical, and potentially, a cost-effective strategy, especially if in addition to a reduction in metabolic ‘‘events,’’ a reduction of cardiovascular events can be demonstrated. The findings of the diabetes prevention studies reviewed herein (Table 2) are noteworthy and timely, given the extraordinary increase in the prevalence of T2DM. Several key issues are addressed by these investigations, but many important questions remain. Are the preventive interventions in these studies truly preventive or do they simply delay the inevitable diagnosis of diabetes? The answer can only result from longer-term studies than have been, or are being, performed. It is reasonable to presume that even if the disease is delayed, less overall years of diabetes exposure would translate to deferred morbidity. Therefore, this may be a worthy goal for individual patients, although it might not be cost effective at a societal level. If we do accept that diabetes prevention (or delay) is an important undertaking, we must clarify the optimal strategy to identify those persons who are at risk and in whom intervention would be warranted. Almost all of the diabetes prevention studies to date targeted patients who had prediabetes (ie, IFG or IGT). The ADA recently decreased its threshold for impaired fasting glucose (100 mg/dL); this will increase the identification of persons who are at risk. Reliance on the fasting glucose alone will fail to detect a substantial proportion of patients who have prediabetes. Therefore, a 2-hour OGTT will be necessary in many patients to demonstrate IGT; however, this may be impractical to implement on a routine basis. Some investigators proposed using other means of identifying those who are at risk for future diabetes based on clinical criteria [33] or more stringent FPG and hemoglobin A1c cut-points [34]. Which is the best approach to screening? Should the formal OGTT be performed in all at-risk individuals? What are the additional cost implications of such a strategy? In the studies that involved diet and exercise interventions [17–19], significant efforts that were well above the standard of care were required to help patients achieve and sustain lifestyle change. They were not necessarily Table 2 Summary of diabetes prevention studies Study, year [Ref.]

Intervention

RRR (%)

Da Qing, 1997 [17] FDPS, 2001 [18] DPP, 2002 [19]

Diet  exercise Diet þ exercise Diet þ exercise Metformin Troglitazone Acarbose

31–46 58 58 31 55 25

TRIPOD, 2002 [20] STOP-NIDDM, 2002 [21]

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practical within the context of our current health care delivery system. In addition, patients who were recruited to clinical trials may not be representative of the general prediabetic population, in terms of enthusiasm and adherence to lifestyle changes and in the ability to meet target lifestyle goals. Therefore, how do we implement the findings regarding lifestyle modification in our practices, where patients may have neither the commitment nor the ready access to nutritional counseling and exercise programs? National health care policies will need to adapt to these emerging needs. An important lesson of the metformin arm of the DPP [19], STOPNIDDM [24], and TRIPOD [26] is that in those patients who cannot or will not initiate lifestyle change, the use of antihyperglycemic pharmacologic agents, particularly those with insulin sensitizing activity, slows the progression to diabetes. Would the combination of lifestyle change plus pharmacotherapy result in even greater risk reduction? Also, with metformin and acarbose, the degree to which prevention occurs is less than with lifestyle modification, and the effect seems to dissipate quickly in many patients upon discontinuation of medication. The more impressive effects of thiazolidinedione therapy in TRIPOD, in terms of RRR and the duration of the effect, must be confirmed in larger trials with a more heterogeneous study population. In this light, the results of the DREAM and ACT NOW trials are awaited anxiously. Although pharmacotherapy remains a reasonable default strategy, the use of medications to prevent a disease which may be avoided more effectively by adopting a healthy lifestyle has ethical and fiscal considerations. Can our health care system afford the additional expense of providing pharmacologic prevention to the millions of patients who have prediabetes who might qualify? Certainly, cost-effectiveness analyses of any positive study results will be tremendously important (although probably difficult to model). Finally, how do we place the results of studies that use lifestyle interventions and antihyperglycemic therapies in the context of the preliminary reports that suggest a similar benefit from other drug classes, such as the angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, and statins? This question will need to be answered by carefully designed long-term trials.

Guidelines for the clinician A working group on diabetes prevention, cosponsored by the ADA and the National Institute of Diabetes, Digestive and Kidney Diseases, recently published a position statement, which now serves as a Clinical Practice Recommendation by the ADA [35]. The group believed that there was substantial evidence that T2DM should be prevented and recommended that individuals who are at high risk be identified and treated with at least lifestyle interventions. Its basic recommendations are listed in Box 2. With

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the data at hand, such recommendations are reasonable. We believe that enough information has accumulated to implement diabetes prevention strategies confidently in all at-risk patients. The identification of individuals who are at greatest risk for developing diabetes (ie, those with prediabetes) seems justifiable, although we continue to prefer the FPG determination as a more practical screen than broad implementation of OGTT. Clearly, lifestyle modification must be the first recommendation to those who have impaired glucose levels. General healthy lifestyle guidelines also could be

Box 2. Recommendations of the American Diabetes Association Working Group on the Prevention of Diabetes  Individuals who are at high risk for developing diabetes should become aware of the benefits of modest weight loss and participation in regular physical activity.  Screening: based on current screening guidelines for diabetes, men and women who are older than 45 years of age, particularly those who have a BMI of greater than 25 kg/m2, are candidates for screening to detect prediabetes (IFG or IGT). Screening should be considered in younger individuals who have a BMI that is greater than 25 kg/m2 and have additional risk factors (see Box 1).  In individuals who have normoglycemia, rescreening at 3-year intervals seems to be reasonable.  How to screen: screening should be carried out only as part of a health care office visit. Either an FPG test or a 2-hour OGTT (75-g glucose load) is appropriate. Positive test results should be confirmed on another day.  Intervention strategy: patients who have prediabetes (IFG or IGT) should be given counseling on weight loss and instruction for increasing physical activity.  Follow-up counseling seems to be important for success.  Monitoring for the development of diabetes should be performed every 1 to 2 years.  Close attention should be given to, and appropriate treatment given for, other cardiovascular disease risk factors (eg, tobacco use, hypertension, dyslipidemia).  Drug therapy should not be used routinely to prevent diabetes until more information is known about its cost-effectiveness. Adapted from Sherwin RS, Anderson RM, Buse JB, et al, for the American Diabetes Association. The prevention or delay of type 2 diabetes. Diabetes Care 2003;26(Suppl 1):S62–9; with permission.

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High-risk patient <100 (“Normal”)

√ FPG FPG>126

FPG 100-125 (IFG)

Treat for diabetes

Consider OGTT

<140 (“Normal”)

2-h PG 140-199 (IGT)

Diet + Exercise

2-h PG ≥200 Treat for diabetes

Aggressive treatment of other CV risk factors (smoking, blood pressure, lipids); prophylactic aspirin therapy

Follow-up every 6-12 months

Adherence & success*

Adherence but failure‡

Nonadherence but success*

Nonadherence & failure‡

Continue diet+exercise

Consider drug therapy

Ongoing counseling

Consider drug therapy

* “success”=stable or improving glycemia, ‡ “failure” = deteriorating glycemia

Fig. 9. The prevention of type 2 diabetes: a proposed algorithm. CV, cardiovascular; PG, plasma glucose.

recommended to those who have features of the insulin resistance syndrome, yet who are normoglycemic. Finally, cardiovascular risk factor modification must be considered to be an integral part of any diabetes prevention strategy. A proposed algorithm for the prevention of T2DM, based, in part, on these recommendations, is outlined in Fig. 9. We are entering an exciting era in the prevention of T2DM. Recently published studies that involved lifestyle and pharmacologic interventions clearly demonstrated their relative effects, at least in the short-term. What is less clear is which intervention will have the greatest acceptance rate by patients who are not participating in clinical trials; which will have the most durable effects; and, which, ultimately, will be the most cost-effective. Furthermore, future implementation of diabetes prevention strategies will depend on whether cardiovascular events can be reduced by those efforts. How we, as clinicians, should implement these strategies optimally in our atrisk patients likely will require years of further study and clinical experience. References [1] Harris MI, Flegal KM, Cowie CC, et al. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in US adults. The Third National Health and Nutrition Examination Survey, 1988–1994. Diabetes Care 1998;21:518–24. [2] 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

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