Effectiveness and Cost-Effectiveness of Diabetes Prevention among Adherent Participants

Abstract

OBJECTIVES

We report the 10 year effectiveness and within-trial cost-effectiveness of the The Diabetes Prevention Program (DPP) and its Outcomes Study (DPPOS) interventions among participants who were adherent to the interventions.

STUDY DESIGN

DPP was a 3-year randomized clinical trial followed by 7-years of open-label modified intervention followup.

METHODS

Data on resource utilization, cost, and quality-of-life were collected prospectively. Economic analyses were performed from health system and societal perspectives. Lifestyle adherence was defined as achieving and maintaining a 5% reduction in initial body weight and metformin adherence as taking metformin at 80% of study visits.

RESULTS

The relative risk reduction was 49.4% among adherent lifestyle participants and 20.8% among adherent metformin participants compared to placebo. Over 10 years, the cumulative, undiscounted, per capita direct medical costs of the interventions, as implemented during the DPP, were greater for adherent lifestyle participants ($4,810) than adherent metformin participants ($2,934) or placebo ($768). Over 10 years, the cumulative, per capita non-intervention-related direct medical costs were $4,250 greater for placebo participants compared to adherent lifestyle participants and $3,251 greater compared to adherent metformin participants. The cumulative quality-adjusted life-years (QALYs) accrued over 10 years were greater for lifestyle (6.80) than metformin (6.74) or placebo (6.67). Without discounting, from both a modified societal perspective (excluding participant time), lifestyle cost <$5,000 per QALY-gained and metformin was cost-saving compared to placebo.

CONCLUSIONS

Over 10 years, lifestyle intervention and metformin were cost-saving compared to placebo. These analyses confirm that lifestyle and metformin represent a good value for money.

Previously, we reported the clinical and economic outcomes of an intent-to-treat analysis of the combined 10 years of the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study (DPP/DPPOS) (1,2). In that analysis, participants were analysed according to their randomized treatment group whether or not they adhered to their assigned treatment. In this paper, we report the results of an “on treatment” or “per-protocol” analysis of DPP/DPPOS. We assess outcomes by treatment group for participants who were adherent to their randomized assignments and compare the effectiveness and cost-utility of the intensive lifestyle intervention (lifestyle) and the metformin intervention (metformin) to the placebo intervention (placebo).

Our previously published 10 year intent-to-treat analysis of DPP/DPPOS used data from all randomized participants including those who did not adhere to their randomized treatments and so, likely underestimated both the effectiveness and the benefits of lifestyle and metformin. In real world clinical practice, neither costs nor benefits are incurred by nonparticipants but among participants, both intervention costs and benefits are likely to be greater. Our goal in this analysis of the DPP/DPPOS is to extend our previous analyses to estimate the clinical effectiveness and cost-effectiveness of diabetes prevention among metformin participants who remained on treatment with metformin and lifestyle participants who succeeded in losing weight.

Methods

Screening

The DPP enrolled 3,234 participants with IGT and fasting hyperglycemia who were at least 25 years of age and had body mass index of 24 kg/m² or higher (22 kg/m² in Asian-Americans) (3). The protocol and informed consent procedures were approved by all responsible institutional review boards. Participants signed written consent forms after discussion of all aspects of the study with study staff. For this analysis, we assigned costs related to finding the participants randomized to lifestyle and metformin but not the participants randomized to placebo. In estimating the costs of finding participants, we assumed that 10.4% of adults 45-74 years of age would be eligible to participate (4). We further assumed that potentially eligible subjects would be tested with a random capillary glucose level (5). If the capillary glucose level was ≥110 mg/dl, an oral glucose tolerance test (OGTT) would be performed (6) and those with abnormal OGTTs would have a 15 minute visit with a physician to discuss the results. Based on the sensitivity, specificity, and reproducibility of the tests, we estimated that 12.8% of subjects screened would be eligible to participate in the DPP and that the average cost per eligible participant identified would be $173.

Interventions

DPP

The goals for participants randomized to lifestyle were to achieve and maintain a weight reduction of at least 7 percent of initial body weight through diet and physical activity of moderate intensity, such as brisk walking, for at least 150 minutes per week (7). A 16-session core curriculum (given approximately weekly in individual participant sessions) and subsequent individual sessions (usually monthly) and group sessions with case managers were designed to reinforce the behavioral changes. The medication interventions (metformin and placebo) were initiated at a dose of 850 mg taken orally once a day. At one month, the dose was increased to 850 mg twice daily. Adherence was reinforced during individual quarterly visits with case managers. Standard lifestyle recommendations were provided to all groups through written information and an annual 20-to-30-minute individual session that emphasized the importance of a healthy lifestyle. Mean follow-up at the end of DPP was 3.2 years. For the purposes of this analysis, we assumed that all subjects were enrolled in DPP for exactly 3 years.

DPP/DPPOS Bridge

At the end of the DPP, all participants, regardless of their random treatment assignment, were offered a group-implemented 16 session lifestyle intervention before their enrolment in the DPP Outcomes Study. During this bridge period, 40% of lifestyle, 58% of metformin, and 57% of placebo participants attended at least one session (8). The original lifestyle group was offered additional lifestyle support and was not encouraged to take metformin. The original metformin group was encouraged to continue metformin and to participate in the group lifestyle intervention. Those randomized to placebo stopped placebo and were encouraged to participate in the group lifestyle intervention. For the purposes of this analysis, we assumed that year 4 represented the DPP/DPPOS bridge.

DPPOS Maintenance

All active participants were eligible for continued follow-up during the DPPOS maintenance phase and 2,766 of 3,150 (88%) enrolled (1). These included 910 participants originally randomized to lifestyle, 924 to metformin, and 932 to placebo. For the purposes of this analysis, we assumed that years 5-10 represented DPPOS maintenance.

During DPPOS maintenance, the group lifestyle intervention was implemented as the Healthy Lifestyle Program (HELP) for all participants. HELP reinforced the original weight loss and physical activity goals and focused on current topics in nutrition, physical activity, stress management, and diabetes prevention. Although all participants were invited to attend all HELP sessions, many chose to attend fewer.

DPP participants initially randomized to lifestyle were also eligible to receive two BOOST sessions per year to reinvigorate their self-management behaviors for weight loss. Those randomized to metformin and placebo were excluded from BOOST sessions. The sessions reinforced specific behavioral self-management activities (e.g. self-monitoring of fat, calories, and/or physical activity, as well as weight checks) important for weight loss and physical activity adherence and/or maintenance. In addition, the sessions promoted home-based behavioral self-management of weight and physical activity through the use of motivational campaigns.

Only metformin participants were encouraged to take metformin. One percent of non-diabetic participants in lifestyle and 3% of non-diabetic participants in placebo took metformin for diabetes prevention at any time during DPPOS maintenance (1). Lifestyle and placebo participants who took metformin during DPPOS maintenance were not excluded from the analyses.

Interventions for Participants with Diabetes

Participants identified with glucose levels diagnostic of diabetes at their semi-annual visits were seen within 6 weeks for glucose testing to confirm the diagnosis. Participants with confirmed newly diagnosed diabetes received individual counseling focused on self-monitoring of blood glucose, were provided with meters and test strips and encouraged to monitor their glucose levels once daily, and, for purpose of analyses, were maintained in their randomized intervention groups. Treatment for diabetes and surveillance for complications and comorbidities were performed by the participants’ own health care providers. Medications used by DPP participants for management of diabetes were recorded every six months on a drug summary form.

Subjects

For these analyses, we wished to assess resource utilization, costs, and outcomes by treatment group among participants randomized to lifestyle and metformin who adhered to their randomized interventions. We assumed that all participants randomized to lifestyle and metformin were adherent during year 1, when the interventions were initially implemented. We defined adherent lifestyle participants as those without diabetes who achieved and maintained 5% weight loss at ≥50% of their semi-annual visits beginning at the end of year 1. We defined adherent metformin participants as those without diabetes who took ≥80% of their prescribed metformin based on pill counts at ≥80% of their semi-annual follow-up visits beginning at the end of year 1. We defined adherent placebo participants as all those randomized to the placebo group regardless of their adoption of lifestyle or metformin treatments during DPP, DPPOS Bridge, or DPPOS maintenance. Of the 1,079 participants randomized to lifestyle, 587 (54%) were defined as adherent at the end of DPP year 1. Of 1,073 participants randomized to metformin, 666 (62%) were defined as adherent at the end of DPP year 1. Participants in the lifestyle and metformin groups were defined as adherent until the time they became non-adherent or developed diabetes. For the most part, participants who were adherent at the end of DPP year 1 remained adherent for the duration of follow-up.

Costs

We calculated the mean per capita direct medical costs associated with the DPP/DPPOS interventions for participants who remained adherent to their randomized treatment assignments over each of the 10 years after randomization. Direct medical costs of the interventions were estimated from the resources used and unit costs adjusted to 2010 U.S. dollars. We have previously reported in detail how costs were calculated (2). To estimate the cost of the lifestyle intervention if it had been administered in a group format rather than individually, we recalculated the costs of lifestyle assuming that the core curriculum and monthly follow-up visits with the lifestyle case managers, which were conducted individually during the 3 years of the DPP, were conducted as group sessions with ten participants. Studies have shown that group lifestyle intervention programs for obesity are at least as effective as individual programs (9,10). Although metformin was implemented with brand name metformin (Glucophage), we assumed that it was implemented with generically-priced metformin throughout the 10 years of DPP/DPPOS.

We also estimated the per capita direct medical costs of care outside the study for adherent participants (2,11). The direct medical cost of care outside the study was estimated from case report forms and surveys administered every 6 months. Direct medical costs included the costs of hospital, emergency room, urgent care, and outpatient services, the cost of telephone calls to health care providers, and the cost of prescription medications (2,11).

Direct non-medical costs were assessed twice, once during DPP and once during DPPOS, and costs were annualized (2). In estimating the direct non-medical costs of the interventions for adherent participants, we considered the cost of food, food preparation items, exercise classes, gym memberships, and personal trainers, and exercise equipment (2). We also considered the costs of transportation to study visits and to medical visits (2). The value of the time that participants spent shopping, cooking, exercising, and traveling to and attending appointments was also assessed (2). The costs of exercise were valued according to whether participants “disliked”, were “neutral”, or “liked” leisure time physical activity (2,12). Although direct non-medical costs are not usually paid by private insurers or government health programs, we included them in our cost calculations from a societal perspective.

Outcomes

We assessed outcomes for adherent participants as both incident diabetes and quality-adjusted life-years (QALYs) (13). QALYs measure length of life adjusted for quality-of-life as assessed by the health utility score. By convention, health utility scores are placed on a continuum where perfect health is assigned a value of 1.0 and health judged equivalent to death is assigned a value of 0.0. We assessed health utilities annually using the Self-Administered Quality of Well-Being Index (QWB-SA) (14). Mathematically, QALYs are calculated as the sum of the product of the number of years of life and the quality-of-life, measured in health utilities, in each of those years.

Perspective

For the primary analysis, we followed the recommendations of the Panel on Cost-Effectiveness in Health in Medicine (13) and took the perspective of a health system. Thus, we included only direct medical costs of the interventions and non-intervention related medical care in our base-case analysis. We included direct nonmedical costs excluding participant time in a sensitivity analysis from a modified societal perspective and direct nonmedical costs including participant time in a sensitivity analysis from a full societal perspective. These sensitivity analyses assessed the impact of covering the cost of the interventions implemented by the study participants on society as a whole.

Analyses

The analyses of lifestyle and metformin were conducted for participants who adhered to the lifestyle intervention (as assessed by weight loss) and who regularly took metformin (as assessed by pill counts). The analyses of placebo were conducted for all participants randomized to the placebo group. For the DPP group lifestyle analysis, we estimated what the costs of lifestyle would have been during the 3 years of DPP if the 16 session core curriculum and monthly follow-up visits with the case managers had been conducted as closed group sessions with ten participants. We assumed that outcomes for DPP group lifestyle would have been the same as observed for the lifestyle intervention as originally implemented. We excluded from the analyses the costs of the research component of the DPP/DPPOS. All costs were expressed as year 2010 U.S. dollars. Analyses were performed with a ten-year time horizon. Data on resource utilization were aggregated using SAS (SAS Institute, Cary, NC). The aggregated resource utilization data were then multiplied by the unit cost and by the probability that a participant was followed during the time period. The latter analyses and the tables and figures were generated using Excel (Microsoft Inc, Redmond, WA). Initial analyses were performed without discounting. Subsequently, where noted, both costs and health outcomes were converted to net present value using a 3% discount rate.

Results

At 10 years, the cumulative incidence of diabetes was 52.4% among participants originally randomized to the minimal intervention arm that included placebo medication and standard lifestyle recommendations (i.e. the ‘placebo’ group). The incidence of diabetes was 41.5% among metformin participants who regularly took metformin, and 26.5% among lifestyle participants who achieved and maintained a 5% reduction in initial body weight (Figure 1). Compared to placebo, the absolute risk reduction at 10 years was 25.9% with lifestyle and 10.9% with metformin. The relative risk reduction was 49.4% with lifestyle compared to placebo and 20.8% with metformin compared to placebo. Due largely to the reduced incidence of diabetes, quality-of-life, as assessed by health utility scores, was better among adherent lifestyle and adherent metformin participants than placebo participants. At 10 years, the mean undiscounted cumulative QALYs-accrued were 6.80 for lifestyle, 6.74 for metformin, and 6.67 for placebo participants. Compared to placebo participants, adherent lifestyle participants accrued 0.13 more QALY (i.e. years of perfect health) over 10 years and adherent metformin participants accrued 0.07 more QALY.

Figure 1.

Cumulative incidence of confirmed diabetes by intervention group and study year - Adherence analysis

The annual undiscounted per capita direct medical costs of lifestyle, DPP group lifestyle, metformin, and placebo over 10 years for adherent participants are summarized in Table 1 and Figure 2a. The costs of lifestyle ($3,801) are $1,578 or over 70% greater than the costs of offering lifestyle in a group format ($2,223) in DPP years 1-3 (DPP group lifestyle) because of the difference in resource utilization between an individual- and group-implemented intervention. The per capita costs of lifestyle were substantially lower during DPPOS than during DPP because of the change from an individual to a group implemented intervention, less frequent intervention sessions, and lower session attendance. The costs of placebo were slightly higher during DPPOS than during DPP because placebo participants engaged in the group lifestyle intervention.

Table 1.

Undiscounted per capita direct medical costs of the DPP/DPPOS interventions by intervention group and study year ($) - Adherence analysis

Year	Lifestyle	Metformin	Placebo	DPP Group Lifestyle*
Screening	173	173	0	173
1-DPP	1,826	602	88	898
2-DPP	887	321	51	562
3-DPP	915	329	48	590
4 (Bridge)	175	355	221	175
5-DPPOS	119	190	58	119
6-DPPOS	124	190	57	124
7-DPPOS	142	188	56	142
8-DPPOS	146	188	55	146
9-DPPOS	145	189	57	145
10-DPPOS	158	209	77	158
Total	4,810	2,934	768	3,232

^*Sensitivity analysis. Assumes that DPP core curriculum and follow-up visits were conducted as group sessions with ten participants.

Figure 2.

Adherence analysis for:

A: Cumulative, undiscounted, per participant, direct medical costs of the DPP/DPPOS interventions by intervention group and study year.

B: Cumulative, undiscounted, per participant, direct medical costs of medical care received outside the DPP/DPPOS by intervention group and study year.

C: Cumulative, undiscounted, per participant, total direct medical costs of the DPP/DPPOS interventions and medical care received outside the DPP/DPPOS by intervention group and study year.

D: Cumulative, undiscounted, per participant, total Quality of Well-Being Index by intervention group and year.

The cumulative undiscounted per participant cost of the lifestyle intervention ($4,810) was substantially greater than the estimated cost of the DPP group lifestyle intervention ($3,232), the metformin intervention ($2,934), or the placebo intervention ($768) (Figure 2b). Over 10 years, the cumulative undiscounted per capita incremental direct medical costs of the interventions were greater for adherent participants in lifestyle ($4,042), group lifestyle ($2,464), and metformin ($2,166) compared to placebo.

The cumulative undiscounted per capita direct medical costs of non-intervention-related medical care by intervention group and year following randomization for adherent participants are shown in Table 2 and Figure 2c. These are the costs of medical care received outside the DPP/DPPOS. The cumulative direct medical costs of non-intervention-related medical care ($23,218 to $27,468 per person over 10 years) were substantially greater than the costs of the interventions ($768 to $4,810 per person over 10 years). Among all groups, the costs of non-intervention-related medical care increased over time. Over 10 years, the cumulative, per capita non-intervention-related direct medical costs were $4,250 greater for placebo participants compared to adherent lifestyle participants and $3,251 greater for placebo participants compared to adherent metformin participants.

Table 2.

Undiscounted per capita direct medical costs of care outside the DPP/DPPOS by intervention group and study year ($) - Adherence analysis

Costs by year	Lifestyle	Metformin	Placebo
1-DPP	1,423	1,517	1,617
2-DPP	1,909	1,729	2,045
3-DPP	1,875	1,671	2,018
4 (Bridge)	2,113	2,056	2,330
5-DPPOS	1,865	2,106	2,543
6-DPPOS	2,495	2,665	2,636
7-DPPOS	2,306	2,747	2,875
8-DPPOS	3,199	3,400	3,319
9-DPPOS	3,460	3,085	3,265
10-DPPOS	2,572	3,241	4,822
TOTAL	23,218	24,217	27,468

Costs by category	Lifestyle	Metformin	Placebo
Outpatient visits	6,741	6,835	7,325
Inpatient care	4,748	4,538	6,856
ER visits	1,855	1,344	1,825
Urgent care visits	1,575	1,836	1,811
Calls to physicians	670	698	712
Prescription medications	6,539	6,972	6,959
Self monitoring supplies and laboratory tests for diabetes	1,090	1,994	1,978
TOTAL	23,218	24,217	27,468

By year 10, cumulative undiscounted per participant total direct medical costs of the DPP/DPPOS interventions and medical care received outside the DPP/DPPOS were higher for placebo ($28,236) than for lifestyle ($28,027), DPP group lifestyle ($26,449), or metformin ($27,150) (Figure 2d). Thus, when both intervention and non-intervention-related medical costs were considered, all 3 interventions saved money relative to the placebo intervention.

Cumulative, 10-year, diet-, physical activity-, transportation- and time-related costs were similar across treatment groups ($147,704 for lifestyle, $146,999 for metformin, and $147,043 for placebo). Although adherent lifestyle participants spent more time exercising, the adjusted value of the time they spent exercising was not greater than for either metformin or placebo because of their greater enjoyment of leisure time physical activity and the lower opportunity cost.

Table 3 summarizes the differences in costs and QALYs and the incremental cost-effectiveness ratios of lifestyle, DPP group lifestyle, and metformin vs. placebo and for lifestyle compared to metformin. From the health system perspective and without discounting, the total direct medical costs for the lifestyle, DPP group lifestyle, and metformin participants were less than for placebo participants and the interventions were more effective as assessed by QALYs-gained. In other words, all three interventions were cost-saving compared to placebo. With discounting and compared to metformin, lifestyle cost $2,004 more but produced an additional 0.06 QALY over 10 years. From a health system perspective, with both costs and health outcomes discounted at 3% per year, the cost of lifestyle compared to placebo was $19,988 per QALY-gained, the cost of DPP group lifestyle compared to placebo was $9,688 per QALY-gained, and the cost of metformin compared to placebo was $20,183 per QALY-gained. The cost of lifestyle compared to metformin was $19,662 per QALY-gained.

Table 3.

Differences in costs and QALYs and incremental cost-effectiveness ratios for lifestyle and metformin vs placebo over 10 years from three alternative perspectives ($) - Adherence analysis

Differences in costs (Δ cost )	Lifestyle vs placebo	Metformin vs placebo	Lifestyle vs metformin	DPP group lifestyle vs placebo*
Health system perspective1
Undiscounted	−210	−1,086	877	−1,788
Discounted2	3,007	1,897	1,110	1,458
Modified societal perspective3 (undiscounted)	579	−1,465	2,044	−999
Societal perspective4 (undiscounted)	451	−1,130	1,581	−1,126
Differences in QALYs (Δ QALY)
Undiscounted	0.14	0.08	0.06	0.14
Discounted	0.15	0.09	0.06	0.15
Incremental cost-effectiveness ratios (Δ Cost / Δ QALY)
Health system perspective1
Undiscounted	Cost-saving	Cost-saving	14,213	Cost-saving
Discounted2	19,988	20,183	19,662	9,688
Modified societal perspective3 (undiscounted)	4,151	Cost-saving	33,149	Cost-saving
Societal perspective4 (undiscounted)	3,235	Cost-saving	25,644	Cost-saving

^*Sensitivity analysis. Assumes that DPP core curriculum and follow-up visits were conducted as group session with ten participants

¹Includes total direct medical costs

²Both costs and QALYs discounted at 3%

³Includes direct medical and direct nonmedical costs excluding participant time

⁴Includes direct medical and direct nonmedical costs including participant time

Without discounting, from both a modified societal perspective (excluding participant time) and a full societal perspective (including participant time), lifestyle cost <$5,000 per QALY-gained and both DPP group lifestyle and metformin were cost-saving compared to placebo. Compared to metformin, lifestyle cost <$35,000 per QALY-gained.

Discussion

In this 10 year analysis of the combined Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study, the cumulative incidence of diabetes was 26.5% among lifestyle participants who adhered to the lifestyle intervention, 41.5% among metformin participants who adhered to metformin, and 52.4% among placebo participants. Compared to placebo, lifestyle reduced the absolute risk of diabetes by 25.9% and metformin reduced the absolute risk of diabetes by 10.9%. The relative risk reduction associated with lifestyle was 49.4% and that associated with metformin was 20.8%. In our previous intent-to-treat analysis, the risk of diabetes at 10 years was 42% with lifestyle and 47% with metformin and 52% with placebo (2). It is not surprising that lifestyle and metformin were substantially more effective among participants who adhered to the interventions.

The benefit of metformin as assessed by quality-adjusted life-years gained was also greater in this analysis than the intent-to-treat analysis. In this analysis, lifestyle participants accrued 6.80 QALYs over 10 years, metformin participants accrued 6.74 QALYs, and placebo participants accrued 6.67 QALYs. In the intent-to-treat analysis, lifestyle participants accrued a similar number of QALYs (6.81 QALYs) but metformin participants accrued fewer QALYs (6.69 QALYs) (2). The lower QALY-gained in the intent-to-treat analysis of metformin participants may have been related to adverse events experienced by some metformin participants who subsequently were unable to remain adherent to therapy.

The cumulative undiscounted per capita direct medical costs of the DPP/DPPOS lifestyle and metformin interventions were higher in participants who were adherent to treatment than in participants in the intent-to-treat analysis (2). Lifestyle was approximately 5% more expensive ($4,810 vs $4,601), group lifestyle was 7% more expensive ($3,232 vs $3,023), and metformin was 28% more expensive ($2,934 vs $2,300). This likely reflects the greater adherence of participants to their interventions and greater resource utilization, especially in the case of metformin participants.

Undiscounted per capita direct medical costs of care outside the DPP/DPPOS were lower in lifestyle and metformin participants who were adherent to their randomized treatment assignments compared to intent-to-treat participants (2). This could, in part, reflect the substantially lower incidence of diabetes among participants adherent to the lifestyle and metformin interventions. The undiscounted per capita 10 year cumulative direct medical costs of care outside DPPOS were 5% lower for adherent lifestyle participants than intent-to-treat lifestyle participants ($23,218 vs $24,563) and 5% lower for adherent metformin participants than intent-to-treat metformin participants ($24,217 vs $25,615) (2).

In these analyses, from a health system perspective and without discounting, lifestyle, DPP group lifestyle, and metformin were all cost-saving relative to placebo. In our previous undiscounted intent-to-treat analysis, lifestyle cost approximately $6,700 per QALY-gained compared to placebo but both DPP group lifestyle and metformin were cost-saving (2). In both this analysis and our previous intent-to-treat analysis, lifestyle was more expensive than metformin but produced greater health benefits (2). The undiscounted cost per QALY was $14,213 and $10,555, respectively (2). In these analyses, from a health system perspective and with both costs and QALYs discounted at 3%, neither lifestyle, DPP group lifestyle, nor metformin was cost-saving. These differences likely reflect the impact of discounting on early treatment costs. In these analyses, we assumed that all participants randomized to lifestyle and metformin remained adherent during the first year. Because early treatment costs were greater, discounting resulted in the early, relatively expensive preventive interventions being less cost-effective.

The results of this 10 year within trial analysis demonstrate that lifestyle and metformin interventions are even more effective for diabetes prevention in DPP/DPPOS participants who are adherent to their randomized treatments than among the larger group of both adherent and nonadherent participants. In addition, the interventions are extremely cost-effective or even cost-saving. These results are consistent with earlier analyses that assessed the cost-effectiveness of lifestyle and metformin interventions based upon the results of the Finnish Diabetes Prevention Study (15), the DPP (16,17), the DPP/DPPOS (18), and the Indian Diabetes Prevention Study (19). One study which did not find lifestyle intervention to be cost-effective (20) differed from the published lifetime cost-utility analyses (16-18) in that it assumed that the lifestyle intervention continued over the participants’ lifetimes even after they developed diabetes. It also assumed that when participants developed diabetes, their HbA1c remained <7.0% for the remainder of their lives. These assumptions led to potential overestimation of intervention costs and underestimation of the costs and quality-of-life impact of the complications and comorbidities of diabetes. Taken together, these assumptions likely account at least in part for the difference in results.

This analysis has a number of limitations. First, in defining participants as adherent to the lifestyle intervention, we used the outcome (weight loss) to define adherence. This was necessary because all lifestyle participants were strongly encouraged to attend lifestyle sessions and attendance was not a good marker of adoption of the behavioral intervention. Second, the simulated group lifestyle intervention was not empirically tested within the DPP. The decision to implement the lifestyle intervention individually within DPP was pragmatic. The study group was anxious to enroll participants and begin the interventions as quickly as possible. The literature suggests, however, that group-implemented lifestyle interventions are at least as effective as individually-implemented interventions, largely due to the benefits of peer support. Third, we included all participants randomized to placebo in these analyses. During DPPOS, placebo participants were offered and participated in the group lifestyle intervention and 3% were prescribed metformin outside the study. If these interventions were effective in the placebo group, they would have reduced non-intervention-related resource utilization and costs. The relative impact of these potential biases is impossible to determine, but if the intervention costs were less than the savings resulting from a decreased incidence of diabetes, the bias would be conservative making lifestyle and metformin appear less cost-effective relative to placebo.

In summary, this assessment of outcomes among DPP/DPPOS participants who were adherent to their randomized treatment assignments indicates that lifestyle and metformin are likely to be even more effective in real world clinical practice than they were during the randomized controlled clinical trial and its subsequent observational follow-up study. Perhaps not surprisingly, the costs of the interventions, especially the cost of the metformin intervention, were higher among adherent participants, but the benefits, assessed in terms of non-intervention-related direct medical costs, were also greater. Interestingly, the benefits in terms of quality-adjusted life-years gained were similar among adherent and intent-to-treat participants perhaps reflecting the impact of non-diabetes-related comorbidities on quality of life. The impact of discounting on the cost-effectiveness equation highlights the fact that in chronic diseases, prevention is an important investment but often not cost-saving in the short term (21). To the extent that intervention costs are accrued early in the natural history of disease and complications are accrued later, discounting tends to portray a less favorable cost-effectiveness picture. Nevertheless, these analyses confirm that lifestyle, group lifestyle, and metformin represent a good value for money.

Summary.

Over 10 years, among adherent participants, lifestyle intervention and metformin were effective and cost-effective for diabetes prevention compared to placebo.

Summary statement and bulleted points.

Over 10 years, among adherent participants, lifestyle intervention and metformin were effective and cost-effective for diabetes prevention compared to placebo.

• Interventions to delay or prevent chronic diseases are often not cost-saving in the short term, as intervention costs are incurred early and savings from complications averted accrue late in the natural history of disease.

• In real world clinical settings, lifestyle and metformin interventions are likely to be more effective and more cost-effective than they were during the randomized controlled clinical trial and its observational follow-up study.

• Interventions for diabetes prevention represent a good value for money.

DPPOS Research Group Investigators (ALL) (Updated January 2012)

Pennington Biomedical Research Center (Baton Rouge, LA)

George A. Bray, MD*

Annie Chatellier, RN, CCRC**

Crystal Duncan, LPN Frank L. Greenway, MD Erma Levy, RD Donna H. Ryan, MD

University of Chicago (Chicago, IL)

Kenneth S. Polonsky, MD*

Janet Tobian, MD, PhD*

David Ehrmann, MD*

Margaret J. Matulik, RN, BSN**

Bart Clark, MD

Kirsten Czech, MS

Catherine DeSandre, BA

Ruthanne Hilbrich, RD

Wylie McNabb, EdD

Ann R. Semenske, MS, RD

Jefferson Medical College (Philadelphia, PA)

Barry J. Goldstein, MD, PhD*

Kevin Furlong, DO*

Kellie A. Smith, RN, MSN**

Wendi Wildman, RN**

Constance Pepe, MS, RD

University of Miami (Miami, FL)

Ronald B. Goldberg, MD*

Jeanette Calles, MSEd**

Juliet Ojito, RN**

Sumaya Castillo-Florez, MPH

Hermes J. Florez, MD, PhD

Anna Giannella, RD, MS

Olga Lara Beth Veciana

The University of Texas Health Science Center (San Antonio, TX)

Steven M. Haffner, MD, MPH*

Helen P. Hazuda, PhD*

Maria G. Montez, RN, MSHP, CDE**

Carlos Lorenzo, MD, PhD

Arlene Martinez, RN, BSN, CDE

University of Colorado (Denver, CO)

Richard F. Hamman, MD, DrPH*

Lisa Testaverde, MS**

Alexis Bouffard, MA, RN, BSN

Dana Dabelea, MD, PhD

Tonya Jenkins, RD, CDE

Dione Lenz, RN, BSN, CDE

Leigh Perreault, MD

David W. Price, MD

* denotes Principal Investigator

** denotes Program Coordinator

Sheila C. Steinke, MS

Joslin Diabetes Center (Boston, MA)

Edward S. Horton, MD*

Catherine S. Poirier, RN, BSN**

Kati Swift, RN, BSN**

Enrique Caballero, MD

Sharon D. Jackson, MS, RD, CDE

Lori Lambert, MS, RD, LD

Kathleen E. Lawton, RN

Sarah Ledbury, Med, RD

VA Puget Sound Health Care System and University of Washington (Seattle, WA)

Steven E. Kahn, MB, ChB*

Brenda K. Montgomery, RN, BSN, CDE**

Wilfred Fujimoto, MD

Robert H. Knopp, MD

Edward W. Lipkin, MD

Michelle Marr, BA

Anne Murillo, BS

Dace Trence, MD

University of Tennessee (Memphis, TN)

Abbas E. Kitabchi, PhD, MD, FACP*

Mary E. Murphy, RN, MS, CDE, MBA**

William B. Applegate, MD, MPH

Michael Bryer-Ash, MD

Samuel Dagogo-Jack, MD, MSc, FRCP, FACP

Sandra L. Frieson, RN

Helen Lambeth, RN, BSN

Lynne C. Lichtermann, RN, BSN

Hooman Otkaei, MD

Lily M.K. Rutledge, RN, BSN

Amy R. Sherman, RD, LD

Clara M. Smith, RD, MHP, LDN

Judith E. Soberman, MD

Beverly Williams-Cleaves, MD

Northwestern University’s Feinberg School of Medicine (Chicago, IL)

Boyd E. Metzger, MD*

Mark E. Molitch, MD*

Mariana K. Johnson, MS, RN**

Mimi M. Giles, MS, RD

Diane Larsen, BS

Charlotte Niznik, MS, RN, CDE

Samsam C. Pen, BA

Pamela A. Schinleber, RN, MS

Massachusetts General Hospital (Boston, MA)

David M. Nathan, MD*

Charles McKitrick, BSN**

Heather Turgeon, BSN**

Kathy Abbott

Ellen Anderson, MS, RD

Laurie Bissett, MS, RD

Enrico Cagliero, MD

Kali D’Anna Linda Delahanty, MS, RD

Jose C. Florez, MD, PhD⁺

Valerie Goldman, MS, RD

Alexandra Poulos Beverly Tseng

University of California-San Diego (San Diego, CA)

Elizabeth Barrett-Connor, MD*

Mary Lou Carrion-Petersen, RN, BSN**

Javiva Horne, RD

Diana Leos, RN, BSN

Sundar Mudaliar, MD

Jean Smith, RN

Karen Vejvoda, RN, BSN, CDE, CCRC

St. Luke’s-Roosevelt Hospital (New York, NY)

F. Xavier Pi-Sunyer, MD*

Jane E. Lee, MS**

Sandra T. Foo, MD

Susan Hagamen, MS, RN, CDE

Indiana University (Indianapolis, IN)

David G. Marrero, PhD*

Susie M. Kelly, RN, CDE**

Ronald T. Ackermann, MD

Edwin S. Fineberg, MD

Angela Hadden

Marcia A. Jackson

Marion S. Kirkman, MD

Kieren J. Mather, MD

Paris J. Roach, MD

Madelyn L. Wheeler, RD

Medstar Research Institute (Washington, DC)

Robert E. Ratner, MD*

Vanita Aroda, MD*

Sue Shapiro, RN, BSN, CCRC**

Catherine Bavido-Arrage, MS, RD, LD

Peggy Gibbs Gabriel Uwaifo, MD

Renee Wiggins, RD

University of Southern California/UCLA Research Center (Alhambra, CA)

Mohammed F. Saad, MD*

Karol Watson, MD*

Medhat Botrous, MD**

* denotes Principal Investigator

** denotes Program Coordinator

Sujata Jinagouda, MD**

Maria Budget

Claudia Conzues

Perpetua Magpuri

Kathy Ngo

Kathy Xapthalamous

Washington University (St. Louis, MO)

Neil H. White, MD, CDE*

Samia Das, MS, MBA, RD, LD**

Ana Santiago, RD

Angela L. Brown, MD

Cormarie Wernimont, RD, LD

Johns Hopkins School of Medicine (Baltimore, MD)

Christopher D. Saudek, MD* (deceased)

Sherita Hill Golden, MD, MHS, FAHA*

Tracy Whittington, BS**

Jeanne M. Clark, MD

Alicia Greene

Dawn Jiggetts

Henry Mosley

John Reusing

Richard R. Rubin, PhD

Shawne Stephens

Evonne Utsey

University of New Mexico (Albuquerque, NM)

David S. Schade, MD*

Karwyn S. Adams, RN, MSN**

Claire Hemphill, RN, BSN**

Penny Hyde, RN, BSN**

Lisa Butler, BUS

Janene L. Canady, RN, CDE

Kathleen Colleran, MD

Ysela Gonzales, RN, MSN

Doris A. Hernandez-McGinnis

Patricia Katz, LPN

Carolyn King

Albert Einstein College of Medicine (Bronx, NY)

Jill Crandall, MD*

Janet O. Brown, RN, MPH, MSN**

Elsie Adorno, BS

Helena Duffy, MS, C-ANP

Helen Martinez, RN, MSN, FNP-C

Dorothy Pompi, BA

Harry Shamoon, MD

Elizabeth A. Walker, RN, DNSc, CDE

Judith Wylie-Rosett, EdD, RD

University of Pittsburgh (Pittsburgh, PA)

Trevor Orchard, MD*

Susan Jeffries, RN, MSN**

M. Kaye Kramer, BSN, MPH**

Marie Smith, RN, BSN**

Rena R. Wing, PhD

Andrea Kriska, PhD

Jessica Pettigrew, CMA

Linda Semler, MS, RD

Elizabeth Venditti, PhD

Valarie Weinzierl, BS

University of Hawaii (Honolulu, HI)

Richard F. Arakaki, MD*

Narleen K. Baker-Ladao, BS**

Mae K. Isonaga, RD, MPH**

Nina E. Bermudez, MS

Marjorie K. Mau, MD

Southwest American Indian Centers (Phoenix, AZ; Shiprock, NM; Zuni, NM)

William C. Knowler, MD, DrPH*⁺

Norman Cooeyate**

Mary A. Hoskin, RD, MS**

Camille Natewa**

Carol A. Percy, RN, MS**

Kelly J. Acton, MD, MPH

Vickie L. Andre, RN, FNP

Shandiin Begay, MPH

Brian C. Bucca, OD, FAAO

Sherron Cook

Matthew S. Doughty, MD

Justin Glass, MD

Martia Glass, MD

Robert L. Hanson, MD, MPH

Doug Hassenpflug, OD

Louise E. Ingraham, MS, RD, LN

Kathleen M. Kobus, RNC-ANP

Jonathan Krakoff, MD

Catherine Manus, LPN

Cherie McCabe Sara Michaels, MD

Tina Morgan

Julie A. Nelson, RD

Robert J. Roy

Miranda Smart

Darryl P. Tonemah, PhD

Charlton Wilson, MD

George Washington University Biostatistics Center (DPP Coordinating Center Rockville, MD)

Sarah Fowler, PhD*

Tina Brenneman**

Solome Abebe, MS

Julie Bamdad, MS

* denotes Principal Investigator

** denotes Program Coordinator

Melanie Barkalow

Joel Bethepu

Tsedenia Bezabeh

Jackie Callaghan

Costas Christophi, PhD

Sharon L. Edelstein, ScM

Yuping Gao

Robert Gooding

Adrienne Gottlieb

Nisha Grover

Heather Hoffman, PhD

Kathleen Jablonski, PhD

Richard Katz, MD

Preethy Kolinjivadi, MS

John M. Lachin, ScD

Yong Ma, PhD

Susan Reamer

Alla Sapozhnikova

Hanna Sherif, MS

Marinella Temprosa, MS

Qing Pan, PhD

Mary Foulkes, PhD

Nicole Butler

Lifestyle Resource Core

Elizabeth M. Venditti, PhD*

Andrea M. Kriska, PhD

Linda Semler, MS, RD

Valerie Weinzierl, BS

Central Biochemistry Laboratory (Seattle, WA)

Santica Marcovina, PhD, ScD*

Greg Strylewicz, PhD**

John Albers, PhD

Epidemiological Cardiology Research Center- Epicare (Winston-Salem, NC)

Ronald J. Prineas, MD, PhD*

Teresa Alexander

Charles Campbell, MS

Sharon Hall

Susan Hensley

Yabing Li, MD

Margaret Mills

Elsayed Soliman, MD

Zhuming Zhang, MD

Fundus Photo Reading Center (Madison, WI)

Ronald Danis, MD*

Matthew Davis, MD*

Larry Hubbard*

Ryan Endres**

Deborah Elsas**

Samantha Johnson**

Vonnie Gama

Anne Goulding

Carotid Ultrasound

Gregory Evans

CT Scan Reading Center

Elizabeth Stamm

Neurocognitive Assessment Group

Jose A. Luchsinger, MD, MPH

NIH/NIDDK (Bethesda, MD)

Judith Fradkin, MD

Sanford Garfield, PhD

Centers for Disease Control & Prevention (Atlanta, GA)

Edward Gregg, PhD

Ping Zhang, PhD

University of Michigan (Ann Arbor, MI)

William H. Herman, MD, MPH

Morton B. Brown, PhD

Nutrition Coding Center (Columbia, SC)

Elizabeth Mayer-Davis, PhD*

Robert R. Moran, PhD**

Quality of Well-Being Center (La Jolla, CA)

Ted Ganiats, MD*

Andrew J. Sarkin, PhD**

Naomi Katzir

Erik Groessl, PhD

Coronary Artery Calcification Reading Center

Matthew Budoff, MD

Chris Dailing

+Genetics Working Group

Jose C. Florez, MD, PhD^{1, 2}

David Altshuler, MD, PhD^{1, 2}

Paul I.W. de Bakker, PhD²

Paul W. Franks, PhD, MPhil, MS^{6, 7}

Robert L. Hanson, MD, MPH³

Kathleen Jablonski, PhD⁵

William C. Knowler, MD, DrPH³

Toni I. Pollin, PhD⁴

Alan R. Shuldiner, MD⁴

1=Massachusetts General Hospital

2=Broad Institute

3=NIDDK

4=University of Maryland

5=Coordinating Center

6= Lund University, Sweden

7=Harvard School of Public Health

* denotes Principal Investigator

** denotes Program Coordinator