Thomas J. Hoerger

The Cost-Effectiveness of Lifestyle Modification or Metformin in Preventing Type 2 Diabetes in Adults with Impaired Glucose Tolerance

Context The Diabetes Prevention Program (DPP) showed that lifestyle changes or metformin effectively decreased the development of type 2 diabetes in adults with impaired glucose tolerance. The economics of these interventions is important to policymakers. Contribution This cost-effectiveness model estimates that the DPP life-style intervention would cost society about

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8800 and metformin would cost about

Screening for type 2 diabetes mellitus: A cost-effectiveness analysis

29900 per quality-adjusted life-year saved. While lifestyle intervention had a favorable cost-effectiveness profile at any adult age, metformin was not cost-effective after age 65 years. Implications The cost-effectiveness of lifestyle intervention to prevent type 2 diabetes in high-risk individuals is within the range that American society typically finds acceptable for health care interventions. The Editors During the past half century, the number of persons with diagnosed diabetes in the United States has increased 4- to 6-fold (1). Recent large clinical trials from Asia, Europe, and North America have demonstrated that behavioral and medication interventions can delay or prevent the development of type 2 diabetes in persons with impaired glucose tolerance, which is defined by a plasma glucose level between 7.77 mmol/L (140 mg/dL) and 11.04 mmol/L (199 mg/dL) 2 hours after a 75-g oral glucose load (2-6). The Diabetes Prevention Program (DPP) randomly assigned 3234 nondiabetic persons 25 years of age or older with impaired glucose tolerance and fasting glucose levels between 5.27 mmol/L (95 mg/dL) and 6.94 mmol/L (125 mg/dL) to placebo; a lifestyle-modification program with the goals of at least a 7% weight loss and 150 minutes of physical activity per week; or metformin, 850 mg twice daily (4). The mean age of participants was 51 years, and the mean body mass index was 34.0 kg/m2; 68% were women and 45% were members of minority groups (4). The average follow-up was 2.8 years. Compared with the placebo intervention, the lifestyle intervention reduced the incidence of type 2 diabetes by 58% and the metformin intervention reduced the incidence of type 2 diabetes by 31% (4). We have previously described the costs of the DPP interventions and their cost-effectiveness within the 3-year trial period (7, 8). In this analysis, we project the costs, health outcomes, and cost-effectiveness of the DPP lifestyle and metformin interventions over a lifetime relative to the placebo intervention. Methods Clinical Trial The lifestyle intervention involved a healthy, low-calorie, low-fat diet and moderate physical activity, such as brisk walking. The lifestyle intervention was implemented with a 16-lesson core curriculum covering diet, exercise, and behavior modification that was taught by case managers on a one-on-one basis, followed by individual sessions (usually monthly) and group sessions with case managers (9). At the end of the study, 38% of participants in the lifestyle intervention group had lost at least 7% of their initial body weight. The metformin and placebo interventions were initiated at a dosage of 850 mg once a day. At 1 month, the dosage of metformin or placebo was increased to 850 mg twice daily. Case managers reinforced adherence during individual quarterly sessions (10). At the end of the study, 72% of participants in the metformin intervention group and 77% of participants in the placebo intervention group took at least 80% of the prescribed dose. All participants received standard lifestyle recommendations through written information and an annual 20- to 30-minute individual session that emphasized the importance of a healthy lifestyle (10). Simulation Model We assessed the progression from impaired glucose tolerance to onset of diabetes to clinically diagnosed diabetes to diabetes with complications and death by using a lifetime simulation model originally developed by the Centers for Disease Control and Prevention and Research Triangle Institute International. The model has a Markov structure and includes annual transition probabilities between disease states (11). In addition to disease progression, the model tracks costs and quality-adjusted life-years (QALYs). The model has been described elsewhere (11). For our analyses, we modified the model to include data from the DPP on progression, costs, and quality of life associated with impaired glucose tolerance, data from the United Kingdom Prospective Diabetes Study (UKPDS) on diabetes progression and complications, and new data on cost and quality of life associated with diabetes. A technical report describing the model is available. Supplement. Technical Report Disease Progression, Complications, and Comorbid Conditions Impaired Glucose Tolerance to Onset of Type 2 Diabetes We analyzed data from the DPP to assess the annual hazard of diabetes onset in the lifestyle, metformin, and placebo intervention groups. For patients receiving the placebo intervention, the annual hazard of diabetes onset was 10.8 per 100 person-years. At 3 years of follow-up, the risk reductions for the lifestyle and metformin interventions were 55.8% and 29.9%, respectively. In the base-case analysis, we assumed that the lifestyle and metformin interventions would be applied until diabetes onset and that the health and quality-of-life benefits associated with the interventions persisted until diabetes onset. Complications and Comorbid Conditions Associated with Impaired Glucose Tolerance We analyzed data from the DPP and other published sources to assess the prevalence of complications and comorbid conditions in participants with impaired glucose tolerance. At baseline, 6.0% of DPP participants had microalbuminuria and 0.4% had nephropathy. The DPP did not measure peripheral neuropathy, but previous studies found that the prevalence of neuropathy in persons with impaired glucose tolerance was 74% of that in persons with newly diagnosed type 2 diabetes (12) and 12.3% of persons with newly diagnosed type 2 diabetes have neuropathy (13). Therefore, we assumed that at baseline, 8.5% of DPP participants had clinical neuropathy. At baseline, 28% of DPP participants had hypertension, 45% had dyslipidemia, 7% were smokers, 1.1% had a history of cerebrovascular disease, and 2.0% had a history of myocardial infarction. No other complications were present. We assumed that during impaired glucose tolerance, microvascular or neuropathic complications would not progress. We assumed that hypertension and dyslipidemia developed at the rates observed in the DPP. On the basis of 2 large studies (14, 15), we assumed that the incidences of coronary heart disease and cerebrovascular disease in patients with impaired glucose tolerance were 58% and 56%, respectively, of those observed in patients with type 2 diabetes. We further assumed that nondiabetes-related mortality for persons with impaired glucose tolerance was the same as for persons with diabetes (16). Onset of Type 2 Diabetes to Clinical Diagnosis of Type 2 Diabetes In the DPP, participants were tested for diabetes every 6 months; diabetes was diagnosed at onset. In routine clinical practice, type 2 diabetes is estimated to develop 8 to 12 years before its clinical diagnosis (17, 18). In our base-case analysis, we therefore assumed that a 10-year delay occurred between the onset and clinical diagnosis of diabetes. Participants in the DPP had a mean hemoglobin A1c level of 6.4% at the onset of diabetes. Participants in the UKPDS had a mean hemoglobin A1c of 7.1% after a dietary run-in period but before randomization (13). Both DPP placebo participants and UKPDS participants received standard lifestyle recommendations. Accordingly, we assumed that during the 10-year interval between onset and clinical diagnosis of diabetes, patients were treated for type 2 diabetes and that hemoglobin A1c level increased at 0.07% per year from 6.4% to 7.1%. Complications and Comorbid Conditions Associated with Undiagnosed Diabetes We further assumed that between onset and clinical diagnosis of diabetes, microvascular and neuropathic complications progressed slowly, such that by clinical diagnosis of type 2 diabetes, their prevalence reached the level observed in the UKPDS cohort at randomization (13, 19, 20). We assumed that blood pressure and lipid levels progressed as they did in DPP participants and that cardiovascular complications occurred as they would in type 2 diabetes according to risk factors and hemglobin A1c level (21, 22). Clinical Diagnosis of Type 2 Diabetes to Diabetes with Complications and Death We assumed that after clinical diagnosis, all persons with type 2 diabetes received intensive glycemic management as described in the UKPDS (13). We modeled changes in hemoglobin A1c and diabetes treatments to reflect those observed in the UKPDS intensive therapy group. We based risk for retinopathy progression on UKPDS 38 (23), risk for nephropathy progression on UKPDS 64 (20), and risk for neuropathy progression on UKPDS 33 (13). We based risk for cerebrovascular disease on UKPDS 60 (22) and risk for coronary heart disease on UKPDS 56 (21). Costs Costs of Impaired Glucose Tolerance To estimate the total direct medical costs of impaired glucose tolerance, we considered the costs of the DPP interventions (the cost of identifying participants, implementing and maintaining the interventions, and monitoring and treating the side effects of the interventions) and the costs of the medical care outside the DPP (7). In analyses from the perspective of society, we included both direct medical costs and direct nonmedical costs. We did not include indirect costs because they are captured in the assessment of QALYs (24). Table 1 shows the total direct medical costs by treatment group, sex, and year in the DPP (7). Costs were higher in the lifestyle and metformin interventions than in the placebo intervention and higher in women than in men. Costs decreased over time in all 3 intervention groups but after year 1 tended to decrease more in the lifestyle than t

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To estimate the fraction of United States (U.S.) adults who are eligible for treatment to reduce elevated low-density lipoprotein (LDL) cholesterol levels based on Adult Treatment Panel II (ATP II) guidelines and the percent reduction in LDL cholesterol required by those who qualify for treatment, we analyzed data on 7,423 respondents to Phase 2 of the third National Health and Nutrition Examination Survey (NHANES III) administered between 1991 and 1994. Approximately 28% of the U.S. adult population aged > or = 20 years is eligible for treatment based on ATP II guidelines. Eighty-two percent of adults with coronary heart disease are not at their target LDL cholesterol level of 100 mg/dl. Of those eligible for treatment, 65% report that they receive no treatment. Overall, 40% of people who qualify for drug therapy require an LDL cholesterol reduction of > 30% to meet their ATP II treatment goal. Approximately 75% of those with coronary heart disease who qualify for drug therapy require an LDL cholesterol reduction of >30%. Although elevated LDL cholesterol levels can be treated, prevalence rates in the U.S. adult population remain high. Several recent studies indicate that a considerable percentage of people treated with drug therapy do not reach their treatment goals. The findings in this study provide at least a partial explanation for why many patients receiving therapy do not reach their treatment goals: they require a larger reduction in LDL cholesterol than many therapies can provide.

'Profit' variability in for-profit and not-for-profit hospitals.

Context In 2003, the U.S. Preventive Services Task Force recommended screening for type 2 diabetes in adults with hypertension or hyperlipidemia. The economic implications of this recommendation are unclear. Contribution Diabetes screening for 55-year-old hypertensive persons would cost the U.S. health care system

Individual and aggregate years-of-life-lost associated with overweight and obesity.

34 375 per quality-adjusted life-year gained. Expanding screening to all adults regardless of the presence of hypertension would cost an additional

A dynamic Markov model for forecasting diabetes prevalence in the United States through 2050

360 966 per quality-adjusted life-year. Implications The cost-effectiveness of targeting diabetes screening to hypertensive adults older than 55 years of age is similar to the cost-effectiveness of many accepted health care interventions. Universal diabetes screening is far more costly. The Editors Although many adults who meet criteria for type 2 diabetes (hereafter, diabetes) have not been identified (1), screening for diabetes remains controversial (2-11). Direct evidence indicates that various treatments to reduce complications are effective among people with clinically detected diabetes (12-14), but no direct evidence tells us the magnitude of any further benefit from starting these treatments earlier, after detection by screening (15). In the absence of direct evidence, researchers have applied mathematical models of diabetes progression to the issue of screening. One analysis found that the cost per quality-adjusted life-year (QALY) gained by universal diabetes screening was lower for younger than for older people:

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13 376 at age 25 to 34 years, increasing to

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116 908 at age 55 to 64 years (16). This conclusion followed from the models focus on the provision of glycemic control after screening to prevent microvascular complications. The analysis did not consider treatments to reduce the risks for complications of cardiovascular disease (CVD). More recent research suggests that the benefits of CVD risk reduction may be substantial for people with diabetes. The Hypertension Optimal Treatment (HOT) trial found that the optimal blood pressure target is lower for people with hypertension and diabetes than for people with hypertension without diabetes (14). Other research supports the finding that intensive control of hypertension is beneficial among people with diabetes (15, 17-19). Because the benefit may be greater for older people (at greater risk for CVD), the conclusion of the previous analysis, that diabetes screening is most cost-effective among younger people, needs to be reconsidered. We performed a new cost-effectiveness analysis to compare universal diabetes screening (universal screening) and diabetes screening targeted to patients with hypertension (targeted screening). When an updated version of the model used in the previous analysis that includes benefits from intensive treatment of hypertension was applied, we estimated the incremental cost-effectiveness of these 2 strategies for people in different age groups. Our analysis considers a one-time opportunistic screening for men and women of all races and ethnicities. Methods The Model We used a Markov model of diabetes disease progression to simulate lifetime diabetes-related health care costs and QALYs for people with diabetes (Appendix Figure 1). Demographic characteristics of the simulated cohort are based on 1997 population estimates projected from the 1990 U.S. Census and data on the distribution of people with diabetes by hypertension, cholesterol level, and smoking status (20). As people progress through the simulation model from the onset of diabetes to death, they can develop 5 types of complications: nephropathy, neuropathy, retinopathy, coronary heart disease (CHD), and stroke. People can die of some of these complications or of other causes. The model includes transition probabilities between disease stages on each of the 5 complication paths. The basic model structure has been described previously (16, 21). Key model parameters are presented in the Appendix Tables 1 to 10. To incorporate screening into the model, we first added a screening module in which some patients with diabetes are identified earlier than they would usually have been in the absence of screening. Second, we made assumptions about the transition probabilities between disease stages from the onset of diabetes to the time of usual clinical diagnosis of diabetes on the basis of the knowledge that progression is relatively slow during this period (15). After clinical diagnosis, disease progression depends on the number of years after normal diagnosis. Screening allows for earlier diagnosis, which in turn allows for earlier treatment interventions, such as intensive glycemic control and intensive hypertension control. These interventions decrease the transition probabilities, thereby delaying or preventing progression to diabetes complications. Costs are incurred for screening and diagnostic testing; standard glycemic control and, if the person is hypertensive, standard hypertension control; interventions (intensive glycemic control and, if the person is hypertensive, intensive hypertension control); and complications over the remaining lifetime of each person with diabetes. The sum of these costs and the models estimate of the expected QALYs for each screening strategy are used to calculate the incremental cost-effectiveness ratio of screening relative to no screening. We discounted future costs and QALYs at a 3% annual rate. Costs are measured in 1997 U.S. dollars. Interventions We assumed that, in the absence of screening, diabetes would be diagnosed 10 years after its onset (15). With one-time opportunistic screening, diabetes would be diagnosed on average 5 years after onset and therefore patients would begin treatment 5 years earlier. After diabetes diagnosis, all patients are treated with intensive glycemic control and, if they have hypertension, with intensive hypertension control. With targeted screening, only people with hypertension are screened. Those who screen positive and receive a diagnosis of diabetes begin intensive glycemic control and intensive hypertensive control 5 years earlier than they would in the absence of screening. With universal screening, all people, regardless of hypertension status, are screened. Those who screen positive and receive a diagnosis of diabetes begin intensive glycemic control 5 years earlier than in the absence of screening and begin intensive hypertension control 5 years earlier if they have hypertension. We defined hypertension as a blood pressure of 140/90 mm Hg or higher. We assumed that 19% of people age 25 to 44 years, 47% of people age 45 to 64 years, and 60% of people age 65 to 74 years had hypertension and therefore were included in targeted screening (20). Treatment of hypertension is modeled as standard (with a target diastolic blood pressure of 90 mm Hg) or intensive (with a target diastolic blood pressure of 80 mm Hg), as in the HOT trial (14). All persons with hypertension receive standard hypertension treatment until they receive a diagnosis of diabetes, after which they receive intensive hypertension treatment. The incremental cost of intensive hypertension control relative to standard control is

Lifetime Direct Medical Costs of Treating Type 2 Diabetes and Diabetic Complications

149 per year. In the HOT trial, the relative risk reduction for CHD events (fatal and nonfatal myocardial infarction) was 51%, and the relative risk reduction for stroke was about 30%. Although neither of these separate relative risk reductions was statistically significant, the relative risk reduction (51%) for the aggregate outcome of major CVD events was statistically significant (P = 0.005). We initially modeled the relative risk reduction for CHD events for intensive hypertension control to be 51%, with no risk reduction for stroke. We conducted a sensitivity analysis that included a 30% relative risk reduction for stroke on the basis of other studies showing that intensive hypertension control reduces risk among people with diabetes (17, 19). Model estimates of the effects of glycemic control are based on the United Kingdom Prospective Diabetes Study (UKPDS), a 10-year randomized, controlled trial of intensive versus conventional glycemic control (12). On the basis of the UKPDS, the reduction in hemoglobin A1c from intensive glycemic treatment is modeled as slowing the progression of microvascular complications (12). The incremental cost of intensive glycemic control (relative to standard control) ranges from