TYPE TWO DIABETES













Reference [2]
Age (years) U.S. prevalence
(% of total population)
20 - 44 4.1%
45 - 64 16.2%
≥ 65 25.9%




  • Incidence ratio = incidence with affected family members/incidence with no affected family members
  • Reference [4]
Relative with T2DM Incidence ratio
One parent 2.0
Two parents 5.3
One sibling 2.8
Two siblings 37.0
One sibling / One parent 4.6
One sibling / Two parents 7.1

  • Data are from NHANES 2011 - 2016 survey of U.S. adults and are adjusted for age, sex, and BMI
  • Reference [40]
Race % of adults with diabetes
Non-hispanic white 11.9%
Asian-Americans 27%
Hispanics 20.3%
Black 18.4%









ADA T2DM Screening Recommendations
Adults
  • 1. Screen all adults beginning at age 45 years
  • 2. Screen overweight women who are planning to become pregnant
  • 3. Screen adults regardless of age who are overweight (BMI ≥ 25 or BMI ≥ 23 in Asian Americans) and have one of the following risk factors:
    • Physical inactivity
    • First-degree relative with diabetes
    • High-risk ethnicity (African-American, Hispanic, Asian, Native-American, Pacific Islander)
    • Women with diabetes during pregnancy or who delivered a baby weighing > 9 pounds
    • Hypertension (blood pressure ≥ 140/90 mmHg)
    • HDL cholesterol < 35 mg/dl and/or triglycerides > 250 mg/dl
    • Women with polycystic ovary syndrome
    • History of prediabetes (see prediabetes below)
    • Acanthosis nigricans
    • History of heart disease or stroke
  • 3. For normal results, rescreen in a minimum of 3 years, or sooner if patient is at very high risk. Rescreen patients with prediabetes yearly. Women with a history of gestational diabetes should have lifelong testing at least every 3 years. [38]
Children
  • 1. Screen children who are overweight (BMI > 85th percentile for age and sex, weight for height > 85th percentile, or weight > 120% of ideal for height) and have one of the following risk factors:
    • Family history of T2DM in first- or second-degree relative
    • High-risk ethnicity (African-American, Hispanic, Asian, Native-American, Pacific Islander)
    • Acanthosis nigricans
    • Polycystic ovary syndrome
    • Hypertension (blood pressure ≥ 140/90 mmHg)
    • HDL cholesterol < 35 mg/dl and/or triglycerides > 250 mg/dl
    • Maternal history of diabetes or gestational diabetes during the child’s gestation
    • History of being born small for gestational age (babies born small for gestational age have a higher incidence of insulin resistance later in life if they become obese) [38]
  • 2. Screening should begin at 10 years of age or at the onset of puberty, whichever comes first
  • 3. For normal results, rescreen every 3 years. [1]
Patients taking second generation antipsychotics
  • Fasting blood sugar at baseline, 12 weeks, and annually thereafter
  • Fasting lipid profile at baseline, 12 weeks, and every 5 years thereafter
  • See antipsychotics for more








  • Reference [24]
5-year risk of developing T2DM based on A1C value
A1C value 5-year incidence of T2DM
5.0 - 5.5% < 5 - 9%
5.5 - 6.0% 9 - 25%
6.0 - 6.5% 25 - 50%



DIRECT Study - Weight Loss Program vs Standard Care for Remission of T2DM, Lancet (2018) [PubMed abstract]
  • A study in the Lancet enrolled 306 overweight patients with T2DM
Main inclusion criteria
  • Age 20 - 65 years
  • Diagnosed with T2DM within the previous 6 years
  • BMI 27 - 45
Main exclusion criteria
  • Current insulin use
  • A1C ≥ 12%
  • CrCl < 30 ml/min
  • Weight loss > 5 kg within the past 6 months
Baseline characteristics
  • Average age - 53 years
  • Average BMI - 35
  • Average weight - 220 lbs (100 kg)
  • Average A1C - 7.6% (SD 1.12%)
  • Average time since diagnosis - 3 years
  • Number of oral DM meds: 0 - 24% | 1 - 48% | ≥ 2 - 27%
Randomized treatment groups
  • Group 1 (149 patients) - Weight loss program (intervention group)
  • Group 2 (149 patients) - Usual care
  • In Group 1, all DM medications were discontinued on Day 1 of the weight loss program. In Group 2, DM meds were continued.
  • Weight loss program consisted of 3 months (extendable up to 5 months if wished by participant) of a total diet replacement phase using a low energy formula diet (825–853 kcal/day; 59% carbohydrate, 13% fat, 26% protein, 2% fiber). After that, structured food reintroduction of 2 – 8 weeks (about 50% carbohydrate, 35% total fat, and 15% protein), and an ongoing structured program with monthly visits for long-term weight loss maintenance.
  • In both groups, subjects were encouraged to continue their usual amount of physical activity
  • The study was a cluster randomized trial at 49 primary care practices
Primary outcome: The co-primary outcomes were a reduction in weight of 33 lbs (15 kg) or more, and remission of diabetes, defined as HbA1c less than 6.5% after at least 2 months off all antidiabetic medications, from baseline to month 12
Results

Duration: 12 months
Outcome Intervention Usual care Comparisons
Primary outcome (weight loss ≥ 33 lbs) 24% 0% p<0.0001
Primary outcome (remission of diabetes) 46% 4% p<0.0001
Average weight loss 22 lbs 2.2 lbs p<0.0001
Average change in A1C -0.9% +0.1% p<0.0001
Using DM meds 26% 82% N/A
  • In the intervention group, 32 patients withdrew from the intervention

Remission of diabetes in all patients by weight loss
Weight gain 0 - 11 lbs 11 - 22 lbs 22 - 33 lbs ≥ 33 lbs
0% 7% 34% 57% 86%

Findings: Our findings show that, at 12 months, almost half of participants achieved remission to a non-diabetic state and off antidiabetic drugs. Remission of type 2 diabetes is a practical target for primary care
Two-year Follow-up Results for Weight Loss vs Usual Care in T2DM Remission, Lancet Diabetes Endocrinol (2019) [PubMed abstract]
  • A follow-up study looked at 2-year outcomes among participants in the DIRECT study
Results

Duration: 2 years
Outcome Intervention Usual care Comparisons
Weight loss ≥ 33 lbs 11% 2% p=0.0023
Remission of diabetes 36% 3% p<0.0001
Average weight loss 16.7 lbs 5 lbs p<0.01
Average change in A1C -0.5% 0% p<0.01
Using DM meds 40% 84% N/A

Remission of diabetes in all patients by weight loss at 2 years
< 11 lbs 11 - 22 lbs 22 - 33 lbs ≥ 33 lbs
5.2% 29% 60% 70%

Findings: The DIRECT program sustained remissions at 24 months for more than a third of people with type 2 diabetes. Sustained remission was linked to the extent of sustained weight loss.







  • Reference [39]
ADA T2DM Treatment Recommendations for Adults
Step 1 - initial therapy
  • Initial therapy for most diabetics should be metformin and lifestyle changes including weight loss and exercise (see diabetic diet)
  • The early introduction of insulin (see insulin therapy) should be considered if there is evidence of ongoing catabolism (weight loss), if symptoms of hyperglycemia are present, or when A1C is > 10% or blood glucose levels > 300 mg/dL
  • Consider initiating dual therapy in patients with newly diagnosed type 2 diabetes who have A1C ≥ 1.5% above their glycemic target
  • After 3 - 6 months, if blood sugar goals are not met, then proceed to Step 2
Step 2 - intensify therapy
  • Patients with CVD or at high-risk for CVD , use one of the following:
    • GLP-1 analog - use one with proven ASCVD benefit: liraglutide, semaglutide, or dulaglutide
    • SGLT2 inhibitor - use one with proven ASCVD benefit: empagliflozin, canagliflozin
    • If additional therapy is needed, consider the following:
      • Add other class from above (GLP-1 analog or SGLT2 inhibitor)
      • DPP-4 inhibitor if not on GLP-1 analog
      • Glitazone
      • Sulfonylurea
      • Basal insulin
    • High-risk for CVD defined as age ≥ 55 years with > 50% stenosis of the coronary, carotid, or lower extremity arteries or left ventricular hypertrophy

  • Patients with heart failure or chronic kidney disease (CKD)*, use the following:
    • SGLT2 inhibitor - empagliflozin, canagliflozin, or dapagliflozin are preferred
    • If additional therapy is needed, consider the following:
      • GLP-1 analog with ASCVD benefit (liraglutide, semaglutide, dulaglutide)
      • DPP-4 inhibitor (not saxagliptin) if patient has heart failure and not on GLP-1 analog
      • Sulfonylurea
      • Basal insulin
      • Avoid glitazone if patient has heart failure
    • *Particularly in patients with HFrEF and an EF < 45% and CKD patients with GFR 30 - 60 ml/min or albuminuria

  • Patients without ASCVD or CKD, consider the following:
    • Drugs with lower risk of hypoglycemia
      • GLP-1 analog
      • DPP-4 inhibitor
      • Glitazone
      • SGLT2 inhibitor
      • Also consider: if sulfonylurea is used, avoid glyburide because it has been associated with a higher risk of hypoglycemia in trials. If insulin is used, glargine and degludec are preferred over detemir and NPH
    • Drugs that may promote weight loss
      • GLP-1 analog: semaglutide > liraglutide > dulaglutide > exenatide > lixisenatide
      • SGLT2 inhibitor
    • Drugs that are cheaper

  • Reference [39]
ADA T2DM Treatment Recommendations for Youth (10 - 19 years)
Step 1 - initial therapy
  • Overweight youth should be encouraged to lose 7 - 10% of their body weight (see diabetic diet and weight loss)
  • A1C < 8.5% and asymptomatic: metformin (titrate up to 2000 mg/day as tolerated) is the initial treatment of choice
  • A1C ≥ 8.5% or blood sugar ≥ 250 mg/dl with symptoms (polyuria, polydipsia, weight loss, etc.): start metformin and treat initially with basal insulin (0.5 units/kg/day). Titrate metformin up to 2000 mg/day and escalate insulin every 2 - 3 days based on blood sugar readings.
  • Blood sugar ≥ 600 mg/dl or ketoacidosis: hospitalize and treat accordingly
  • Patients should have panel of pancreatic autoantibodies tested to exclude the possibility of autoimmune type one diabetes (see insulin antibodies for more)
Step 2
  • Patients not meeting goals
    • Goals not met on metformin: add basal insulin or liraglutide
    • Goals not met on metformin + basal insulin or liraglutide: add remaining drug
    • Goals not met on basal insulin doses up to 1.5 units/kg/day: switch to basal-premeal regimen [39]
  • Patients initiated on metformin + insulin who are meeting goals
    • Insulin can be tapered over 2 – 6 weeks by decreasing the insulin dose 10 – 30% every few days
  • If pancreatic autoantibodies are positive
    • Switch to insulin-only therapy (multi-dose insulin or pump) and discontinue metformin




Intensive Insulin Therapy in Newly Diagnosed Type 2 Diabetics, Lancet (2008) [PubMed abstract]
  • A study in the Lancet enrolled 382 patients with newly diagnosed type 2 diabetes
Main inclusion criteria
  • Newly diagnosed type 2 diabetes
  • No previous diabetes therapy
Main exclusion criteria
  • Diabetic complications
  • Positive for GAD65A antibodies (islet cell autoantibody)
  • Maturity onset diabetes in youth and mitochondrial diabetes mellitus
Baseline characteristics
  • Average age 51 years
  • Average BMI - 25
  • Average fasting blood sugar - 207 mg/dl
  • Average HgA1C - 9.7%
Randomized treatment groups
  • Group 1 (137 patients) - Patients were put on an insulin pump
  • Group 2 (124 patients) - Patients were put on intensive insulin therapy with multiple insulin injections a day
  • Group 3 (121 patients) - Patients were treated with sulfonylurea and metformin
  • After patients maintained normal blood sugars for 2 weeks, all medications were stopped and patients were continued on diet and exercise therapy alone for one year
  • Patients who did not achieve normal blood sugars within 2 weeks were excluded from the study
  • Patients were followed-up monthly during the first 3 months, then every 3 months
Primary outcome: Relapse back into elevated blood sugars at 1 year. Relapse was defined as fasting blood sugar > 126 mg/dl or 2-hour postprandial glucose > 180 mg/dl.
Results

Duration: 12 months
Outcome Insulin pump Intensive insulin Oral meds Comparisons
Primary outcome (relapse at 1 year) 49% 55% 73% 1 and 2 vs 3 p=0.0012
Achieved normal blood sugar 97% 95% 84% N/A
Average time to normal blood sugar 4 days 5.6 days 9.3 days N/A
Hypoglycemia during intensive phase 31% 28% 19% N/A
  • Acute insulin response was measured after initial intensive therapy. The response was maintained at one-year in the insulin pump and intensive insulin groups, but declined significantly in the oral meds group

Findings: Early intensive insulin therapy in patients with newly diagnosed type 2 diabetes has favourable outcomes on recovery and maintenance of beta-cell function and protracted glycaemic remission compared with treatment with oral hypoglycemic agents















Diabetes Prevention Program Trial - Metformin vs Lifestyle Changes vs Placebo for the Prevention of T2DM, NEJM (2002), [PubMed abstract]
  • The Diabetes Prevention Program trial enrolled 3234 patients with prediabetes
Main inclusion criteria
  • Age ≥ 25 years
  • BMI ≥ 24 (≥ 22 in Asians)
  • Fasting blood glucose of 95 - 125 mg/dl
  • OGTT of 140 - 199 mg/dl
Main exclusion criteria
  • Taking a medication that affects blood glucose
Baseline characteristics
  • Average age 50.6 years
  • Average BMI - 34
  • Average weight - 207 lbs (94 kg)
  • Average fasting glucose 106.5 mg/dl
  • Average HgA1C - 5.91%
Randomized treatment groups
  • Group 1 (1082 patients) - Placebo twice a day
  • Group 2 (1073 patients) - Metformin 850 mg twice a day
  • Group 3 (1079 patients) - Intensive lifestyle intervention (7% weight loss + 150 minutes exercise/week)
  • Groups 1 and 2 were given standard lifestyle recommendations in written form
  • Group 3 was given one-on-one counseling during the first 24 weeks
Primary outcome: Diagnosis of diabetes based on an annual 2-hour OGTT ≥ 200 mg/dl or semiannual fasting glucose ≥ 126 mg/dl
Results

Duration: Average of 2.8 years
Outcome Placebo Metformin Diet/Exercise Comparisons
Primary outcome (%/year) 11% 7.8% 4.8% p<0.001 for all comparisons
Weight loss 0.22 lbs 4.6 lbs 12.3 lbs p<0.001 for all comparisons
Gastrointestinal symptoms 30.7% 77.8% 12.9% p<0.05 for all comparisons
  • In the diet/exercise group, 50% of patients achieved ≥ 7% weight loss

Findings: Lifestyle changes and treatment with metformin both reduced the incidence of diabetes in persons at high risk. The lifestyle intervention was more effective than metformin.
ACT NOW Study - Pioglitazone vs Placebo for Prevention of T2DM, NEJM (2011) [PubMed abstract]
  • The ACT NOW study enrolled 602 patients with impaired glucose tolerance
Main inclusion criteria
  • OGTT of 140 - 199 mg/dl
  • BMI ≥ 25
  • At least one risk factor for diabetes
Main exclusion criteria
  • Treatment with diabetes medications within 1 year
  • Cardiovascular disease
  • Serum creatinine ≥ 1.6 mg/dl in men or ≥ 1.5 mg/dl in women
  • Significant liver disease
Baseline characteristics
  • Average age 52 years
  • Average BMI - 34
  • Average HgA1C - 5.5%
  • Average fasting blood sugar - 105 mg/dl
  • Average 2-hour OGTT - 168 mg/dl
Randomized treatment groups
  • Group 1 (303 patients) - Pioglitazone 45 mg once daily
  • Group 2 (299 patients) - Placebo once daily
  • Pioglitazone was started at 30 mg once daily and increased to 45 mg after 1 month
  • Patients were followed-up at 2, 4, 6, 8, 10, and 12 months and every 3 months thereafter
  • Fasting blood sugar was measured at every visit and 2-hour OGTT was performed annually
Primary outcome: Development of diabetes defined as fasting blood sugar ≥ 126 mg/dl or 2-hour OGTT ≥ 200 mg/dl
Results

Duration: Median of 2.4 years
Outcome Pioglitazone Placebo Comparisons
Primary outcome 5% 16.7% p<0.001
Incidence of worsening edema 12.9% 6.4% p=0.007
Weight gain 8.36 lbs 1.32 lbs p<0.001
Dropout rate 29.7% 23.7% N/A

Findings: As compared with placebo, pioglitazone reduced the risk of conversion of impaired glucose tolerance to type 2 diabetes mellitus by 72% but was associated with significant weight gain and edema
XENDOS trial - Orlistat vs Placebo for the Prevention of T2DM, Diabetes Care (2004) [PubMed abstract]
  • The XENDOS trial enrolled 3305 patients with a BMI ≥ 30 and an average body weight of 242 pounds
Main inclusion criteria
  • 30 - 60 years of age
  • BMI ≥ 30
  • Normal blood sugar or impaired glucose tolerance (FBS of < 120 mg/dl and OGTT of 120 - 180 mg/dl)
Main exclusion criteria
  • Diabetes
  • Cardiovascular disease
  • Gastrointestinal disease
Baseline characteristics
  • Average age 43 years
  • Average weight - 242 pounds (110 kg)
  • Average BMI - 37
  • Average fasting blood sugar - 83 mg/dl
  • Patients with impaired glucose tolerance - 21%
Randomized treatment groups
  • Group 1 (1640 patients) - Orlistat 120 mg three times a day + weight loss counseling
  • Group 2 (1637 patients) - Placebo + weight loss counseling
  • All patients were prescribed a diet with a caloric deficit of 800 calories a day
  • 2-hour OGTT was performed every 6 months
Primary outcome: Time to onset of type 2 diabetes and change in body weight after 4 years
Results

Duration: 4 years
Outcome Orlistat Placebo Comparisons
Primary outcome (diabetes) 6.2% 9% HR 0.63, 95% CI [0.46 - 0.86], p=0.0032
Primary outcome (weight loss) 12.8 lbs 6.6 lbs p<0.001
Dropouts 48% 66% p<0.0001
LDL cholesterol (% decrease from baseline) 12.8% 5.1% p<0.01
GI side effects (during year 1) 91% 65% N/A
GI side effects (during year 4) 36% 23% N/A
  • The orlistat group had significant decreases in vitamin A, K, E, and D when compared to placebo. However, the average level of each vitamin remained within the normal reference range throughout the study.
  • Significant diabetes prevention was only seen in patients with impaired glucose tolerance. The incidence of diabetes was low in normal patients (2.7%) and therefore, the study was underpowered to detect a difference in this group.

Findings: Compared with lifestyle changes alone, orlistat plus lifestyle changes resulted in a greater reduction in the incidence of type 2 diabetes over 4 years and produced greater weight loss in a clinically representative obese population. Difference in diabetes incidence was detectable only in the impaired glucose tolerance subgroup; weight loss was similar in subjects with impaired glucose tolerance or normal glucose tolerance.
STOP-NIDDM - Acarbose vs Placebo for the Prevention of T2DM, Lancet (2002) [PubMed abstract]
  • The STOP-NIDDM trial enrolled 1429 prediabetics
Main inclusion criteria
  • Age 40 - 70 years
  • BMI 25 - 40
  • OGTT of 140 - 200 mg/dl and FBS of 100 - 139 mg/dl
Baseline characteristics
  • Average age 54 years
  • Average weight - 191 lbs (87 kg)
  • Average BMI - 31
  • Average fasting glucose - 112 mg/dl
  • Average 2-hour GTT - 167 mg/dl
Randomized treatment groups
  • Group 1 (682 patients) - Acarbose with a target dose of 100 mg three times a day (mean dose achieved 194 mg/day)
  • Group 2 (686 patients) - Placebo three times a day
  • All patients were counseled on weight loss and encouraged to exercise
Primary outcome: Development of diabetes based on a 2-hour OGTT of > 200 mg/dl
Results

Duration: Average of 3.3 years
Outcome Acarbose Placebo Comparisons
Primary outcome (percent with diabetes) 32% 42% HR 0.75, 95%CI [0.63 - 0.90], p=0.0015
Flatulence 68% 27% N/A
Diarrhea 32% 17% N/A
Abdominal pain 17% 12% N/A
Dropout rate 31% 19% N/A
  • At the conclusion of the trial, all patients who had not developed diabetes were given placebo for 3 months, after which a glucose tolerance test was repeated. In the acarbose group, 15% of patients converted to diabetes compared to 10% in the placebo group.

Findings: Acarbose could be used, either as an alternative or in addition to changes in lifestyle, to delay development of type 2 diabetes in patients with impaired glucose tolerance
NAVIGATOR study - Nateglinide vs Placebo for the Prevention of T2DM, NEJM (2010) [PubMed abstract]
  • The NAVIGATOR study enrolled 9306 patients with impaired glucose tolerance and either cardiovascular disease or risk factors for cardiovascular disease
Main inclusion criteria
  • Age ≥ 50 years
  • Fasting glucose of 95 - 126 mg/dl
  • Documented CVD or risk factors for CVD
Main exclusion criteria
  • Significant liver disease
  • Serum creatinine > 2.5 mg/dl
  • Current use of ACE inhibitor or ARB
  • Use or oral DM med or insulin within past 5 years
  • NYHA class III or IV heart failure
Baseline characteristics
  • Average age 64 years
  • Average BMI - 30.5
  • Average BP - 140/83
  • History of cardiovascular disease - 24%
  • Average HgA1C - 5.8%
  • Average fasting glucose - 110 mg/dl
Randomized treatment groups
  • Group 1 (4645 patients) - Nateglinide 60 mg three times a day before meals
  • Group 2 (4661 patients) - Placebo three times a day
  • Nateglinide was started at 30 mg before meals and increased to 60 mg after 2 weeks
  • Fasting blood sugar was measured every 6 months for 3 years, then annually. Oral glucose tolerance tests were also performed annually.
  • All participants were required to participate in a lifestyle modification program
  • Another factor in the trial randomized patients to valsartan
Primary outcomes:
  • 1. Progression to diabetes
  • 2. Composite of death from a cardiovascular cause, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina
Results

Duration: Progression to diabetes - median of 5 years | Composite cardiovascular outcome - median of 6.3 years
Outcome Nateglinide Placebo Comparisons
Primary outcome (diabetes incidence) 36% 33.9% HR 1.07 95%CI [1.0 - 1.15], p=0.05
Primary outcome (cardiovascular outcomes) 14.2% 15.2% HR 0.93 95%CI [0.83 - 1.03], p=0.16
Myocardial infarction 2.9% 3.1% HR 0.95 95%CI [0.75 - 1.20], p=0.66
Overall mortality 6.7% 6.7% HR 1.0 95%CI [0.85 - 1.17], p=0.98
Hypoglycemia incidence 19.6% 11.3% p<0.001
Drug discontinuation at 5 years 30.1% 29% N/A

Findings: Among persons with impaired glucose tolerance and established cardiovascular disease or cardiovascular risk factors, assignment to nateglinide for 5 years did not reduce the incidence of diabetes or the coprimary composite cardiovascular outcomes.
Diet and Exercise for the Prevention of T2DM, NEJM (2001) [PubMed abstract]
  • A study in the NEJM enrolled 522 patients with impaired glucose tolerance
Main inclusion criteria
  • Age 40 - 65 years
  • OGTT of 140 - 200 mg/dl
  • BMI ≥ 25
Main exclusion criteria
  • Fasting blood glucose ≥ 140 mg/dl
  • Diagnosis of diabetes
Baseline characteristics
  • Average age 55 years
  • Average BMI - 31
  • Average fasting blood sugar - 109 mg/dl
  • Average 2-hour OGTT - 159 mg/dl
Randomized treatment groups
  • Group 1 (265 patients) - Detailed advice on diet and exercise that included ongoing meetings with a nutritionist and voluntary weight training groups (intervention group)
  • Group 2 (257 patients) - Oral and written information on diet and exercise, but no individual therapy (control group)
  • All subjects underwent annual 2-hour OGTT
Primary outcome: Development of diabetes defined as fasting blood sugar ≥ 140 mg/dl or 2-hour OGTT ≥ 200 mg/dl
Results

Duration: Average of 3.2 years
Outcome Intervention Control Comparisons
Primary outcome (diabetes incidence at 4 years) 11% 23% HR 0.40 95%CI [0.3 - 0.7], p<0.001
Percent of body weight lost at 1 year 4.7% 0.9% p<0.001
Weight loss at 2 years 7.7 lbs 1.76 lbs p<0.001
Dropouts 8.7% 6.6% N/A

Findings: Type 2 diabetes can be prevented by changes in the lifestyles of high-risk subjects