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

  • Reference [5]
Race % of adults with diabetes
Non-hispanic white 7.1%
Asian-Americans 8.4%
Hispanics 11.8%
African Americans 12.6%









ADA T2DM Screening Recommendations
Adults
  • 1. Screen all adults beginning at age 45 years
  • 2. 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%


Overview
  • In patients with T2DM who are overweight, weight loss can have a profound effect on blood sugar control even leading to remission in many cases
  • A study published in the Lancet in 2018 demonstrated just how effective weight loss can be for T2DM. The study is detailed below along with a follow-up study that looked at 2-year results.
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.
Summary
  • The DIRECT study showed the profound effect that weight loss can have on diabetes in overweight diabetics
  • Most patients in the study had relatively mild disease (average baseline A1C was 7.6% with a standard deviation of around 1.12%), but the effects of weight loss were remarkable. Overweight diabetics with any severity of diabetes are likely to see significant benefit from weight loss.
  • See weight loss for more information



  • 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
  • If patient has atherosclerotic cardiovascular disease (ASCVD), 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

  • If patient has 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 > exenatide ER)
      • 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

  • If patient does NOT have 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
      • SGLT2 inhibitor
    • Drugs that are cheaper
      • Sulfonylurea
      • Glitazone
      • NPH and regular (R) insulin [38,39]

  • 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 while titrating metformin
  • 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



  • Reference [38,39]
ADA Insulin Dosing Recommendations for Adults with T2DM
Step 1 - start with basal insulin
  • Initial dose: 10 units/day or 0.1 - 0.2 units/kg/day
  • Adjust dose: increase dose by 10 - 15% or 2 - 4 units once or twice weekly to achieve fasting blood sugar goal (see adjusting basal insulin for more)
  • If hypoglycemia occurs: decrease dose by 10 - 20% or 4 units
  • If A1C is still above target despite achieving fasting blood sugar goal, or if A1C is not at target and insulin dose is > 0.7 - 1.0 units/kg, proceed to Step 2
Step 2 - add premeal insulin before largest meal
  • Initial dose: 4 units or 0.1 units/kg or 10% of basal dose
    • If A1C < 8%, consider decreasing basal insulin dose by same amount
  • Adjust dose: increase dose by 1 - 2 units or 10 - 15% twice weekly to achieve pre- and postprandial goals (see adjusting premeal insulin for more)
  • If hypoglycemia occurs: decrease dose 2 - 4 units or 10 - 20%
  • If A1C still not at target, proceed to Step 3
Step 3 - add premeal insulin before other meals in stepwise fashion
  • Add prandial insulin to an additional meal and use the guidelines in Step 2 to adjust
  • If not controlled with 2 preprandial doses, add to a third meal
  • Stepwise addition of prandial insulin every 3 months is associated with a lower risk of hypoglycemia and greater patient satisfaction [38,39]

  • Reference [39]
ADA Insulin Recommendations for Youth with T2DM
Basal insulin
  • Initial dose: 0.5 units/kg/day
  • Adjust dose: Increase every 3 - 5 days based on blood sugar readings to a maximum of 1.5 units/kg/day (see adjusting basal insulin for more)
  • If pancreatic autoantibodies are positive, consider starting basal-premeal regimen or insulin pump therapy

  • Reference [39]
ADA Insulin Recommendations for Elderly with T2DM
Overview
  • In order to avoid hypoglycemia, the ADA recommends that insulin regimens be simplified in elderly patients who have cognitive impairment, multiple coexisting chronic illnesses, and/or functional dependence
  • The information below gives general recommendations that can be used for simplifying regimens in appropriate patients
Basal insulin
  • Change timing from bedtime to morning
  • When titrating basal insulin, use a fasting blood sugar goal of 90 - 150 mg/dl and make adjustments based on a week of values
  • If 50% of fasting blood sugar values are above goal, increase basal dose by 2 units
  • If > 2 fasting blood sugar values/week are < 80 mg/dl, decrease basal dose by 2 units
Premeal (prandial) insulin
  • Initial therapy
    • Do not use short-acting insulin at bedtime
    • If premeal insulin dose is ≤ 10 units, discontinue premeal insulin and add noninsulin agent
    • If premeal insulin dose is > 10 units, decrease dose by 50% and add noninsulin agent. Titrate noninsulin agent while decreasing premeal insulin dose with goal of stopping premeal insulin.
  • Adjusting therapy
    • Use a blood glucose premeal goal of 90 - 150 mg/dl
    • Every 2 weeks, adjust insulin dose and noninsulin therapy based on pre-lunch and pre-dinner glucose readings
    • If 50% of premeal blood sugar values are above goal over 2 weeks, increase intensity of noninsulin therapy
    • If > 2 premeal values/week are < 90 mg/dl, decrease intensity of therapy
  • Sliding scale for premeal blood sugar values
    • Blood sugar > 250 mg/dl: give 2 units of short- or rapid-acting insulin
    • Blood sugar > 350 mg/dl: give 4 units of short- or rapid-acting insulin
  • Noninsulin agents
    • If GFR ≥ 45 ml/min, use metformin as noninsulin agent
    • If GFR < 45 ml/min or metformin is already being used, see adult treatment recommendations above for guidance on other agents






Overview
  • A handful of small studies have shown that newly-diagnosed type 2 diabetics who are treated with insulin initially show improved blood sugar control and beta-cell function than patients who are treated with oral medications
  • One of the larger studies to look at this effect is detailed below
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 therapy 31% 28% 19% N/A
  • Acute insulin response was measured after initial intensive therapy. The response was maintained at 1-year in Groups 1 and 2, but declined significantly in Group 3.

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
Summary
  • Early insulin therapy appears to help preserve beta-cell function in some type 2 diabetics
  • Although the results of the study are intriguing, treating newly diagnosed type 2 diabetics with an insulin pump is not feasible, and starting new diabetics on multiple insulin injections a day will be a hard sell in most cases
ADA recommendations
  • The ADA recommends that providers consider insulin therapy in newly diagnosed type 2 diabetics who have A1C ≥ 10% and/or have ongoing symptoms of hyperglycemia (e.g. weight loss, polyuria, polydipsia)


















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 Group 3, 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
  • Group 1 had significant decreases in vitamin A, K, E, and D when compared to Group 2. However, the average level of each vitamin remained within the normal reference range in Group 1 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 Group 1, 15% of patients converted to diabetes compared to 10% in Group 2.

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
Summary
  • Weight loss and exercise are superior to medications in preventing the development of diabetes
  • It's unclear if medications truly prevent diabetes, or if they merely treat early diabetes and thus mask its diagnosis. There is no question that diet and exercise prevent diabetes.
  • Patients with impaired glucose tolerance and mild diabetes should pursue weight loss and exercise measures aggressively. They should also understand that they have control over their condition. Metformin may be considered in patients who do not respond to these measures.
ADA recommendations for patients with prediabetes
  • Lifestyle modification program with target goals of 7% weight loss and physical activity of at least 150 minutes a week
  • Metformin may be considered in patients with multiple risk factors, especially if they do not respond to lifestyle modification
  • Other drug interventions are not recommended [39]