- ACRONYMS AND DEFINITIONS
- A1C - Hemoglobin A1C
- ADA - American Diabetes Association
- AN - Acanthosis Nigricans
- ASCVD - Atherosclerotic cardiovascular disease
- CrCl - Creatinine clearance
- DKA - Diabetic ketoacidosis
- DM - Diabetes mellitus
- FBS - Fasting blood sugar
- HLA - Human Leukocyte Antigens
- LADA - Latent Autoimmune Diabetes in Adults
- OGTT - Oral glucose tolerance test
- T1DM - Type one diabetes mellitus
- T2DM - Type two diabetes mellitus
- USPSTF - U.S. Preventive Services Task Force
- DEFINITION
- Diabetes
- Type two diabetes is also called "Non-Insulin-Dependent Diabetes Mellitus (NIDDM)" and "Adult-onset diabetes"
- There are primarily two types of diabetes - Type 1 diabetes (T1DM) and Type 2 diabetes (T2DM)
- Type two diabetes accounts for 90 - 95% of the overall cases of diabetes
- Physiology
- Beta cells (also called islet cells) in the pancreas secrete insulin in response to rising blood sugar
- Insulin stimulates cells in various tissues (muscle, liver, and fat) to absorb sugar from the blood
- In T2DM, two problems occur simultaneously that lead to elevated blood sugars; beta cells secrete an inadequate amount of insulin to bring the blood sugar into the normal range, and the tissues of the body become resistant to the effects of insulin
- This is in contrast to type one diabetes where a person does not make any insulin [1]
- PREVALENCE OF TYPE 2 DIABETES
- Overview
- Type 2 diabetes has become a worldwide epidemic. In 2010, the worldwide prevalence of Type 2 Diabetes was 6.4%. [3]
- In the United States, the estimated prevalence of diagnosed and undiagnosed diabetes is shown in the table below
Age (years) | U.S. prevalence (% of total population) |
---|---|
20 - 44 | 4.1% |
45 - 64 | 16.2% |
≥ 65 | 25.9% |
- RISK FACTORS
- Overview
- Major risk factors for T2DM are discussed below
- An online risk calculator derived from data on the U.K. population is available online. The calculator uses the answers to some basic questions to predict the 10-year risk of diabetes. It is available at the link below.
- Family history
- Family history of T2DM is the strongest known risk factor for developing the disease
- The table below shows the results from a study in Sweden that looked at the risk of diabetes based on family history
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 |
- Ethnicity
- Certain ethnicities are at higher risk for diabetes
- The table below shows the prevalence of diabetes by race in U.S. adults
Race | % of adults with diabetes |
---|---|
Non-hispanic white | 11.9% |
Asian-Americans | 27% |
Hispanics | 20.3% |
Black | 18.4% |
- Obesity
- Defined as a BMI ≥ 30 kg/m²
- Overeating causes excessive insulin secretion
- Over time, insulin becomes less effective as the tissues of the body develop tolerance to its effects
- Physical inactivity
- Gestational diabetes
- Women with a history of gestational diabetes are at increased risk of developing T2DM
- In a large meta-analysis that included 20 studies, the following was seen:
- The relative risk of developing T2DM later in life in women who had gestational diabetes was 7.43 times the risk of women without gestational diabetes [6]
- Metabolic syndrome
- Defined as obesity, high triglycerides (> 150 mg/dl), and low HDL (< 40 mg/dl)
- Polycystic ovary syndrome (PCOS)
- Women with polycystic ovary syndrome have a higher risk of developing T2DM
- Medications
- Antipsychotics
- Beta blockers
- Corticosteroids
- Inhaled corticosteroids (Flovent®, Advair®, Beclovent®, etc.) [7]
- Sirolimus (Rapamune®)
- Proton pump inhibitors (e.g. Nexium, Prevacid, Prilosec) [41]
- Statins
- Thiazide diuretics
- ACANTHOSIS NIGRICANS (AN)
- Overview
- Acanthosis Nigricans is a skin condition characterized by darkening (hyperpigmentation) and thickening of the skin
- Affected areas include the neck (most often, 93-99% of the time), armpits, elbows, and knees
- Acanthosis Nigricans (AN) is more prevalent among certain ethnicities [8,9]
- In one study, the prevalence of AN among different ethnicities was as follows:
- African-American - 26.8%
- Hispanic - 26.1%
- White - 6%
- All other - 17.1% [9]
- Association with diabetes
- AN is mostly a benign hereditary condition, but it has also been associated with insulin resistance and an increased risk of T2DM
- In one study, the prevalence of T2DM in patients with AN was as follows:
- White patients: prevalence of diabetes was 2.1 times greater in patients with AN compared to those without
- Other ethnicities: prevalence of diabetes was 1.47 times greater in patients with AN compared to those without [9]
- ADA recommendations
- The ADA recommends that adults with obesity and AN be tested for diabetes
- The ADA recommends that children with obesity, AN, and one additional risk factor (see screening below) be tested for diabetes
- SYMPTOMS OF TYPE 2 DIABETES
- Overview
- Unlike T1DM where diabetes symptoms tend to intensify acutely, T2DM tends to develop more slowly, often over years
- In a large number of patients with T2DM, the classic symptoms of diabetes may not be present or severe enough to be recognized by the patient
- Classic symptoms of diabetes
- Increased urination (polyuria)
- Increased thirst (polydipsia)
- Weight loss
- Increased hunger and visual changes may also be present, but are less frequent
- SCREENING FOR TYPE 2 DIABETES
ADA T2DM Screening Recommendations |
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Adults
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Children
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Patients taking second generation antipsychotics
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- USPSTF recommendations
- Screen for prediabetes and type 2 diabetes in adults aged 35 to 70 years who are overweight or obese
- The current evidence is insufficient to assess the balance of benefits and harms of screening for type 2 diabetes in children and adolescents younger than 18 years
- Screening every 3 years may be reasonable [42]
- DIAGNOSIS OF TYPE 2 DIABETES
- Blood sugar values
- The diagnosis of T2DM can be made with several different types of blood sugar measurements
- If any one of the tests listed below is positive, then a diagnosis of diabetes can be made
- Fasting blood sugar
- Defined as no caloric intake for 8 hours prior to blood sugar being drawn
- Blood sugar ≥ 126 mg/dl is diagnostic for diabetes
- Two-hour oral glucose tolerance test (2-hour OGTT)
- 75 gram load of glucose solution is consumed
- Two hours after consumption, blood glucose is drawn
- Blood sugar ≥ 200 mg/dl is diagnostic for diabetes
- Random blood sugar
- Blood sugar drawn without regard for last calories consumed
- Classic symptoms of high blood sugar need to be present (weight loss, increased thirst and urination)
- Blood sugar ≥ 200 mg/dl is diagnostic for diabetes [1]
- Hemoglobin A1C test
- The ADA began issuing guidelines for using the A1C to diagnose diabetes in 2010
- The A1C test is less sensitive than the fasting glucose level for diagnosing diabetes. Approximately 1/3 of patients with an A1C < 6.5% will have a fasting glucose level ≥ 126. The lower sensitivity appears to be more of an issue in adolescents than adults. See hemoglobin A1C for a complete review of the A1C test. [1,20]
- The A1C values listed below are used to diagnose diabetes and prediabetes
- Diagnosis of diabetes
- A1C ≥ 6.5%
- Diagnosis of prediabetes
- A1C 5.7 - 6.4%
- PREDIABETES (GLUCOSE INTOLERANCE)
- Overview
- Prediabetes is a condition where a person's blood sugar does not meet the criteria for diabetes, but it is above the normal range
- Patients with prediabetes are at increased risk of developing diabetes
- Other terms for prediabetes
- Glucose intolerance
- Impaired glucose tolerance (IGT)
- Impaired fasting glucose
- Diagnosis of prediabetes
- The diagnosis of prediabetes can be made with several different types of blood sugar measurements
- If any one of the tests listed below is positive, then a diagnosis of prediabetes can be made
- Fasting blood sugar
- Defined as no caloric intake for 8 hours prior to blood sugar being drawn
- Prediabetes = blood sugar 100 - 125 mg/dl
- Two-hour oral glucose tolerance test (2-hour OGTT)
- 75 gram load of glucose solution is consumed
- Two hours after consumption, blood glucose is drawn
- Prediabetes = blood sugar 140 - 199 mg/dl
- Hemoglobin A1C test
- Prediabetes = A1C value 5.7 - 6.4% [1]
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% |
- WEIGHT LOSS FOR T2DM
- 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.
- 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 |
|
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
- 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
- BLOOD SUGAR GOALS
- See blood sugar goals in diabetes for recommendations on target blood sugar values and A1C values
- TREATMENT RECOMMENDATIONS FOR TYPE 2 DIABETES
ADA T2DM Treatment Recommendations for Adults |
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Step 1 - initial therapy
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Step 2 - intensify therapy
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ADA T2DM Treatment Recommendations for Youth (10 - 19 years) |
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Step 1 - initial therapy
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Step 2
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- EARLY INSULIN THERAPY IN TYPE 2 DIABETES
- 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
- 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 |
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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
- 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)
- 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
- 1,5-ANHYDROGLUCITOL (1,5AG)
- Overview
- 1,5-anhydroglucitol is a monosaccharide that is absorbed from the diet
- 1,5AG undergoes minimal degradation and metabolism so its blood concentration remains fairly constant
- 1,5AG is reabsorbed by the kidneys after it is excreted into the urine
- When blood sugar levels are very high (ex. after a meal), glucose is excreted by the kidneys
- Glucose excretion blocks 1,5AG reabsorption, and 1,5AG blood concentrations will decrease
- Because of this relationship, 1,5AG concentrations can be used as a measure of postprandial (post-meal) glucose levels
- 1,5AG best reflects blood sugar control over the previous 2 weeks [22,23]
- Summary
- 1,5AG can be used as a measure of postprandial (post-meal) blood sugar levels
- Checking post-meal blood sugars with a finger stick is simpler and more direct
- 1,5AG is not widely used, and its utility in diabetes management has not been validated
- FRUCTOSAMINE
- Like hemoglobin, other proteins will form a bond with glucose (glycosylation), and their amount of glycosylation can be used to estimate blood sugar control
- "Fructosamine" is a term used to describe proteins (albumin and others) that have been glycosylated. The amount of fructosamines reflects diabetic control over the last 2 - 3 weeks.
- Fructosamine levels may be useful in patients with abnormal hemoglobin because their hemoglobin A1C test may not be accurate
- The clinical utility of fructosamine has not been validated in clinical trials [16]
- LATENT AUTOIMMUNE DIABETES IN ADULTS (LADA)
- Physiology
- In T1DM, insulin-producing beta cells are destroyed by islet cell autoantibodies. In most cases, total destruction occurs in childhood or adolescence, and insulin production ceases. A small subset of patients, however, continue to make insulin for many years, and insulin production does not stop until adulthood. These patients are often diagnosed with T2DM that eventually becomes unresponsive to non-insulin therapies. This condition is sometimes referred to as latent autoimmune diabetes in adults (LADA).
- Incidence
- The incidence of LADA is not well-defined, but studies have looked at the prevalence of islet cell autoantibodies in type two diabetics
- Approximately 10% of patients with T2DM who are 40 - 75 years old have islet cell autoantibodies
- Approximately 25% of patients with T2DM who are younger than 35 years old have islet cell autoantibodies [36]
- Signs of LADA
- LADA can be challenging to diagnose because it develops gradually, and affected patients will already be using insulin in many cases
- Signs that a patient has developed LADA may include the following:
- Patient requires a significant amount of insulin
- Blood sugar control is erratic with very high numbers and episodes of hypoglycemia
- Blood sugar control that changes abruptly
- Type 2 diabetic that develops DKA
- Diagnosis
- There is no consensus on what criteria constitutes a diagnosis of LADA. In general, LADA may be diagnosed when a patient with T2DM is found to be positive for islet cell autoantibodies; GAD65A antibodies are the most common type of antibody found. Once the diagnosis of LADA is made, patients typically progress to insulin dependence within 6 years. [16,36]
- Checking a C-peptide level in patients with suspected LADA may be more helpful than autoantibody tests because it directly measures the amount of insulin production (see insulin production illustration)
- Treatment
- Since patients with LADA still make insulin for some time, therapy with insulin-sensitizing agents is logical until insulin production ceases. Some studies have shown that early insulin therapy may help preserve remaining beta-cell function better than insulin-sensitizing and insulin-secreting agents. [35]
- PREVENTION OF TYPE 2 DIABETES
- Overview
- A number of trials have looked at medications and diet and exercise in the prevention of T2DM. Some of the larger trials are detailed below.
- 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 |
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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.
- 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
- 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 |
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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.
- 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 |
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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
- 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.
- 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
- 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]
- 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.
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