- 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
- Gestational diabetes - Diabetes during pregnancy
- HLA - Human Leukocyte Antigens
- LADA - Latent Autoimmune Diabetes in Adults
- T1DM - Type one diabetes mellitus
- T2DM - Type two diabetes mellitus
- 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 (Type 1 about 5-10%)
- 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:
- The Beta-cells secrete an inadequate amount of insulin to lower the blood sugar to its normal range
- 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.
- Major risk factors for diabetes
- 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 T2DM by race in the United States
Race | % of adults with diabetes |
---|---|
Non-hispanic white | 7.1% |
Asian-Americans | 8.4% |
Hispanics | 11.8% |
African Americans | 12.6% |
- Obesity
- Defined as a BMI ≥ 25 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
- Medications that have been associated with increased diabetes risk include:
- 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 is has also been associated with insulin resistance and an increased risk of T2DM
- In one study, the prevalence of T2DM in patients with AN wa as follows:
- White patients: prevalence of diabetes was 2.1 times that in patients with AN compared to those without
- Other ethnicities: prevalence of diabetes was 1.47 times that in patients with AN compared to those without [9]
- Professional guidelines:
- 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
- StraightHealthcare analysis:
- AN is typically a benign condition that is more prevalent among certain ethnicities
- Its presence is associated with a higher incidence of diabetes and insulin resistance
- Patients who are overweight and have AN should be tested for diabetes
- White patients with AN appear to be at a greater risk for diabetes than other ethnicities with AN
- SYMPTOMS OF TYPE 2 DIABETES
- Overview
- Unlike T1DM where 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
- The classic symptoms of diabetes include:
- 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 recommendations for screening asymptomatic 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]
ADA recommendations for screening asymptomatic 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 be begin at 10 years of age or at the onset of puberty, whichever comes first
- 3. For normal results, rescreen every 3 years. [1]
ADA recommendations for screening patients on 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
- DIAGNOSIS OF TYPE 2 DM
- Blood sugar values
- The diagnosis of T2DM can be made with several different types of blood sugar measurements
- If any one of the following tests is positive, the 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 glucose tolerance test (2hr GTT)
- 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. [1,20]
- The ADA felt that since a large number of patients with T2DM are unaware they have diabetes, the practicality of the test (it does not require fasting) would offset its lower sensitivity in helping diagnose diabetes
- The ADA makes the following recommendations for using A1C levels to diagnose diabetes:
- Diagnosis of diabetes
- A1C ≥ 6.5%
- Diagnosis of prediabetes
- A1C 5.7 - 6.4%
- PREDIABETES (GLUCOSE INTOLERANCE)
- Other terms for prediabetes
- Glucose intolerance
- Impaired glucose tolerance (IGT)
- Impaired fasting glucose
- Definition
- 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
- Risk for developing T2DM
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% |
- Diagnosis
- The ADA set forth the following criteria for the diagnosis of prediabetes:
- 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 glucose tolerance test
- 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
- Can be drawn anytime regardless of fasting
- Prediabetes = A1C value 5.7 - 6.4%
- Should not be used under conditions of abnormal red blood cell turnover such as pregnancy, recent blood loss, blood transfusion, or certain anemias
- See hemoglobin A1C for more [1]
- WEIGHT LOSS FOR T2DM
- Weight loss
- T2DM may be treated with weight loss, oral medications, insulin, and non-insulin injectable medications (e.g. GLP-1 analogs)
- In patients with T2DM who are overweight, weight loss can have a profound effect on blood sugar control often leading to remission in many cases
- A study published in the Lancet in 2018 showed just how effective weight loss can be for T2DM. The study is detailed below.
- 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 | Average time since diabetes diagnosis - 3 years
- 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% | Number of oral DM meds: 0 - 24%, 1 - 48%, ≥ 2 - 27%
- Patients were randomized to one of two groups:
- Group 1 (149 patients) - Weight loss program
- 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
- At 12 months, the following was seen:
- Primary outcome (weight loss ≥ 33 lbs (15 kg)): Group 1 - 24%, Group 2 - 0% (p<0.0001)
- Primary outcome (remission of diabetes): Group 1 - 46%, Group 2 - 4% (p<0.0001)
- Average weight loss: Group 1 - 22 lbs (10 kg), Group 2 - 2.2 lbs (1 kg) (diff 19.4 lbs, p<0.0001)
- Average change in A1C: Group 1 -0.9%, Group 2 +0.1% (diff 0.85%, p<0.0001)
- Dropout rate: 23 participants (8%) overall
- Remission of DM in all patients by weight loss:
- Weight gain: 0%
- 0 - 11 lbs (5 kg): 7%
- 11 lbs - 22 lbs (5 - 10 kg): 34%
- 22 lbs - 33 lbs (10 - 15 kg): 57%
- ≥ 33 lbs (≥ 15 kg): 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
- StraightHealthcare analysis:
- This 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 this doesn't discount the fact that diabetes remission was achieved in almost all patients who lost ≥ 33 lbs. Overweight diabetics with any degree of control are likely to see significant effects from weight loss.
- See weight loss for more information
- TREATMENT RECOMMENDATIONS FOR TYPE 2 DIABETES
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 > exenatide ER
- 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 or canagliflozin 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]
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 initiated on metformin + insulin
- If blood sugar goals are being met, insulin can be tapered over 2 – 6 weeks by decreasing the insulin dose 10 – 30% every few days
- Goals not met on metformin: add basal insulin
- Goals not met on basal insulin doses up to 1.5 units/kg/day: switch to basal-premeal regimen [39]
- ADA INSULIN DOSING RECOMMENDATIONS
ADA Recommendations for Insulin in 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
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%
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]
ADA Recommendations for Insulin in 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
ADA Recommendations for Insulin in 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
- 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
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.
- 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
- 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
- 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
- BLOOD SUGAR GOALS
- See blood sugar goals in diabetes for recommendations on target blood sugar values and A1C values
- EARLY INSULIN THERAPY IN TYPE 2 DIABETES
- ADA recommendations
- The ADA recommends that providers "consider" insulin therapy in newly diagnosed type 2 diabetics who have A1C ≥ 10% (see type 2 treatment for more)
- This recommendation is based on a handful of studies that have shown improved blood sugar control and beta-cell function in patients who are treated initially with insulin. One of the larger studies 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%
- Patients were randomized to 1 of 3 groups:
- Group 1 (137 patients) - Patients were put on an insulin pump (97% of patients achieved normal blood sugar in an average of 4 days)
- Group 2 (124 patients) - Patients were put on intensive insulin therapy with multiple injections a day (95% of patients achieved normal blood sugar in an average of 5.6 days)
- Group 3 (121 patients) - Patients were treated with sulfonylurea and metformin (84% of patients achieved normal blood sugar in an average 9.3 days)
- 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.
- At one year, the following results were seen:
- Failure to achieve glycemic control during initial therapy: Group 1 - 4 patients, Group 2 - 6 patients, Group 3 - 13 patients
- Primary outcome (relapse rate at 1 year): Group 1 - 49%, Group 2 - 55%, Group 3 - 73.3% (1 and 2 vs 3, p=0.0012)
- Hypoglycemia during intensive therapy: Group 1 - 31%, Group 2 - 28%, Group 3 - 19%
- 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.
- StraightHealthcare analysis:
- Results from this study are intriguing
- Early insulin therapy appears to help preserve beta-cell function in some type 2 diabetics
- Treating newly diagnosed type 2 diabetics with an insulin pump is not feasible for a number of reasons. Insulin injections may be more practical if therapy is started while the patient is hospitalized.
- In practice, starting newly diagnosed type 2 diabetics on insulin will be a hard sell in most cases
- EXERCISE AND INSULIN
- See exercise and insulin for guidelines on adjusting insulin therapy for exercise
- DIABETES MANAGEMENT
- See diabetes management for recommendations on managing diabetes and diabetic complications
- 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]
- StraightHealthcare analysis:
- 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
- T1DM involves the destruction of insulin-producing Beta-cells by islet cell autoantibodies
- In most cases, Beta-cell are destroyed and insulin production ceases in childhood or adolescence
- On rare occasions, patients with islet cell autoantibodies will continue to make insulin for many years into adulthood before their Beta-cells are finally destroyed and insulin production ceases
- These patients are often diagnosed as adults with T2DM until their diabetes becomes unresponsive to oral agents (insulin production ceases), and they become insulin-dependent
- This condition is sometimes referred to as Latent Autoimmune Diabetes in Adults (LADA)
- Prevalence
- 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]
- 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 autoantibodies are commonly found in LADA, but other autoantibodies may be present
- Once the diagnosis of LADA is made, patients typically progress to insulin-dependence within 6 years [16, 36]
- Treatment
- Since patients with LADA still make insulin for some time, therapy with insulin-sensitizing agents is logical
- Some studies have shown that early insulin therapy may help preserve the remaining beta-cell function better than therapy with insulin secretagogues or insulin-sensitizing agents [35]
- There is no consensus recommendation for the treatment of LADA
- StraightHealthcare analysis:
- LADA can be challenging to diagnose because it develops gradually, and affected patients will already be using insulin in many cases
- Checking a C-peptide level can help diagnose the condition, and would likely be more useful than autoantibody tests. (see insulin production illustration)
- 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 (low blood sugar)
- Blood sugar control that changes abruptly
- Type 2 diabetic that develops DKA
- PREVENTION OF TYPE 2 DIABETES
Metformin
- 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; 2-hour oral glucose tolerance test (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%
- Patients were randomized to 1 of 3 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
- After 2.8 years, the following was seen:
- Primary outcome (cases per 100 person-years): Group 1 - 11, Group 2 - 7.8, Group 3 - 4.8 (1 vs 2, p<0.001; 1 vs 3, p<0.001; 2 vs 3, p<0.001)
- Weight loss: Group 1 - 0.22 lbs (0.1 kg), Group 2 - 4.6 lbs (2.1 kg), Group 3 - 12.3 lbs (5.6 kg) (1 vs 2, p<0.001; 1 vs 3, p<0.001; 2 vs 3, p<0.001)
- Gastrointestinal symptoms: Group 1 - 30.7%, Group 2 - 77.8%, Group 3 - 12.9%
- In Group 3, 50% of patients achieved ≥ 7% weight loss [27]
Pioglitazone (Actos®)
- The ACT NOW study enrolled 602 patients with impaired glucose tolerance
- Main inclusion criteria: impaired glucose tolerance defined as 2-hour oral glucose tolerance test (OGTT) of 140 - 199 mg/dl; BMI ≥ 25; at least one risk factor for diabetes (family history, PCOS, history of gestational DM, ≥ 1 component of metabolic syndrome, minority ethnic background)
- 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
- Patients were randomized to 1 of 2 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
- After a median follow-up of 2.4 years, the following was seen:
- Primary outcome: Group 1 - 5%, Group 2 - 16.7% (HR 0.28, 95%CI [0.16 - 0.49], p<0.001)
- Incidence of worsening edema: Group 1 - 12.9%, Group 2 - 6.4% (p=0.007)
- Weight gain > 1 kg: Group 1 - 67.7%, Group 2 - 42.8%
- Dropout rate: Group 1 - 29.7%, Group 2 - 23.7% [31]
Orlistat (Xenical®)
- 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 defined as fasting blood sugar of < 120 mg/dl and 2-hour oral glucose tolerance test (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%
- Patients were randomized to 1 of 2 groups:
- Group 1 (1640 patients) - Weight loss counseling + orlistat 120 mg three times a day
- Group 1 (1637 patients) - Weight loss counseling + placebo
- 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
- After 4 years, the following was seen:
- Primary outcome (diabetes): Group 1 - 6.2%, Group 2 - 9% (HR 0.63, 95% CI [0.46 - 0.86], p=0.0032)
- Primary outcome (weight loss): Group 1 - 12.8 lbs (5.8 kg), Group 2 - 6.6 lbs (3 kg) (p<0.001)
- Dropouts: Group 1 - 48%, Group 2 - 66%
- LDL cholesterol (average % decrease from baseline): Group 1 - 12.8%, Group 2 - 5.1% (p<0.01)
- Gastrointestinal side effects (during year 1): Group 1 - 91%, Group 2 - 65%
- Gastrointestinal side effects (during year 4): Group 1 - 36%, Group 2 - 23%
- 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. [25]
Acarbose (Precose®)
- The STOP-NIDDM trial enrolled 1429 prediabetics
- Main inclusion criteria: age 40 - 70 years; BMI 25 - 40; impaired glucose tolerance defined as 2-hour 75 gram oral glucose tolerance test (OGTT) of 140 - 200 mg/dl and a fasting plasma glucose 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
- Patients were randomized to one of two groups:
- Group 1 (682 patients) - Acarbose with a target dose 100 mg three times a day (mean dose achieved 194 mg/day)
- Group 1 (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
- After an average follow-up of 3.3 years, the following was seen:
- Primary outcome (percent with diabetes): Group 1 - 32%, Group 2 - 42% (HR 0.75, 95%CI [0.63 - 0.90], p=0.0015)
- Flatulence: Group 1 - 68%, Group 2 - 27%
- Diarrhea: Group 1 - 32%, Group 2 - 17%
- Abdominal pain: Group 1 - 17%, Group 2 - 12%
- Dropout rate: Group 1 - 31%, Group 2 - 19%
- 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. [33]
Nateglinide (Starlix®)
- 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 + known cardiovascular disease (if ≥ 50 years) or ≥ 1 of the following (if ≥ 55 years) - premature family history of CAD, smoker, hypertension, dyslipidemia, left ventricular hypertrophy, microalbuminuria
- 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
- Patients were randomized to 1 of 2 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
- During follow-up, the following was seen:
- The median follow-up for the progression to diabetes was 5 years. The median follow-up for the composite cardiovascular outcome was 6.3 years.
- Primary outcome (diabetes incidence): Group 1 - 36%, Group 2 - 33.9% (HR 1.07 95%CI [1.0 - 1.15], p=0.05)
- Primary outcome (cardiovascular outcomes): Group 1 - 14.2%, Group 2 - 15.2% (HR 0.93 95%CI [0.83 - 1.03], p=0.16)
- Myocardial infarction: Group 1 - 2.9%, Group 2 - 3.1% (HR 0.95 95%CI [0.75 - 1.20], p=0.66)
- Overall mortality: Group 1 - 6.7%, Group 2 - 6.7% (HR 1.0 95%CI [0.85 - 1.17], p=0.98)
- Drug discontinuation at 5 years: Group 1 - 30.1%, Group 2 - 29%
- Hypoglycemia incidence: Group 1 - 19.6%, Group 2 - 11.3% (p<0.001)[32]
Diet and exercise
- A study in the NEJM enrolled 522 patients with impaired glucose tolerance
- Main inclusion criteria: age 40 - 65 years; impaired glucose tolerance defined as 2-hour oral glucose tolerance test (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
- Patients were randomized to 1 of 2 groups:
- Group 1 (265 patients) - Detailed advice on diet and exercise that included ongoing meetings with a nutritionist and voluntary weight training groups
- Group 2 (257 patients) - Oral and written information on diet and exercise, but no individual therapy
- 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
- After an average follow-up of 3.2 years, the following was seen:
- Primary outcome (diabetes incidence at 4 years): Group 1 - 11%, Group 2 - 23% (HR 0.40 95%CI [0.3 - 0.7], p<0.001)
- Percent of body weight lost at 1 year: Group 1 - 4.7%, Group 2 - 0.9% (p<0.001)
- Dropouts: Group 1 - 8.7%, Group 2 - 6.6% [34]
- Professional guidelines:
- The ADA recommends the following for patients with impaired glucose tolerance:
- 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
- StraightHealthcare analysis:
- 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
- BIBLIOGRAPHY
- What is PMID?
- PI = Manufacturer's Package Insert
- # PMID
- 1 - 21193625
- 2 - CDC website
- 3 - 21705072
- 4 - 19903751
- 5 - CDC National Diabetes Fact Sheet 2011
- 6 - 19465232
- 7 - 20870201
- 8 - 17548847
- 9 - 20616290
- 10 - 19820011
- 11 - NGSP website
- 12 - 20032277
- 13 - 15345893
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- 25 - 14693982
- 26 - 16391903
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- 30 - 19277602
- 31 - 21428766
- 32 - 20228402
- 33 - 12086760
- 34 - 11333990
- 35 - 21901702
- 36 - 16306343
- 37 - ADA 2015 Standards of medical care in diabetes
- 38 - PMID 29222370 - ADA 2018 Standards of medical care in diabetes
- 39 - ADA Standards of Medical Care in Diabetes (2019)