TYPE TWO DIABETES

• ACRONYMS AND DEFINITIONS

• A1C - Hemoglobin A1C
• ADA - American Diabetes Association
• AN - Acanthosis Nigricans
• 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

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• 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]

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• 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

Reference [2]

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

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• 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.
• Online diabetes risk predictor


• 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

• ✝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

• Ethnicity
• Certain ethnicities are at higher risk for diabetes
• The table below shows the prevalence of T2DM by race in the United States

• Reference [5]

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:
• Antipsychotics
• Thiazide diuretics
• Sirolimus (Rapamune®)
• Statins
• Beta blockers
• Inhaled corticosteroids (Flovent®, Advair®, Beclovent®, etc.) [7]
• Corticosteroids

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• 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

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• 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

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• 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

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• 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%

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• 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

Reference [24]

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]

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• TREATMENT RECOMMENDATIONS FOR TYPE 2 DIABETES

• 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 how effective weight loss can be for T2DM. The study is detailed below.


• Weight Loss 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 | 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%


• 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

ADA T2DM treatment recommendations
For diabetics with A1C < 9% 1. Initial therapy for these patients should be the following: Lifestyle changes including weight loss and exercise (see diabetic diet for more) Metformin 2. After 3 months, if blood sugar goals are not met, then add one of the following: If patient has cardiovascular disease, use one of the following: Liraglutide Empagliflozin If patient does not have cardiovascular disease, choose one of the following based on individual patient factors: Sulfonylurea Insulin Glitazone DPP-4 inhibitor GLP-1 analog SGLT2 inhibitor 3. After 3 months, if blood sugar goals are not met, then add a third drug from the list above Special considerations: For patients taking metformin + DPP-4 inhibitor: add sulfonylurea or glitazone or SGLT2 inhibitor or insulin For patients taking metformin + SGLT2 inhibitor: add sulfonylurea or glitazone or DPP-4 inhibitor or insulin For patients taking metformin + GLP-1 analog: add sulfonylurea or glitazone or insulin For patients taking metformin + insulin: add glitazone or DPP-4 inhibitor or SGLT2 inhibitor or GLP-1 analog For patients taking metformin + sulfonylurea: add any other med For patients taking metformin + glitazone: add any other med 4. After 3 months, if blood sugar goals are not met on three meds then consider the following: If taking all oral meds, add insulin or GLP-1 analog If using GLP-1 analog, add basal insulin If on optimally titrated basal insulin, add GLP-1 analog or mealtime insulin [37]
For diabetics with A1C between 9 - 10%: Use steps above, but consider initiating therapy with metformin and a drug from Step 2
For diabetics with A1C ≥ 10% and/or blood sugar ≥ 300 mg/dl: Consider initiating therapy with the following: Metformin + Basal insulin + Mealtime insulin or GLP-1 analog After control is achieved, medication tapering may be attempted [37,38]

• Reference [38]

ADA algorithm for initiating insulin in type two diabetes
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 If hypoglycemia occurs: decrease dose by 10 - 20% or 4 units If blood sugars are still uncontrolled after fasting target is achieved or if insulin dose is > 0.5 units/kg/day, proceed to Step 2 Alternatively, may consider adding GLP-1 analog
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% once or twice weekly to achieve pre- and postprandial goals If hypoglycemia occurs: decrease dose 2 - 4 units or 10 - 20% Alternative regimen - change basal insulin to twice daily premixed insulin Initial dose: divide basal dose and give as premixed insulin twice daily (2/3 AM and 1/3 PM OR 1/2 AM and 1/2 PM) Adjust dose: increase dose by 1 - 2 units or 10 - 15% once or twice weekly to achieve pre- and postprandial goals If hypoglycemia occurs: decrease dose 2 - 4 units or 10 - 20% If blood sugars are still uncontrolled, proceed to Step 3
Step 3 - add premeal insulin before ≥ 2 meals Initial dose: 4 units OR 0.1 units/kg OR 10% of basal dose before each meal If A1C < 8%, consider decreasing basal insulin dose by same amount Adjust dose: increase dose by 1 - 2 units or 10 - 15% once or twice weekly to achieve pre- and postprandial goals If hypoglycemia occurs: decrease dose 2 - 4 units or 10 - 20% Alternative regimen (twice daily premixed insulin): Add additional injection before lunch Adjust dose: increase dose by 1 - 2 units or 10 - 15% once or twice weekly to achieve pre- and postprandial goals If hypoglycemia occurs: decrease dose 2 - 4 units or 10 - 20%

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• BLOOD SUGAR GOALS

• NOTE: The goals presented here are for nonpregnant adult diabetics. Pregnant or gestational diabetics have different goals. Children may also have different goals.



• Blood sugar values

• The ADA makes two recommendations for blood sugar fingerstick values in diabetics:
• Premeal blood sugar: 80 - 130 mg/dl
• Peak post-meal blood sugar (within 1-2 hours after the start of a meal): < 180 mg/dl [37]



• Hemoglobin A1C goals

• The hemoglobin A1C test reflects the average blood sugar over the previous 3 months
• See hemoglobin A1C test for more information


• The ADA recommends the following for A1C goals in diabetics:
• Diabetics with good control should have an A1C drawn every 6 months, while those with suboptimal control should have one checked every 3 months
• The A1C goal should be < 7% for most diabetics
• Lower A1C goals (< 6.5%) may be appropriate for selected individual patients if this can be achieved without significant hypoglycemia or other adverse effects of treatment. Appropriate patients might include those with short duration of diabetes, type 2 diabetes treated with lifestyle or metformin only, long life expectancy, or no significant cardiovascular disease
• Higher A1C goals (< 8%) may be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, extensive comorbid conditions, or long-standing diabetes in whom the general goal is difficult to attain [37]


• StraightHealthcare analysis:
• Results from clinical trials have not consistently defined an ideal A1C goal for all diabetics (see A1C trials for more)
• Based on the available evidence, the A1C goals below are reasonable
• A1C goal of 6 - 7% is appropriate for patients who are:
• Compliant
• Motivated
• Recently diagnosed with diabetes or have a history of good blood sugar control
• Ideally < 50 years old
• At low risk for heart disease
• A1C goal of 7 - 8.5% may be more appropriate for patients who are:
• Older than 50 years
• Have a longer history of diabetes ( > 5 years)
• Less compliant
• Less motivated
• At high-risk for heart disease
• Long history of poor blood sugar control

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• 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.


• 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%
• 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

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• 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

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• 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]

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• 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

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• PREVENTION OF TYPE 2 DIABETES

• Metformin

• Diabetes Prevention Program Trial - Metformin vs Lifestyle Changes vs Placebo, 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; 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®)

• ACT NOW Study - Pioglitazone vs Placebo to Prevent DM2, NEJM (2011) [PubMed abstract]
• 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®)

• XENDOS trial - Orlistat vs Placebo to Prevent DM, 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 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®)

• STOP-NIDDM - Acarbose vs Placebo to Prevent Diabetes, Lancet (2002) [PubMed abstract]
• 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®)

• NAVIGATOR study - Nateglinide vs Placebo to Prevent Diabetes, 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 + 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

• Diet and Exercise for Diabetes Prevention, NEJM (2001) [PubMed abstract]
• 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

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• BIBLIOGRAPHY

• What is PMID?
• PI = Manufacturer's Package Insert

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• 37 - ADA 2015 Standards of medical care in diabetes
• 38 - PMID 29222370 - ADA 2018 Standards of medical care in diabetes