• ACRONYMS AND DEFINITIONS

• A1C - Hemoglobin A1C
• ADA - American Diabetes Association
• AHA/ACC - American Heart Association / American College of Cardiology
• ARB - Angiotensin receptor blocker
• BP - Blood pressure
• CVD - Cardiovascular disease
• DBP - Diastolic blood pressure
• DKD - Diabetic kidney disease
• GFB - Glomerular filtration barrier
• GFR - Glomerular filtration rate
• NGSP - National Glycohemoglobin Standardization Program
• NKF - National Kidney Foundation
• SBP - Systolic blood pressure
• T1DM - Type one diabetes mellitus
• T2DM - Type two diabetes mellitus
• 1 kilogram = 2.2 pounds

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• INITIAL EVALUATION

• The ADA recommends the following evaluation for newly diagnosed diabetics:


• Comprehensive physical exam and medical history
• Labs
• Hemoglobin A1C
• Fasting Lipid Profile
• Liver function tests
• Spot urine albumin-to-creatinine ratio
• Serum creatinine with calculated GFR
• Vitamin B12 - if taking metformin
• Serum potassium - if taking ACE, ARB, or diuretic
• If type one diabetic, also consider:
• Thyroid Stimulating Hormone (TSH)
• Celiac disease screening
• Referrals
• Annual dilated eye exam
• Family planning for women of reproductive age
• Registered dietician for dietary counseling
• Diabetes self-management education
• Dental exam
• Mental health professional, if needed [1]


• StraightHealthcare analysis:
• In practice, the appropriate initial evaluation will depend on the patient and available resources

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• CHECKING BLOOD SUGARS

• ADA recommendations
• The ADA gives specific recommendations for patients on intensive insulin regimens (daily multi-dose insulin), but says the information is insufficient to make specific recommendations for patients using oral agents and/or basal insulin only
• A study published in JAMA Internal Medicine compared daily blood sugar monitoring to no monitoring in non-insulin treated type two diabetics. After one year, the study found that daily monitoring had no significant effect on hemoglobin A1C levels. [PubMed abstract]


• ADA glucose monitoring recommendations for intensive insulin regimens (daily multi-dose insulin or insulin pump):
• Prior to meals and snacks
• Bedtime
• Occasionally postprandially
• Prior to exercise
• Symptoms of hypoglycemia, after treating hypoglycemia, and until normoglycemic
• Prior to critical tasks such as driving [44]


• Recommendations for other patients will depend on individual patient characteristics. In general, the following is true:
• Daily fasting blood sugars are helpful for adjusting basal insulins
• Patients with symptoms of hypoglycemia (see hypoglycemia below) should check their blood sugar immediately
• Patients at high risk for hypoglycemia may need to check blood sugars more frequently
• Patients on medications associated with hypoglycemia (any insulin, sulfonylureas, meglitinides) may need to check blood sugars more frequently
• Patients should increase testing with medication adjustments or changes
• Patients with high fluctuations in blood sugar levels should check more frequently
• Patients with variable eating habits may need to check more frequently
• Diabetics who are well-controlled on agents that do not cause hypoglycemia (e.g. metformin) do not need to monitor blood sugars frequently

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• CONTINUOUS BLOOD SUGAR MONITORING

• Overview
• New devices are available that can provide a continuous blood sugar measurement
• These devices contain an electrochemical sensor that is placed under the skin (subcutaneous)
• The sensor reads the sugar concentration of the interstitial fluid. The sensor has to be replaced every 3 - 7 days depending on the model.
• Interstitial fluid sugar concentrations correlate well with blood sugar concentrations, but calibration with blood sugar concentrations is required with some devices
• Some models can be connected to insulin pumps to help regulate insulin output
• For some devices, confirmation of readings with a traditional fingerstick glucose is recommended before making treatment decisions. Some newer models are FDA-approved to guide treatment decisions without confirmatory fingersticks. [1,2,44]
• StraightHealthcare analysis:
• Continuous blood sugar monitors are not widely used
• They are most appropriate for highly-motivated type one diabetics
• Further studies are needed to determine if their benefits justify their cost

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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 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 [26]


• HEMOGLOBIN A1C GOALS
• See hemoglobin A1C for a comprehensive review of the A1C test
• In patients without diabetes or prediabetes, the normal range for the A1C is ≤ 5.6%
• The appropriate A1C range for diabetics has been the subject of much debate
• While targeting the normal range would seem intuitive, some studies have shown that lower A1C targets lead to worse outcomes in diabetics


• Clinical trials
• Results from clinical studies targeting different A1C goals have been mixed
• A synopsis of some of the larger clinical trials is presented below


• A1C clinical trials results table

• Professional guidelines:
• 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
• 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 [26]


• StraightHealthcare analysis:
• The available evidence does not definitively define the ideal A1C goal for all patients
• A trend was seen in the trials where the duration of diabetes upon starting intensive therapy seemed to affect the outcomes
• The UKPDS trial had some of the best outcomes for the intensive group, and patients in that trial were newly- diagnosed diabetics upon entering (had diabetes < 1 year)
• The ACCORD trial had some of the worst outcomes in the intensive group, and patients in that trial had a long duration of diabetes upon entering (average 10 years)
• A subgroup analysis of the VADT trial found that intensive therapy did not reduce heart attacks in patients at high-risk for heart disease [1, 4]


• Based on the available evidence, the following A1C goals 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 [1,4]

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• HEMOGLOBIN A1C

• HEMOGLOBIN A1C
• The Hemoglobin A1C test is widely used to diagnose diabetes and to measure the effectiveness of diabetes treatment
• See A1C goals in diabetes for a review of target A1C levels


• PHYSIOLOGY
• Red blood cells are comprised of hemoglobin
• Over time, as hemoglobin is exposed to glucose (blood sugar) in the bloodstream, a chemical bond will form between hemoglobin and glucose (a process called glycosylation)
• The amount of hemoglobin that will form a bond to glucose is proportional to the concentration of glucose in the bloodstream
• The Hemoglobin A1C test gives the percentage of hemoglobin that has formed a bond with glucose
• This percentage can then be translated into an average blood sugar
• Example:
• Hemoglobin A1C = 6%, which means 6% of hemoglobin is bound to glucose (glycosylated)
• For 6% of hemoglobin to be bound to glucose, the average blood sugar will be around 120 mg/dl


• TESTING INTERVAL
• Red blood cells have an average lifespan of 120 days
• The Hemoglobin A1C reflects the average blood sugar over the last 120 days
• Most practitioners consider it a reflection of the last 3 months


• CONVERTING A1C TO AVERAGE BLOOD SUGAR
• The A1C is widely used to monitor the effectiveness of diabetes therapy
• The A1C reflects the average blood sugar for the 3 months prior to the lab being drawn
• See target A1C levels in diabetes for a discussion of A1C goals in diabetes


• A1C values can be converted to average blood sugar with the following formula:


• A1C CONVERSION FORMULA:
• Average blood sugar for last 3 months (mg/dl) = (28.7 X A1C value) - 46.7


• Example: A1C = 6.6%, Average blood sugar = (28.7 X 6.6) - 46.7 = 143 mg/dl


• A1C CONVERSION TABLE

Reference [36]

A1C values (%)	Average blood sugar (mg/dl)
5	97
6	126
7	154
8	183
9	212
10	240
11	269
12	298
13	326
14	355
15	384

• PATIENTS VARIABLES THAT CAN AFFECT A1C VALUES


• RACE
• Studies have found that the A1C values differ among ethnicities independent of other glucose measures (e.g. fasting blood sugar, 2hr glucose test, continuous blood sugar monitoring) [33,34,45]
• For patients with identical average blood sugar values, A1C values tend to run higher in non-whites when compared to whites
• Results from studies have yielded the following results


• When compared to whites with similar fasting and post-meal blood sugar levels:
• African-Americans have A1C values 0.4% higher
• Hispanics have A1C values 0.15% higher
• American Indians have A1C values 0.34% higher
• Asians have A1C values 0.22% higher [34,45]


• These findings suggest that race-specific A1C values may be useful in that non-whites may have higher A1C values than whites despite similar blood sugar control
• An observational study called the ARIC study [PubMed abstract] looked at the risk of of stroke, coronary heart disease, and all-cause mortality based on baseline hemoglobin A1C values in blacks and whites


• ARIC study findings:
• Nondiabetic blacks had an average A1C value that was 0.4% higher than nondiabetic whites
• Higher A1C levels were associated with a greater risk for heart disease, stroke, and death
• Race did not modify the association of the A1C test with a person's risk for heart disease, stroke, or death
• Since higher A1C values were still associated with higher risk of heart disease, stroke, and death after adjusting for race, the authors concluded that race-adjusted A1C values were of no clinical benefit [33]


• Professional Guidelines:
• The ADA does not recommend race-adjusted values for A1C
• StraightHealthcare analysis:
• For patients with identical average blood sugars, A1C values run higher in non-whites when compared to whites
• In the ARIC study, race did not modify the association of the A1C value with significant clinical outcomes
• Based on the available evidence, it would not improve care to use race-adjusted A1C values


• AGE
• A1C values tend to rise with age in patients without diabetes
• An increase of around 0.11% every 10 years after the age of 40 has been seen in studies [32,35]


• ABNORMAL HEMOGLOBIN
• Patients with abnormal hemoglobin may have inaccurate A1C tests
• Some common hemoglobin variants include Hemoglobin S, C, D, or E (Hemoglobin A is normal)
• Abnormal hemoglobin is more common among Africans (Hemoglobin S, D and C) and people of Indian and Southeast Asian heritage (Hemoglobin E)
• In one study, patients with sickle cell trait had hemoglobin A1C values that were 0.30% lower on average when compared to patients without sickle cell trait who had comparable 2-hour glucose tolerance tests. [PubMed abstract]
• Some A1C testing methods are not affected by abnormal hemoglobin
• The National Glycohemoglobin Standardization Program (NGSP) has a website that lists different lab tests and whether they are affected by hemoglobin abnormalities
• StraightHealthcare analysis:
• Not all hemoglobin abnormalities cause symptoms (ex. anemia), so some affected individuals may not be aware they have an abnormality
• If A1C tests do not agree with blood sugar measurements, and a person is from a susceptible population, then hemoglobin studies may be appropriate
• If a hemoglobin abnormality is present, the NGSP website offers information on which tests will not be affected by the abnormality [27]


• ABNORMAL RED BLOOD CELL LIFE SPAN
• Shortened life span (falsely lowered A1C)
• The average life of a red blood cell (RBC) is 120 days
• Conditions that shorten the average RBC life span (e.g. blood loss, hemolytic anemia, splenomegaly, spherocytosis) may falsely lower A1C values because the circulating red blood cells' exposure to glycosylation has been reduced
• Conditions that increase erythropoiesis (e.g. erythropoietin administration) may also shorten the RBC life span leading to falsely lower A1C values
• In these patients, blood sugar values and/or other glycosylated proteins should be used to evaluate diabetes control [1,32,37]
• Prolonged life span (falsely elevated A1C)
• The average life of a red blood cell (RBC) is 120 days
• Conditions that prolong the average RBC life span (e.g. splenectomy) may falsely elevate A1C values because the circulating red blood cells' exposure to glycosylation has been increased
• Conditions that decrease erythropoiesis (e.g. iron deficiency, vitamin B12 deficiency, kidney failure) may also prolong the RBC life span leading to falsely elevated A1C values
• In these patients, blood sugar values and/or other glycosylated proteins should be used to evaluate diabetes control [1,28,29,30,32,37]


• VITAMIN C, VITAMIN E, AND ASPIRIN
• In a handful of small studies, Vitamin E, Vitamin C, and aspirin have been shown to cause spurious A1C values
• In other studies, no effect has been seen
• It is unclear if these supplements or aspirin affect A1C values
• If there is an effect, it is likely small [31,32]

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• EYE EXAM

• DIABETIC EYE DISEASE
• Diabetic eye disease is also called "Diabetic retinopathy"
• Diabetes is the number one cause of blindness
• Glaucoma, cataracts, and other eye disorders are also more common in diabetics [1]


• Professional guidelines:
• The ADA recommends the following for eye exams in diabetics:
• Type 1 Diabetics
• Adults and children > 10 years old should have a dilated eye exam within 5 years of being diagnosed with T1DM
• If there is no evidence of retinopathy for one or more annual eye exams, then exams every 2 years may be considered
• Type 2 Diabetics
• Patients diagnosed with T2DM should have a dilated eye exam shortly after the diagnosis is made
• If there is no evidence of retinopathy for one or more annual eye exams, then exams every 2 years may be considered
• Women with preexisting type 1 or 2 diabetes who become pregnant
• Patients should be counseled on the risk of development and/or progression of diabetic retinopathy
• Eye examinations should occur before pregnancy or in the first trimester
• Monitor every trimester and for 1 year postpartum as indicated by the degree of retinopathy [42]

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• DIABETIC KIDNEY DISEASE

• TERMS AND DEFINITIONS
• Diabetic kidney disease - also called "diabetic nephropathy"
• Proteinuria - protein in the urine, also referred to as "Albuminuria" and "Nephropathy"
• Albumin - main protein that circulates in the blood. Main protein detected in the urine if proteinuria exists. The terms "albumin" and "protein" are often used interchangeably in DKD
• Microalbuminuria - defined as 30 - 300 mg of protein excreted in the urine over a 24 hour period
• Macroalbuminuria - defined as > 300 mg of protein excreted in the urine over a 24 hour period


• PREVALENCE
• Diabetes is the leading cause of chronic kidney disease in developed countries
• 45% of kidney failure cases in the U.S. are secondary to diabetes [5]
• 20 - 40% of patients with diabetes will have some degree of diabetic kidney disease [1]
• The presence of diabetic kidney disease is a marker for an increased risk of heart disease. Diabetics with any degree of diabetic kidney disease have twice the heart disease risk as those without [5]


• MECHANISM
• In the kidneys, a layer of specialized cells form what's called the Glomerular Filtration Barrier (GFB)
• The GFB serves as a membrane between the blood and urine
• The GFB acts as a filter by selectively allowing the passage of water and chemicals from the blood into the urine for elimination from the body
• In diabetes, elevated blood sugar levels damage the GFB
• The damaged GFB allows protein to pass from the blood into the urine
• The urine can be tested for the presence of protein (proteinuria)
• Albumin is the main protein in blood, and also the protein that is typically found in urine
• The term "albuminuria" is often interchanged with "proteinuria" [6]


• SCREENING RECOMMENDATIONS


• The ADA recommends the following screening for DKD:
• Type one diabetics
• Start screening type one diabetics 5 years after the diagnosis of T1DM
• Screen patients annually with urine albumin-to-creatinine ratio test and GFR
• Type two diabetics
• Start screening type two diabetics immediately after the diagnosis of T2DM
• Screen patients annually with urine albumin-to-creatinine ratio test and GFR
• When a test is positive:
• A positive screening test should be repeated up to 2 times (a second positive test establishes the diagnosis) within a 3 - 6 month time period before a diagnosis is made [1]


• SCREENING METHODS


• There are three main methods to check for protein in the urine:
• Spot albumin-to-creatinine ratio
• Preferred method
• Requires only a urine sample
• Is not affected by hydration status of patient (creatinine corrects for this)
• See Spot albumin-to-creatinine ratio for more
• 24 hour urine for protein
• Most exact
• Requires all urine to be collected over a 24 hour period
• Is burdensome to patient and often not done correctly
• Spot urine albumin
• Least exact of the 3 methods
• Unlike albumin-to-creatinine ratio, can be affected by patient's hydration status


• PROGNOSIS


• Microalbuminuria
• Defined as 30 - 300 mg of protein excreted in the urine over a 24 hour period
• Microalbuminuria has been an inconsistent predictor of kidney disease progression [5,21,22]
• Depending on the study, diabetics with microalbuminuria have done the following:
• Worsen to macroalbuminuria: 14 - 38% (9 trials, length of trials ranged from 2 - 18 years)
• Improve back to no significant proteinuria: 17-58% (7 trials, length of trials ranged from 2 - 18 years) [5]
• Macroalbuminuria
• Defined as > 300 mg of protein excreted in the urine over a 24 hour period
• Most patients with macroalbuminuria will progress to advanced kidney disease [1]
• In a study of 1439 type one diabetics that had an average follow-up of 19 years, the following was seen:
• Patients with macroalbuminuria had a 5.7% decrease in kidney function (GFR) per year
• Patients with microalbuminuria had a 1.4% decrease in kidney function (GFR) per year
• Patients with no proteinuria had a 1.2% decrease in kidney function (GFR) per year
• Of the patients who developed a GFR < 60ml/min, 61% had a history of macroalbuminuria, 16% had a history of microalbuminuria, and 24% had no history of proteinuria [22]


• TREATMENT


• MEDICATIONS
• ACE inhibitors
• Angiotensin receptor blockers (ARBs)
• Professional guidelines:
• The ADA makes the following recommendations for treating proteinuria:
• In diabetics with micro- or macroalbuminuria, ACE inhibitors or ARBs should be prescribed
• If one class is not tolerated (ex. ACE cough), then the other class should be tried
• StraightHealthcare analysis:
• ACE inhibitors and ARBs are superior to other classes of blood pressure medications for treating proteinuria. When it comes to hard renal outcomes like end-stage kidney disease, there is no evidence that ACE inhibitors and ARBs are superior to other classes of blood pressure medications. [39,40]
• ACE inhibitors and ARBs should be used first-line to treat proteinuria while keeping in mind that good blood pressure and blood sugar control are paramount
• A question that often arises is whether micro- or macroalbuminuria levels should be used as guides to therapy (example - increasing ACE/ARB doses in an attempt to lower albuminuria levels). Currently, the ADA and the NKF do not recommend this practice as it has not been tested in prospective clinical trials [1,5]


• PROTEIN-RESTRICTED DIET
• High protein intake has been shown to induce "hyperfiltration" in the kidneys as evidenced by an increase in GFR when patients consume high protein diets
• The increase in GFR has raised theoretical concerns that protein may increase intraglomerular pressure and lead to long-term loss of kidney function
• The Recommended Dietary Allowance (RDA) for protein in the general population is 0.8 grams per kilogram (kg) of body weight per day
• Studies have shown that on average, the general population consumes 1.04 grams of protein per kg of body weight per day [5]
• There have been no large, long-term studies that have looked at the effects of protein-restricted diets on diabetic kidney disease. Studies in patients with various etiologies of chronic kidney disease have shown that protein-restricted diets have a marginal to null effect on disease progression. [7,23]
• Professional guidelines:
• The ADA recommends the following in patients with diabetic kidney disease:
• For people with diabetic kidney disease, reducing the amount of dietary protein below the recommended daily allowance of 0.8 g/kg/day (based on ideal body weight) is not recommended because it does not alter glycemic measures, cardiovascular risk measures, or the course of GFR decline.
• If protein intake is high, dietary protein limitation is a consideration particularly in patients whose diabetic kidney disease is progressing despite optimal glucose and blood pressure control and use of an ACE inhibitor or ARB [26]
• StraightHealthcare analysis:
• Although it has not been studied extensively, the effect of a protein-restricted diet on DKD is most likely small and insignificant
• Diabetics should avoid high protein diets (> 1.2 grams/kg/day), but the benefits of following a protein-restricted diet is likely not worth the effort and could potentially be harmful
• Diabetics with kidney disease should focus their efforts on blood sugar control, blood pressure control, weight control, and exercise


• OTHER KIDNEY DISEASE
• Diabetics with kidney disease are typically assumed to have DKD without further workup
• Other causes of kidney disease may occur in diabetics, and practitioners should be on the lookout for atypical signs that may signal another etiology for kidney disease is present
• Possible signs that another etiology for kidney disease is present include:
• Resistant hypertension - renal (kidney) artery disease
• Rapid increase in serum creatinine after ACE inhibitor or ARB - renal artery disease
• Rapidly increasing proteinuria - other glomerular disease
• Urinary sediment - other glomerular disease
• Absence of diabetic eye disease (retinopathy) - retinopathy typically occurs with DKD [5]

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• DIABETIC NEUROPATHY

• OVERVIEW
• Diabetic neuropathy is nerve damage caused by the metabolic abnormalities associated with diabetes
• The exact mechanism by which diabetes damages nerves is unknown, but it is believed to occur through oxidative and inflammatory processes induced by hyperglycemia and dyslipidemia
• In studies, diabetic neuropathy has been seen in up to 20% of type 1 diabetics after 20 years of disease. In type 2 diabetics, studies have found a prevalence as high as 50% after 10 years of disease.


• TYPES OF NEUROPATHY
• The two most common types of neuropathy seen in diabetics are distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathies


• DISTAL SYMMETRIC POLYNEUROPATHY (DSPN)
• Accounts for 75% of diabetic neuropathies
• May be divided into large or small fiber disease
• Neuropathy occurs in a symmetric pattern and progresses in a distal to proximal pattern
• Feet are most commonly affected
• DSPN is a clinical diagnosis

• Reference [43]

Small nerve fibers
Function	Pain sensation (nociception) Hot/cold sensation
Symptoms	Pain, burning, electric shocks, tingling Exaggerated response to painful stimuli (hyperalgesia) Pain from minimal contact (e.g. socks, shoes, bed sheets) (allodynia) Pain is typically worse at night
Exam findings	Loss of thermal discrimination (hot/cold) Loss of pinprick sensation Hyperalgesia

• Reference [43]

Large nerve fibers
Function	Pressure Balance and position sense (proprioception)
Symptoms	Numbness Tingling Poor balance
Exam findings	Loss of ankle reflexes Loss of sense of vibration Loss of proprioception Loss of light touch sensation (10-g monofilament)

• AUTONOMIC NEUROPATHIES
• Autonomic neuropathies affect the sympathetic and parasympathetic nerve systems
• Symptoms will depend on the system that is affected

• Reference [43]

System	Symptoms
Cardiovascular	Resting tachycardia Orthostatic hypotension Abnormal blood pressure regulation Hypoglycemia unawareness
Gastrointestinal	Gastroparesis Esophageal dysfunction (dysphagia, GERD) Diarrhea and constipation Fecal incontinence Hypoglycemia unawareness
Urogenital	Bladder dysfunction (incontinence, frequency, etc.) Erectile dysfunction Female sexual dysfunction
Sudomotor (sweat glands)	Gustatory sweating (face and neck sweating when eating) Dry skin Hypoglycemia unawareness

• TREATMENT


• Overview
• There are no therapies that can reverse diabetic neuropathy so prevention is key
• Blood glucose control is the most important factor in preventing diabetic neuropathy and stopping its progression
• Distal symmetric polyneuropathy may be treated with a handful of medications
• Recommendations from the ADA are presented below


• FDA-approved therapies
• Pregabalin (Lyrica®)
• Dosing (ADA recommended)
• Starting: 25 - 75 mg one to three times a day
• Effective: 300 - 600 mg a day
• Other
• FDA-approved for diabetic peripheral neuropathy
• Preferred first-line agent by ADA
• See pregabalin for more
• Duloxetine (Cymbalta®)
• Dosing (ADA recommended)
• Starting: 20 - 30 mg once daily
• Effective: 60 - 120 mg/day
• May be given in one or two divided doses
• Other
• FDA-approved for diabetic peripheral neuropathy
• Preferred first-line agent by ADA
• See duloxetine for more


• Other therapies (non FDA-approved)
• Gabapentin (Neurontin®)
• Dosing (ADA recommended)
• Starting: 100 - 300 mg one to three times a day
• Target: 900 - 3600 mg/day
• Other
• Efficacy has been mixed in clinical trials
• See gabapentin for more
• Venlafaxine (Effexor®)
• Dosing (ADA recommended)
• Starting: 37.5 mg once daily
• Target: 75 - 225 mg/day
• Other
• Has shown some effectiveness in clinical trials
• See venlafaxine for more
• Amitriptyline (Elavil®)
• Dosing (ADA recommended)
• Starting: 10 - 25 mg once daily
• Target: 25 - 100 mg/day
• Other
• Has shown some effectiveness in small trials
• See amitriptyline for more

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• FOOT CARE

• FOOT CARE
• Neuropathy and poor circulation in diabetics make their feet susceptible to infections
• Diabetes is the number one cause of amputations of the lower extremities
• In one series, the following causes were found to initiate foot ulcers:
• Rubbing from footwear - 21%
• Results of injuries (mostly falls) - 11%
• Bacterial skin infections resulting from fungal infections - 4%
• Self-inflicted trauma (ex. cutting toenails) - 4% [18]


• Professional guidelines:
• The ADA recommends that all diabetics have an annual comprehensive foot exam that includes:
• Assessment of foot pulses
• Testing for sensation that includes 10-g monofilament plus one of:
• Vibration using 128-Hz tuning fork
• Pinprick sensation
• Ankle reflexes
• Vibration perception threshold
• Referral to a foot specialist is recommended in diabetics who have the following risk factors:
• Smoker
• Loss of protective sensation
• Structural abnormalities
• History of foot complications
• Patients with weak pulses or symptoms of intermittent claudication should be referred for an ankle-brachial index (screening test for peripheral vascular disease) [1]
• StraightHealthcare analysis:
• All diabetics should wear comfortable, appropriately fitted shoes (ex. good tennis shoes), at all times
• Diabetics with good blood sugar control and no neuropathy should check their feet periodically for sores, cracks, fungal infections, and calluses
• Diabetics with poor blood sugar control and/or neuropathy should examine their feet daily for sores, cracks, fungal infections, and calluses
• Preventative measures including diabetic shoes, custom orthotics, and frequent physician exams have not been evaluated extensively in well-done trials and are largely unproven [18, 19]
• Significant foot deformities and large calluses should be evaluated by a foot specialist
• The underlying key to preventing neuropathy and foot problems is good blood sugar control

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• BLOOD PRESSURE GOALS

• BLOOD PRESSURE CONTROL IN DIABETES
• The ideal blood pressure (BP) range in diabetics has not been completely determined
• The ACCORD study compared outcomes between diabetics who were treated to a target SBP of < 120 to those treated to a target of < 140


• ACCORD Study - Intensive vs Standard Blood Pressure Control in DM, NEJM (2010) [PubMed abstract]
• The ACCORD study enrolled 4733 type 2 diabetics with an average SBP of 139 mmHg
• Main inclusion criteria: SBP 130 - 180; type 2 diabetes; HgA1C 7.5% - 11%; ≥ 40 years old with cardiovascular disease or ≥ 55 years old with atherosclerosis, albuminuria, left ventricular hypertrophy, or at least two additional risk factors for cardiovascular disease (dyslipidemia, hypertension, smoking, or obesity)
• Main exclusion criteria: BMI ≥ 45; serum creatinine > 1.5 mg/dl; significant liver disease; cardiovascular event within last 3 months
• Baseline characteristics: average age 62 years; previous cardiovascular event - 34%; average BMI - 32; average BP - 139/76; median duration of diabetes - 10 years; average HgA1C - 8.3%; average LDL - 110 mg/dl; average GFR - 92 ml/min
• Patients were randomized to 1 of 2 groups:
• Group 1 (2362 patients) - Target SBP < 120 mmHg (intensive therapy)
• Group 2 (2371 patients) - Target SBP < 140 mmHg (standard therapy)
• Blood pressure medications used were ACE/ARBs, thiazide diuretics, beta blockers, calcium channel blockers, reserpine, and/or alpha blockers
• No specific treatment regimen or drug was required
• PRIMARY OUTCOME: Composite of nonfatal myocardial infarction, nonfatal stroke, or death from cardiovascular causes
• After an average follow-up of 4.7 years, the following was seen:
• Average SBP at 1 year (mmHg): Group 1 - 119.3, Group 2 - 133.5 (diff 14.2, 95%CI [13.7 - 14.7])
• Average DBP at 1 year (mmHg): Group 1 - 64.4, Group 2 - 70.5 (diff 6.1, 95%CI [5.7 - 6.5])
• Primary outcome: Group 1 - 1.87%/year, Group 2 - 2.09%/year (HR 0.88, 95%CI [0.73 - 1.06], p=0.20)
• Overall mortality: Group 1 - 1.28%/year, Group 2 - 1.19%/year (HR 1.07, 95%CI [0.85 - 1.35], p=0.55)
• Stroke: Group 1 - 0.32%/year, Group 2 - 0.53%/year (HR 0.59, 95%CI [0.39 - 0.89], p=0.01)
• Nonfatal myocardial infarction: Group 1 - 1.13%/year, Group 2 - 1.28%/year (HR 0.87, 95%CI [0.68 - 1.10], p=0.25)
• Hypokalemia (< 3.2 mEq/L): Group 1 - 2.1%, Group 2 - 1.1% (p=0.01)
• Estimated GFR < 30 ml/min: Group 1 - 4.2%, Group 2 - 2.2% (p<0.001)
• Macroalbuminuria: Group 1 - 6.6%, Group 2 - 8.7% (p=0.009)
• Average # of BP meds after first year: Group 1 - 3.4, Group 2 - 2.1 [8]


• StraightHealthcare analysis:
• The ACCORD trial found that intensive blood pressure therapy did not improve CVD outcomes in type two diabetics when compared to standard therapy
• Intensive therapy increased the risk of hypokalemia and GFR < 30 ml/min while decreasing the risk of macroalbuminuria
• For years, it was recommended that diabetics be treated to a blood pressure goal of < 130/80
• After the ACCORD study, the recommendation was changed to < 140/90


• Professional guidelines:
• The ADA makes the following recommendations for blood pressure goals in diabetics:
• Systolic blood pressure goal < 140 mmHg
• Diastolic blood pressure goal < 90 mmHg
• A goal of < 130/80 mmHg may be appropriate in patients at high risk for CVD
• Other blood pressure recommendations
• For patients with albuminuria, initiate therapy with an ACE inhibitor or angiotensin receptor blocker (ARB)
• For patients without albuminuria, initiate therapy with an ACE inhibitor, ARB, thiazide diuretic, or dihydropyridine calcium channel blocker
• For patients with BP > 120/80, lifestyle interventions should be tried
• For patients with BP ≥ 140/90, lifestyle interventions and pharmacological therapy should be used
• For patients with BP ≥ 160/100, lifestyle interventions and two-drug pharmacological therapy should be used
• For patients with resistant hypertension, an aldosterone antagonist should be considered [44]

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• LIPID GOALS

• ADA recommendations
• In 2015, the ADA changed its cholesterol treatment recommendations to coincide with the 2013 AHA cholesterol treatment guidelines
• The new guidelines emphasize treatment based on risk factors as opposed to lipid values

• Lipid levels should be monitored annually or as needed
• CVD risk factors defined as: LDL cholesterol ≥ 100 mg/dL; high blood pressure; smoking; overweight and obesity
• Ezetimibe + moderate-intensity statin may be used in patients who cannot tolerate high-intensity statins
• See statin intensity chart
• Reference [26,38]

Age	Risk factors	Recommended statin intensity
< 40 years	None	None
	Any CVD risk factor	Moderate or high
	Documented CVD	High
40 - 75 years	None	Moderate
	Any CVD risk factor	High
	Documented CVD	High
> 75 years	None	Moderate
	Any CVD risk factor	Moderate or High
	Documented CVD	High

• Recommendations based on HDL and triglyceride levels
• Triglycerides ≥ 150 mg/dl and/or HDL cholesterol < 40 mg/dL for men, < 50 mg/dL for women - intensify lifestyle therapy and optimize glycemic control
• Triglycerides ≥ 500 mg/dl - evaluate for secondary causes of hypertriglyceridemia and consider medical therapy to reduce risk of pancreatitis [26]

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• IMMUNIZATIONS

• In addition to standard recommendations, the ADA recommends the following for diabetics:
• A one time Pneumovax (PPSV23) regardless of age. Revaccination is recommended at age 65 years or at least 5 years after the first dose, whichever is later.
• Three-dose hepatitis B series if previously unvaccinated and aged 19 - 59 years. If ≥ 60 years, vaccination may be considered.
• See screening and immunizations recommendations for healthy adults for more

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• EXERCISE FOR DIABETES

• EXERCISE FOR DIABETES
• Exercise is an important part of blood sugar control
• Several large meta-analyses have looked at the effect of exercise on blood sugar control


• JAMA meta-analysis (2011) [PubMed abstract]
• A meta-analysis in the JAMA found the following effect of exercise versus no intervention on A1C levels in diabetics:
• Duration of exercise
• Structured exercise (aerobic and resistance) of > 150 minutes a week was associated with an average A1C reduction of 0.89%
• Structured exercise (aerobic and resistance) of < 150 minutes a week was associated with an average A1C reduction of 0.36%
• Type of exercise
• Structured aerobic training resulted in an average A1C reduction of 0.73% (20 trials)
• Structured resistance training (weightlifting) resulted in an average A1C reduction of 0.57% (4 trials)
• Combination resistance and aerobic training resulted in an average A1C reduction of 0.51% (7 trials) [13]
• Cochrane meta-analysis (2006) [PubMed abstract]
• A Cochrane meta-analysis found the following effect of exercise versus no intervention on A1C levels in diabetics:
• Structured exercise resulted in an average A1C reduction of 0.62% (13 trials) [14]


• Professional guidelines:
• The ADA recommends the following exercise goals for diabetics:
• Adults with diabetes should be advised to perform ≥ 150 minutes of moderate- to vigorous-intensity aerobic activity per week, spread over at least 3 days/week, with no more than 2 consecutive days without activity
• Adults with diabetes should engage in 2 – 3 sessions/week of resistance exercise on nonconsecutive days [44]
• Children and adolescents with type one or two diabetes should engage in ≥ 60 minutes of moderate- or vigorous-intensity aerobic activity, with vigorous muscle-strengthening and bone-strengthening activities at least 3 days/week
• See exercise and insulin for information on managing insulin with exercise
• StraightHealthcare analysis:
• Exercise has an overwhelmingly positive effect on blood sugar control (not to mention its positive effect on other conditions)
• Despite this knowledge, it is generally difficult to get people to exercise
• Individual definitions of exercise also vary greatly (ex. many people consider typical ambulation at work as substantial exercise)
• Capable patients who are serious about controlling their blood sugars should involve themselves in a structured exercise program of significant intensity
• The ADA goals are a good starting point, and should be increased as physical fitness improves

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• LOW BLOOD SUGAR (HYPOGLYCEMIA)

• HYPOGLYCEMIA
• Low blood sugar or "hypoglycemia" is defined as a blood sugar < 70 mg/dl
• Diabetics who use insulin, sulfonylureas, and meglitinides are at the highest risk for hypoglycemia


• RISK FACTORS FOR HYPOGLYCEMIA
• Insulin doses that are excessive, ill-timed, or wrong type
• Medications that affect glucose metabolism
• Missing meals or snacks
• Alcohol ingestion
• Increased exercise - both acutely and delayed (within 24 hours of exercise, particularly at night)
• Increased sensitivity to insulin (weight loss, medication changes)
• Kidney failure - as kidneys fail, insulin clearance decreases leading to elevated insulin levels [15]


• SYMPTOMS OF HYPOGLYCEMIA
• Tremor
• Palpitations
• Sweating
• Hunger
• Headache
• Anxiety
• Confusion


• TREATMENT OF HYPOGLYCEMIA
• Ingestion of 15 - 20 g of glucose (tablet preferred) or glucose-containing food (fruit juice, soft drink, crackers, milk)
• May repeat in 15 - 20 minutes if symptoms are not improved
• In individuals with type 2 diabetes, protein intake may enhance or increase the insulin response to dietary carbohydrates. Therefore, carbohydrate sources high in protein should not be used to treat or prevent hypoglycemia due to the potential concurrent rise in endogenous insulin.


• Response to glucose:
• 10g of glucose will raise blood sugar levels by approximately 40 mg/dl over 30 minutes
• 20g of glucose will raise blood sugar levels by approximately 60 mg/dl over 45 minutes


• Blood sugar should be retested in 60 minutes
• Blood sugar response to glucose is transient (typically < 2 hours) therefore a meal or snack should be consumed to prevent recurrent hypoglycemia [16, 41]


• GLUCAGON
• Glucagon is a natural hormone that the body secretes in response to hypoglycemia
• Glucagon stimulates the liver to release sugar into the bloodstream
• Glucagon can only be given as an injection (intramuscular, subcutaneous, or intravenous)
• Glucagon is available in a kit that has 1 mg of glucagon powder and 1 ml of diluting solution for injection
• When glucagon is given subcutaneously or intramuscularly it causes a rise in blood sugar within 8 - 10 minutes with a peak effect around 30 minutes [17]
• Professional guidelines:
• The ADA states that glucagon should be prescribed to individuals at risk of severe hypoglycemia
• Caregivers and family members should be instructed on how to administer [1]
• StraightHealthcare analysis:
• Type one diabetics and type two diabetics on insulin should carry glucose tablets at all times in case they experience hypoglycemia
• Type one diabetics (or patients with LADA) who have experienced significant hypoglycemic episodes despite insulin adjustments may want to carry glucagon
• Glucagon is not generally useful in most type two diabetics

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• DAILY ASPIRIN IN DIABETES

• Overview
• Daily low-dose aspirin has been shown to prevent heart attacks and strokes. It also increases the risk of gastrointestinal bleeding.
• For the secondary prevention of CVD, aspirin is clearly beneficial. For the primary prevention of CVD, the overall net benefit of aspirin is much less clear.


• Primary prevention
• The ADA makes the following recommendations for aspirin in the primary prevention of CVD:
• Aspirin therapy (75 – 162 mg/day) may be considered as a primary prevention strategy in those with type one or type two diabetes who are at increased cardiovascular risk and not at increased bleeding risk (see ACCP bleeding risk for more)
• Increased cardiovascular risk includes most men and women with diabetes aged ≥ 50 years who have at least one additional major risk factor
• Major risk factors are defined as the following:
• Family history of premature CVD (defined as CVD in a first-degree male relative < 55 years old, or CVD in a first-degree female relative < 65 years old)
• Hypertension
• Dyslipidemia
• Smoking
• Albuminuria


• Secondary prevention
• Diabetics with a history of CVD should receive daily aspirin therapy (75 - 162 mg/day)
• For diabetics with CVD and aspirin allergy, clopidogrel (Plavix®) should be used
• The combination of aspirin + clopidogrel is reasonable for up to a year after a heart attack [1,20,38]


• StraightHealthcare analysis:
• Aspirin is clearly clearly beneficial for the secondary prevention of CVD. It's benefits in primary prevention are much less clear.
• Several professional organizations (e.g. USPSTF) have recently recommended daily low-dose aspirin for the primary prevention of CVD in high-risk patients even though no conclusive benefit has been seen in randomized controlled trials. (see aspirin in CAD prevention, and aspirin in stroke prevention for more)
• An online risk/benefit calculator for using aspirin in primary prevention has been developed by a Spanish university (online aspirin risk/benefit calculator). The calculator has not been validated in any type of controlled trial.

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• BIBLIOGRAPHY

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

• #     PMID
• 1 - 21193625
• 2 - 18779236
• 3 - 19465231
• 4 - 21502652
• 5 - 17276798
• 6 - 18347777
• 7 - 17943769
• 8 - 20228401
• 9 - 20606150
• 10 - 18945920
• 11 - 18502299
• 12 - 15504992
• 13 - 21540423
• 14 - 16855995
• 15 - 1276613
• 16 - 18165339
• 17 - Glucagon PI
• 18 - 15644549
• 19 - 12020336
• 20 - 20508178
• 21 - 10969821
• 22 - 20413518
• 23 - 8114857
• 24 - 22517736
• 25 - 24357209 - ADA 2014 GL
• 26 - ADA 2015 Standards of Medical Care in Diabetes
• 27 - NGSP website
• 28 - 20032277
• 29 - 15345893
• 30 - 10453183
• 31 - 16698007
• 32 - 21617108
• 33 - 20200384
• 34 - 17536077
• 35 - 18628569
• 36 - 18540046
• 37 - 26864415 - Factors affecting A1C
• 38 - 26696680 - ADA 2016 exec summary
• 39 - 26868137 - MA in DKD BMJ
• 40 - 16338452 - MA in DKD Lancet
• 41 - 12766131
• 42 - 28223445 - Diabetic Retinopathy: A Position Statement by the American Diabetes Association, Diabetes Care 2017
• 43 - 27999003 - Diabetic Neuropathy: A Position Statement by the American Diabetes Association, Diabetes Care 2017
• 44 - ADA 2018 Standards of Medical Care in Diabetes
• 45 - 28605777 - Racial Differences in the Relationship of Glucose Concentrations and Hemoglobin A1c Levels, Ann Intern Med (2017)