DIABETES MANAGEMENT

• ACRONYMS AND DEFINITIONS

• A1C - Hemoglobin A1C
• AAN - American Academy of Neurology
• ACP - American College of Physicians
• ADA - American Diabetes Association
• AHA/ACC - American Heart Association / American College of Cardiology
• ARB - Angiotensin receptor blocker
• BP - Blood pressure
• CKD - Chronic kidney disease
• 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
• RCT - Randomized controlled trial
• SBP - Systolic blood pressure
• T1DM - Type one diabetes mellitus
• T2DM - Type two diabetes mellitus

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• DIABETIC EVALUATION

• Reference [48]

ADA recommendations for medical evaluation in diabetics
All diabetics Comprehensive physical exam and medical history - initial and annually Labs - initial and annually Hemoglobin A1C, if results not available in past 3 months Lipid Profile Liver function tests Spot urine albumin-to-creatinine ratio Serum creatinine with calculated GFR Vitamin B12 - when indicated if taking metformin Serum potassium - if taking ACE, ARB, or diuretic Referrals Dilated eye exam - see eye exam recommendations below Family planning for women of reproductive age Registered dietician for dietary counseling Diabetes self-management education Dental exam Mental health professional, if needed [48]
Type 1 diabetics Adults Thyroid Stimulating Hormone (TSH) Celiac disease screening Children Check a TSH at diagnosis and every 1 - 2 years thereafter. Consider testing for antithyroid peroxidase and antithyroglobulin antibodies soon after diagnosis. Screen children with type 1 diabetes for celiac disease by measuring IgA tissue transglutaminase (tTG) antibodies, with documentation of normal total serum IgA levels, soon after the diagnosis of diabetes, or IgG to tTG and deamidated gliadin antibodies if IgA deficient. Repeat screening within 2 years of diabetes diagnosis and then again after 5 years and as indicated (see celiac disease for more).[48]

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• BLOOD SUGAR MONITORING

• Choosing a meter
• A vast array of glucose meters are available today. Some glucometers can make Bluetooth connections to phones and send readings to apps for charting and sharing. Some meters are thumbnail-sized devices that plug into smartphones for easy transport. The FreeStyle Libre measures glucose levels in interstitial fluid through a patch that is worn for 14 days. Bells and whistles are nice, but the most important feature of any meter is its accuracy. The FDA requires that meter manufacturers meet a standard referred to as ISO 15197, which states that 95% of the meter's readings must be within 15% of a reference standard for blood sugar readings > 100 mg/dl and within 15 mg/dl for readings < 100 mg/dl. Despite this requirement, independent aftermarket testing has found that many meters don't meet the standard.
• Results from two studies that looked at the accuracy of a number of meters are presented in the table below. A pdf version of the table is also available.

• PDF version of table

• Factors affecting meter accuracy
• Most glucose meters read blood sugars through an electrochemical reaction. The reaction utilizes one of two enzymes - glucose oxidase or glucose dehydrogenase. The accuracy of each enzyme can be affected by different variables.
• Below are some examples of interfering factors for each type of meter
• Glucose oxidase monitors (e.g. OneTouch Ultra 2, Nova Max, ReliOn Micro/Prime)
• Oxygen saturations - higher oxygen tensions (e.g. arterial blood or oxygen therapy) may result in false-low readings, and low oxygen tensions (e.g. high altitude, hypoxia, or venous blood readings) may lead to false-high readings
• Temperature
• Uric acid
• Galactose
• Xylose
• Acetaminophen
• L-dopa
• Ascorbic acid
• Glucose dehydrogenase monitors (e.g. FreeStyle, Accu-Chek Aviva, Contour Next)
• Icodextrin (used in peritoneal dialysis)
• Temperature

• ADA recommendations
• The ADA gives specific glucose monitoring recommendations for patients on intensive insulin regimens (daily multi-dose insulin) but says the information is insufficient to make recommendations for patients using oral agents and/or basal insulin only
• A study (N=450) published in JAMA Internal Medicine compared daily blood sugar monitoring to no monitoring in non-insulin-treated type two diabetics with A1C levels between 6.5% and 9.5%. After one year, there was no significant difference in A1C levels between the groups. [PMID 28600913]

• ADA 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]

• ADA recommendations for other diabetics
• 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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• BLOOD SUGAR GOALS

• Reference [48]

ADA Blood Sugar Goals for Adults
Blood sugar goals Preprandial (before meal): 80 - 130 mg/dl Peak post-meal blood sugar (within 1 - 2 hours after the start of a meal): < 180 mg/dl Fasting blood sugar (after 8 hours of no calorie consumption): 70 - 100 mg/dl✝ ✝The ADA does not give specific goals for fasting blood sugars, but 70 - 100 mg/dl is typically considered a normal range
A1C goals Less stringent: < 8.0% 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 goal is difficult to achieve despite diabetes self-management education, appropriate glucose monitoring, and effective doses of multiple glucose-lowering agents including insulin. Most diabetics: < 7% More stringent: < 6.5% If this can be achieved without significant hypoglycemia or other adverse effects of treatment (i.e., polypharmacy). 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.

• Reference [48]

ADA Blood Sugar Goals for Youth with Type 1 DM
Blood sugar goals Preprandial (before meal): 90 - 130 mg/dl Bedtime: 90 - 150 mg/dl
A1C goals Least stringent: < 8.0% May be appropriate for patients with a history of severe hypoglycemia, limited life expectancy, or extensive comorbid conditions Less stringent: < 7.5% May be appropriate for patients who cannot articulate symptoms of hypoglycemia; have hypoglycemia unawareness; lack access to analog insulins, advanced insulin delivery technology, and/or continuous glucose monitors; cannot check blood glucose regularly; or have nonglycemic factors that increase A1C (e.g., high glycators). Most youth: < 7.0% More stringent: < 6.5% For selected individual patients if they can be achieved without significant hypoglycemia, negative impacts on well-being, or undue burden of care, or in those who have nonglycemic factors that decrease A1C (e.g., lower erythrocyte life span). Lower targets may also be appropriate during the honeymoon phase.

• Reference [48]

ADA Blood Sugar Goals for Youth with Type 2 DM
Blood sugar goals✝ Preprandial (before meal): 80 - 130 mg/dl Peak post-meal blood sugar (within 1 - 2 hours after the start of a meal): < 180 mg/dl Fasting blood sugar (after 8 hours of no calorie consumption): 70 - 100 mg/dl ✝The ADA does not give specific blood sugar goals for youth patients with T2DM, but they can be assumed to be similar to that of most adults
A1C goals Most youth: < 7% More stringent: < 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 and lesser degrees of b-cell dysfunction and patients treated with lifestyle or metformin only who achieve significant weight improvement.

• ADL - Activities of daily living | LTC - Long-term care
• Reference [48]

ADA Blood Sugar Goals for Elderly
Healthy (few coexisting chronic illnesses, intact cognitive and functional status) A1C goal: < 7.5% Preprandial (before meal): 90 - 130 mg/dl Fasting blood sugar (after 8 hours of no calorie consumption): 90 - 130 mg/dl Bedtime: 90 - 150 mg/dl
Complex / intermediate (multiple coexisting chronic illnesses or 21 instrumental ADL impairments or mild-to-moderate cognitive impairment) A1C goal: < 8.0% Preprandial (before meal): 90 - 150 mg/dl Fasting blood sugar (after 8 hours of no calorie consumption): 90 - 150 mg/dl Bedtime: 100 - 180 mg/dl
Very complex / poor health (LTC or end-stage chronic illnesses or moderate-to-severe cognitive impairment or 21 ADL dependencies) A1C goal: < 8.5% Preprandial (before meal): 100 - 180 mg/dl Fasting blood sugar (after 8 hours of no calorie consumption): 100 - 180 mg/dl Bedtime: 110 - 200 mg/dl

• Clinical trials
• Clinical trials that have compared intensive A1C goals (≤ 7%) to standard goals (7 - 8%) have had mixed results. The table below contains a synopsis of 4 large trials that compared clinical outcomes in type 2 diabetics who were randomized to intensive or standard therapy.

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• HEMOGLOBIN A1C

• Overview
• The hemoglobin A1C test is widely used to diagnose diabetes and measure the effectiveness of therapy (see blood sugar goals)

• Physiology
• Red blood cells contain hemoglobin, a protein that transports oxygen. As RBCs circulate in the bloodstream, the hemoglobin inside them is exposed to glucose. Glucose and hemoglobin form a chemical bond through a process called glycosylation. The amount of hemoglobin that is glycosylated is directly proportional to the concentration of glucose in the bloodstream. The hemoglobin A1C test is the percentage of glycosylated hemoglobin, and it provides an estimate of the average blood sugar over the last 90 days.
• Example:
• Hemoglobin A1C = 6%, which means 6% of hemoglobin is bound to glucose
• For 6% of hemoglobin to be bound to glucose, the average blood sugar has to be around 120 mg/dl

• Testing interval
• Hemoglobin A1C reflects the average blood sugar over the last 90 days. The ADA recommends diabetics with good control have their A1C checked every 6 months, and those with suboptimal control have it checked every 3 months. [48]

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

• Reference [36]

A1C conversion table
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

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• HEMOGLOBIN A1C | Patient variables that 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 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 because non-whites have higher A1C values than whites despite similar blood sugar control. An observational study (N=11,092) examined this issue by comparing the risk of stroke, coronary heart disease, and all-cause mortality across A1C values in blacks and whites.
• The study found the following:
• 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 a 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 [PMID 20200384]


• ADA recommendations
• The ADA does not recommend 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. Abnormal hemoglobin is more common among Africans (Hemoglobin S, D, C) and people of Indian and Southeast Asian descent (Hemoglobin E). In one study, patients with sickle cell trait had average hemoglobin A1C values that were 0.30% lower than patients with normal hemoglobin and comparable 2-hour glucose tolerance tests. [PMID 28170479]
• The National Glycohemoglobin Standardization Program (NGSP) has a website that lists different lab tests and whether they are affected by abnormal hemoglobin

• Abnormal red blood cell lifespan
• Shortened lifespan (lower A1C)
• The average lifespan of an RBC is 120 days. Conditions that increase RBC turnover may lower A1C values because hemoglobin exposure to glucose is reduced. Increased RBC turnover may occur in blood loss, hemolytic anemia, erythropoietin therapy, splenomegaly, spherocytosis, sickle cell disease, pregnancy (second and third trimesters), glucose-6-phosphate dehydrogenase (G6PD) deficiency, and hemodialysis.
• Blood sugar values and/or other glycosylated proteins (e.g. fructosamine) should be used to assess diabetes control in these patients [1,32,37,48]
• Prolonged lifespan (higher A1C)
• Conditions that prolong the average RBC lifespan may elevate A1C values because hemoglobin exposure to glucose is increased. Prolonged RBC lifespan may be seen in splenectomy and conditions that decrease erythropoiesis (e.g. iron deficiency, vitamin B12 deficiency, kidney failure).
• Blood sugar values and/or other glycosylated proteins (e.g. fructosamine) should be used to assess diabetes control in these patients [1,28,29,30,32,37]

• Vitamin C, vitamin E, and aspirin
• Some small studies have found that spurious A1C values can occur in patients who consume vitamin E, vitamin C, or aspirin. Other studies have found no effect. [31,32]

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• EYE EXAM

• Overview
• Diabetic eye disease, also called diabetic retinopathy, is the number one cause of blindness in the U.S. Diabetics are also at greater risk for other eye conditions, including glaucoma and cataracts. [1]


• ADA recommendations for eye exams
• Type 1 Diabetics
• Adults: Adults should have a dilated eye exam within 5 years of being diagnosed with T1DM
• Children: An initial dilated and comprehensive eye examination is recommended once youth have had T1DM for 3 – 5 years, provided they are age ≥ 11 years or puberty has started, whichever is earlier. After the initial examination, repeat dilated and comprehensive eye examination every 2 years. Less frequent examinations, every 4 years, may be acceptable on the advice of an eye care professional and based on risk factor assessment, including a history of glycemic control with A1C < 8%.
• Type 2 Diabetics
• Adults and children: 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, biannual exams 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 [48]

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• DIABETIC KIDNEY DISEASE (DKD)

• Terms and definitions
• Diabetic kidney disease - also called "diabetic nephropathy"
• Proteinuria - protein in the urine, also referred to as "albuminuria" and "nephropathy"
• Albumin - main circulating protein and primary protein detected in the urine. The terms "albumin" and "protein" are often used interchangeably in DKD.
• Microalbuminuria - excretion of 30 to 300 mg of protein in the urine over a 24 hour period
• Macroalbuminuria - excretion of > 300 mg of protein in the urine over a 24 hour period

• Prevalence
• It's estimated that 20 - 40% of patients with diabetes have some degree of kidney disease. DKD is the leading cause of chronic kidney disease in developed countries, and 45% of renal failure patients in the U.S. have diabetes. [1,5]

• Mechanism
• In the glomerulus, a layer of specialized cells forms the glomerular filtration barrier (GFB) that serves as a membrane between the blood and tubular lumen of the nephron. Under normal conditions, the GFB only allows the passage of a small amount of protein into the tubules. In diabetes, elevated blood sugars damage the GFB, and more protein is able to pass into the tubules, leading to proteinuria. [6]

• ADA DKD screening recommendations
• Adults
• At least once a year, assess urinary albumin (e.g., spot urinary albumin-to-creatinine ratio) and estimated GFR in patients with type one diabetes with duration of ≥ 5 years, and in all patients with type two diabetes regardless of treatment. Patients with urinary albumin > 30 mg/g creatinine and/or GFR < 60 ml/min should be monitored twice annually.
• Children with T1DM
• Annual screening for albuminuria with a random (morning sample preferred to avoid effects of exercise) spot urine sample for albumin-to-creatinine ratio should be considered at puberty or at age > 10 years, whichever is earlier, once the child has had diabetes for 5 years
• Children with T2DM
• Urine albumin-to-creatinine ratio should be obtained at the time of diagnosis and annually thereafter. An elevated urine albumin-to-creatinine ratio (> 30 mg/g creatinine) should be confirmed on two of three samples. [48]

• Screening methods
• 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 collection of all urine over a 24-hour period
• Is burdensome 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 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 with an average follow-up of 19 years, the following was seen:
• Patients with macroalbuminuria had a 5.7% decrease in GFR per year
• Patients with microalbuminuria had a 1.4% decrease in GFR per year
• Patients with no proteinuria had a 1.2% decrease in GFR per year
• Of the patients who developed a GFR < 60 ml/min, 61% had a history of macroalbuminuria, 16% had a history of microalbuminuria, and 24% had no history of proteinuria [22]

• ADA treatment recommendations for DKD
• Adults
• Optimize glucose and blood pressure control to reduce the risk or slow the progression of chronic kidney disease
• For patients with T2DM and CKD, consider use of a SGLT2 inhibitor in patients with an eGFR ≥ 30 and particularly in those with > 300 mg/g albuminuria to reduce risk of CKD progression, cardiovascular events, or both. In patients with CKD who are at increased risk for CV events, use of a GLP-1 agonist may reduce risk of progression of albuminuria, cardiovascular events, or both
• In nonpregnant patients with diabetes and hypertension, either an ACE inhibitor or an ARB is recommended for those with modestly elevated urinary albumin-to-creatinine ratio (30 – 299 mg/g creatinine) and is strongly recommended for those with urinary albumin-to-creatinine ratio ≥ 300 mg/g creatinine and/or estimated glomerular filtration rate < 60 mL/min
• Continued monitoring of urinary albumin-to-creatinine ratio in patients with albuminuria treated with an ACE inhibitor or an ARB is reasonable to assess the response to treatment and progression of chronic kidney disease
• Do not discontinue an ACE inhibitor or ARB for minor increases in serum creatinine (< 30%) in the absence of volume depletion
• An ACE inhibitor or an ARB is not recommended for the primary prevention of chronic kidney disease in patients with diabetes who have normal blood pressure, normal urinary albumin-to-creatinine ratio (< 30 mg/g creatinine), and normal estimated GFR [48]
• Children with T1DM
• An ACE inhibitor or an ARB, titrated to normalization of albumin excretion, may be considered when elevated urinary albumin-to-creatinine ratio (> 30 mg/g) is documented (two of three urine samples obtained over a 6-month interval following efforts to improve glycemic control and normalize blood pressure). [48]
• Children with T2DM
• In nonpregnant patients with diabetes and hypertension, either an ACE inhibitor or an ARB is recommended for those with modestly elevated urinary albumin-to-creatinine ratio (30 – 299 mg/g creatinine) and is strongly recommended for those with urinary albumin-to-creatinine ratio > 300 mg/g creatinine and/or estimated GFR < 60 mL/min [48]
• For those with nephropathy, continued monitoring (yearly urinary albumin-to-creatinine ratio, estimated GFR, and serum potassium) may aid in assessing adherence and detecting progression of disease [48]

• Protein and the kidneys
• High protein intake can induce hyperfiltration in the kidneys, increasing GFR. This has raised theoretical concerns that high-protein diets can increase intraglomerular pressure and have a detrimental effect on kidney function.
• The Recommended Dietary Allowance (RDA) for protein is 0.8 grams per kilogram per day. Studies have shown that the average individual consumes 1.04 grams per kg per day.
• No large, long-term studies have evaluated the effects of protein-restricted diets on DKD. Studies in patients with other kidney disease etiologies have found that protein-restricted diets have a marginal to null effect on disease progression. [5,7,23]
• ADA recommendations for dietary protein in DKD
• Adults
• For people with nondialysis-dependent chronic kidney disease, dietary protein intake should be approximately 0.8 g/kg body weight per day (the recommended daily allowance)
• For patients on dialysis, higher levels of dietary protein intake should be considered [48]
• Children with T2DM
• Protein intake should be at the recommended daily allowance of 0.8 g/kg/day [48]
• Summary
• The long-term effects of dietary protein on kidney function are unknown but likely negligible. Diabetics should avoid high-protein diets (> 1.2 grams/kg/day), but the benefits of a protein-restricted diet are likely not worth the effort and may be harmful. Diabetics with kidney disease should focus on blood sugar, blood pressure, and weight control.

• Other kidney disease
• Even though DKD is the most common cause of kidney disease in diabetics, other etiologies should be considered. Signs that another condition may be present include the following:
• Resistant hypertension - renal 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 mechanism responsible for nerve injury is unknown but is believed to occur through oxidative and inflammatory processes induced by hyperglycemia and dyslipidemia.
• In studies, diabetic neuropathy has been observed in up to 20% of type 1 diabetics after 20 years of disease, and 50% of type 2 diabetics after 10 years.
• The two most common types of diabetic neuropathy are distal symmetric polyneuropathy (DSPN) and diabetic autonomic neuropathies

• Distal symmetric polyneuropathy (DSPN)
• DSPN accounts for 75% of diabetic neuropathy cases, and it is divided into large and small fiber diseases (see tables below for features of each). DSPN is typically symmetrical and progresses in a distal to proximal pattern, with the feet being the most common starting point. DSPN is a clinical diagnosis based on common features in at-risk individuals.

• Reference [43]

Features of distal symmetric polyneuropathy (DSPN)
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
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 involve the sympathetic and parasympathetic nervous systems. Symptoms depend on the system affected and are described in the table below.

• 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

• ADA neuropathy screening recommendations
• Screening for distal symmetric polyneuropathy should include a careful history and assessment of either temperature or pinprick sensation (small-fiber function) and vibration sensation using a 128-Hz tuning fork (for large-fiber function)
• All patients should have annual 10-g monofilament testing to identify feet at risk for ulceration and amputation [48]

• ADA neuropathy treatment recommendations
• Diabetic neuropathy is irreversible, so prevention is key
• Blood glucose control is the most important factor in preventing neuropathy and stopping its progression
• Treatment recommendations for DSPN from the ADA are presented in the table below

• 2022 AAN diabetic neuropathy treatment recommendations
• Patients should be counseled that the goal of therapy is to reduce pain and not necessarily to eliminate it
• Clinicians should offer tricyclic antidepressants (TCAs), SNRIs, gabapentinoids, and/or sodium channel blockers to reduce pain (see table below). An intervention to relieve neuropathic pain should be considered a failure for an individual patient when it is either ineffective after 12 weeks at a therapeutic dose or intolerable.
• In patients preferring topical, nontraditional, or nonpharmacologic interventions, providers may offer topicals (capsaicin, glyceryl trinitrate spray, Citrullus colocynthis), nontraditional (ginkgo biloba), and/or nonpharmacologic interventions (CBT, exercise, Tai Chi, mindfulness)
• If a medication fails, the following treatment choice should come from a different drug class
• If a partial response is achieved with one drug, combination therapy with a drug from a different drug class may be considered
• Opioids, including tramadol and tapentadol, should not be used
• Valproic acid should not be given to women of childbearing potential and should only be used in other patients if multiple other medications have failed [51]

• ^✝The AAN recommends treatment for this duration before declaring a medication ineffective
• Reference [51]

Medications for diabetic neuropathy
Drug	Dosing in trials	Time to full effect✝
SNRI
Duloxetine	30 - 120 mg/day	12 weeks
Venlafaxine	150 mg/day	6 weeks
Desvenlafaxine	50 - 400 mg/day	13 weeks
Gabapentinoid
Gabapentin	900 - 3600 mg/day	4 - 8 weeks
Pregabalin	150 - 600 mg/day	5 - 12 weeks
Sodium channel antagonists
Carbamazepine	400 mg/day	5 weeks
Oxcarbazepine	300 - 1800 mg/day	16 weeks
Lamotrigine	25 - 400 mg/day	6 weeks
Lacosamide	200 - 600 mg/day	12 weeks
Valproic acid	20 mg/kg/d	4 - 12 weeks
Tricyclic antidepressants (TCAs)
Amitriptyline	up to 75 mg/day	6 weeks
Nortriptyline	25 - 75 mg/day	6 weeks
Other
Capsaicin cream and patches	Apply as directed	12 weeks
Glyceryl trinitrate spray	0.4 mg/day	12 weeks

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• FOOT CARE

• Foot care
• Diabetic neuropathy and poor circulation increase the risk of foot ulcers and infections, making diabetes the number one cause of lower extremity amputations
• In one study, the following factors were identified as precipitating foot ulcers:
• Rubbing from footwear - 21%
• Results of injuries (mainly falls) - 11%
• Bacterial skin infections resulting from fungal infections - 4%
• Self-inflicted trauma (ex. cutting toenails) - 4% [18]


• ADA recommendations
• 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]
• The use of specialized therapeutic footwear is recommended for high-risk patients with diabetes including those with severe neuropathy, foot deformities, or history of amputation [48]


• Summary
• All diabetics should wear comfortable, well-fitted 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

• Overview
• Optimal blood pressure goals in diabetics have not been defined
• The ACCORD study detailed below compared outcomes between type 2 diabetics treated to a target SBP of less than 120 to those treated to a target of less than 140

• Reference [48]

ADA Blood Pressure Recommendations for Adults with Diabetes
Blood pressure goals Diabetics at lower risk of CVD: < 140/90 mmHg Lower risk defined as 10-year atherosclerotic CVD risk < 15% (AHA risk estimator) Diabetics at higher risk of CVD: < 130/80 mmHg Higher risk defined as existing CVD or 10-year atherosclerotic CVD risk > 15% (AHA risk estimator)
Blood pressure medications If BP is ≥ 160/100 mmHg, a two-drug regimen may be initiated Drugs of choice include ACE inhibitors, ARBs, thiazide-like diuretics, or dihydropyridine calcium channel blockers Do not combine ACE inhibitors, ARBs, and/or direct renin inhibitors ACE or ARB is indicated in patients with urinary albumin-to-creatinine ratio ≥ 30 mg/g Patients with resistant hypertension should be be considered for mineralocorticoid receptor antagonist therapy [48]
Other guidelines See hypertension guidelines for other professional recommendations

• Reference [48]

ADA Blood Pressure Recommendations for Youth with Diabetes
Blood pressure goals < 13 years old: SBP and DBP < 90th percentile for age, sex, and height ≥ 13 years old: SBP < 120 mmHg | DBP < 80 mmHg Elevated BP should be confirmed on 3 separate days
Blood pressure treatment < 13 years old BP > 90th percentile but < 95th percentile: Initial treatment should be diet and exercise for 3 - 6 months. If goal BP is not achieved, medications should be considered. BP ≥ 95th percentile: Treat with diet and weight loss and consider medication. ACE inhibitors and ARBs are preferred, but their potential for teratogenic effects should be considered with females. ≥ 13 years old SBP 120 - 139 mmHg | DBP 80 - 89 mmHg: Initial treatment should be diet and exercise for 3 - 6 months. If goal BP is not achieved, medications should be considered. SBP ≥ 140 mmHg | DBP ≥ 90 mmHg: Treat with diet and weight loss and consider medication. ACE inhibitors and ARBs are preferred, but their potential for teratogenic effects should be considered with females.

• Summary
• The ACCORD trial found that intensive blood pressure therapy in type two diabetics (SBP < 120) did not improve CVD outcomes compared to standard therapy (< 140). Intensive therapy decreased the risk of macroalbuminuria, but it increased the risk of hypokalemia and severe kidney disease (GFR < 30 ml/min).
• After the ACCORD trial, ADA blood pressure guidelines were modified so that individual CVD risk was considered

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• IMMUNIZATIONS

• The ADA recommends that adult diabetics aged 19 to 64 receive the pneumonia vaccine in addition to standard recommended vaccines. See pneumonia vaccine.

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• EXERCISE FOR DIABETES

• Overview
• Exercise can have a very positive effect on diabetes. Two meta-analyses that looked at the impact of exercise on blood sugar control are summarized below.

• STUDY
  Structured exercise vs physical activity advice for HgA1C levels in T2DM, JAMA (2011) [PubMed abstract]
• A meta-analysis in the JAMA compared the effects of structured exercise programs to physical activity advice on HgA1C levels in type 2 diabetics
• 47 randomized controlled trials that encompassed 8538 patients were included in the analysis
• 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]
• Findings: Structured exercise training that consists of aerobic exercise, resistance training, or both combined is associated with A1C reduction in patients with type 2 diabetes. Structured exercise training of more than 150 minutes per week is associated with greater HbA(1c) declines than that of 150 minutes or less per week. Physical activity advice is associated with lower A1C, but only when combined with dietary advice.

• STUDY
  Exercise for Type 2 DM, Cochrane meta-analysis (2006) [PubMed abstract]
• A Cochrane meta-analysis looked at trials that compared exercise to no exercise in type 2 diabetics
• The analysis included 14 randomized controlled trials encompassing 377 patients. Trials ranged from 8 weeks to 12 months in duration.
• The analysis found that structured exercise resulted in an average A1C reduction of 0.62% [14]

• ADA recommendations:
• Adults
• Adults with type 1 or type 2 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. Shorter durations (minimum 75 min/week) of vigorous intensity or interval training may be sufficient for younger and more physically fit individuals
• Adults with type 1 or type 2 diabetes should engage in 2 – 3 sessions/week of resistance exercise on nonconsecutive days
• All adults, and particularly those with type 2 diabetes, should decrease the amount of time spent in daily sedentary behavior. Prolonged sitting should be interrupted every 30 min for blood glucose benefits, particularly in adults with type 2 diabetes.
• Flexibility training and balance training are recommended 2–3 times/week for older adults with diabetes. Yoga and tai chi may be included based on individual preferences to increase flexibility, muscular strength, and balance. [48]
• See exercise and insulin for information on managing insulin with exercise
• Children
• Children and adolescents with type 1 or type 2 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 [48]
• See exercise and insulin for information on managing insulin with exercise

• Summary
• Exercise can have a profound effect on blood sugar control. Despite this, it is often difficult to get people to exercise.
• Capable patients who are serious about controlling their blood sugars should participate in a structured exercise program of significant intensity. The ADA recommendations serve as a good starting point, and activity should be increased as physical fitness improves.

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• EXERCISE AND INSULIN

• See exercise and insulin for a review of adjusting insulin therapy for exercise

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• LOW BLOOD SUGAR (HYPOGLYCEMIA)

• Reference [48]

ADA Classification of Hypoglycemia
Level	Blood sugar (mg/dl)
I	54 - 69
II	< 54
III	A severe event characterized by altered mental and/or physical status requiring assistance

• Risk factors for hypoglycemia
• Use of insulin or insulin secretagogues (e.g., sulfonylureas, meglitinides)
• Insulin doses that are excessive, ill-timed, or wrong type
• Medications that affect glucose metabolism
• Missing meals or snacks
• Alcohol ingestion
• Exercise - see exercise and insulin
• Increased sensitivity to insulin (e.g. weight loss, medication changes)
• Older age
• Cognitive impairment
• Impaired hypoglycemia awareness (e.g. beta blocker use)
• Liver disease
• Kidney disease - as kidneys fail, insulin clearance decreases leading to elevated insulin levels [15,48]

• Symptoms of hypoglycemia
• Tremor
• Palpitations
• Sweating
• Hunger
• Headache
• Anxiety
• Confusion

• Treatment
• Glucose
• Ingestion of 15 - 20 g of glucose (tablet preferred) or glucose-containing food (fruit juice, soft drink, crackers, milk)
• Repeat blood glucose in 15 minutes. If hypoglycemia persists, repeat treatment.
• Once blood sugar returns to normal, patient should consume a meal or snack
• 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. [16,41,48]
• 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


• Glucagon
• Glucagon is a natural hormone secreted in response to hypoglycemia that stimulates the liver to release glucose. In cases of extreme hypoglycemia, glucagon can be given as an injection or nasal powder to raise glucose levels rapidly. Available glucagon products include the following:


• Glucagon injection kits (Glucagon and Glucagen®) - Glucagon kits contain 1 mg of glucagon powder and 1 ml of diluting solution for subcutaneous, intramuscular, or intravenous injection. The kits are available under the names Glucagon (Lilly) and Glucagen® (Novo Nordisk). Dosing is 1 mg in patients weighing > 55 pounds, and 0.5 mg in patients weighing < 55 pounds. Injections are typically administered intramuscularly in the upper arm, thigh, or buttocks. The dose may be repeated in 15 minutes if there is no response.


• Glucagon prefilled syringe and autoinjector (Gvoke®) - Gvoke® comes in a prefilled syringe and autoinjector. It is injected subcutaneously and comes in 2 doses, 0.5 mg and 1 mg. The 1 mg dose is recommended for patients weighing ≥ 99 pounds (45 kg), and the 0.5 mg dose is for patients weighing < 99 pounds (45 kg). The dose may be repeated in 15 minutes if there is no response.


• Glucagon prefilled syringe and autoinjector (Zegalogue®) - Zegalogue® is dasiglucagon, a glucagon analog. It comes in a prefilled syringe and autoinjector. It is injected subcutaneously and comes in a 0.6 mg dose. The recommended dose for adults and children ≥ 6 years old is 0.6 mg injected into the lower abdomen, buttocks, thigh, or outer upper arm. The dose may be repeated in 15 minutes if there is no response.


• Glucagon nasal powder (Baqsimi®) - Baqsimi® comes in a 3 mg intranasal device. The recommended dose for adults and children ≥ 4 years old is 3 mg intranasally. The dose may be repeated in 15 minutes if there is no response.


• Nausea and vomiting are the most common side effects. The intranasal formulation may also cause nasal/facial irritation and headache. [49]
• The effects of intramuscular and intranasal glucagon on blood sugar levels were measured in a trial of type 1 diabetics (N=75) who were given IV insulin to induce hypoglycemia. Results from that trial are detailed in the table below.

• ADA recommendations
• The ADA recommends glucagon be given to patients at increased risk of level II hypoglycemia
• Caregivers and family members should be instructed on how to administer it
• Patients with episodes of level II or III hypoglycemia should have their medications adjusted and/or blood sugar targets raised [1,48]

• Summary
• All diabetics treated with insulin should carry glucose tablets to treat hypoglycemia
• Type one diabetics (or patients with LADA) who have experienced significant hypoglycemic episodes despite insulin adjustments may want to carry glucagon
• Most type two diabetics do not need to carry glucagon

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• ANTIPLATELET THERAPY

• Reference [52]

ADA recommendations for antiplatelet therapy in diabetes
Primary prevention Aspirin therapy (75–162 mg/day) may be considered as a primary prevention strategy in those with diabetes who are at increased cardiovascular risk, after a comprehensive discussion with the patient on the benefits versus the comparable increased risk of bleeding.
Secondary prevention Use aspirin therapy (75 – 162 mg/day) as a secondary prevention strategy in those with diabetes and a history of atherosclerotic cardiovascular disease. For patients with atherosclerotic cardiovascular disease and documented aspirin allergy, clopidogrel (75 mg/day) should be used Dual antiplatelet therapy (with low-dose aspirin and a P2Y12 inhibitor) is reasonable for a year after an acute coronary syndrome and may have benefits beyond this period Long-term treatment with dual antiplatelet therapy should be considered for patients with prior coronary intervention, high ischemic risk, and low bleeding risk to prevent major adverse cardiovascular events Combination therapy with aspirin plus low-dose rivaroxaban should be considered for patients with stable coronary and/or peripheral artery disease and low bleeding risk to prevent major adverse limb and cardiovascular events

• Summary
• Primary prevention of CVD with aspirin is not supported by clinical trials. See primary prevention of CVD for more.
• See antiplatelet therapy in CAD for secondary prevention recommendations

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• 1,5-ANHYDROGLUCITOL (1,5AG)

• 1,5-anhydroglucitol is a monosaccharide derived from food that undergoes minimal metabolism and maintains constant plasma concentrations. In the kidneys, 1,5AG is freely filtered in the glomerulus, and >99% is reabsorbed by sodium-glucose co-transporter 4 (SGLT4) in the proximal tubule. High blood sugar levels cause glucose to spill into the urine, and SGLT4 must absorb glucose in place of 1,5AG. This causes 1,5AG urinary loss, which reduces plasma concentrations.
• 1,5AG plasma concentrations reflect postprandial glucose levels over the preceding 2 weeks, with higher levels indicating better control and vice versa. In practice, 1,5AG levels are rarely ordered. [53]

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• FRUCTOSAMINE

• Like hemoglobin, albumin and other proteins form bonds with glucose and become glycosylated. These glycated proteins are called fructosamines, and albumin is the predominant component, accounting for about 80%. Fructosamine levels are proportional to blood sugar concentrations and can therefore be used to estimate blood sugar control. Albumin is replaced every 20 - 25 days, so fructosamines reflect glucose control over the previous 2 - 3 weeks.
• Fructosamine levels may be useful in patients whose A1C test is invalid due to abnormal hemoglobin or shortened red blood cell lifespan (see abnormal hemoglobin and A1C) [54]

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