DIABETES MANAGEMENT

• ACRONYMS AND DEFINITIONS

• A1C - Hemoglobin A1C
• 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
• 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

---

• 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]

---

• BLOOD SUGAR MONITORING

• Overview
• 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. [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

• 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. Depending on the enzyme, different factors can affect the accuracy of the readings.
• Below are some examples of interfering factors for each type of meter
• Glucose oxidase monitors (e.g. OneTouch UltraLink, Nova Max )
• 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 glucose readings
• Temperature
• Uric acid
• Galactose
• Xylose
• Acetaminophen
• L-dopa
• Ascorbic acid
• Glucose dehydrogenase monitors (e.g. Ascensia Contour, Accu-Chek Aviva)
• Icodextrin (used in peritoneal dialysis)
• Temperature

---

• CONTINUOUS BLOOD SUGAR MONITORING

• 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]

---

• 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
• The effect on clinical outcomes of targeting different A1C goals has been mixed in trials
• The table below contains a synopsis of 4 large trials that compared significant clinical outcomes in type 2 diabetics who were randomized to intensive therapy (A1C goal ≤ 7%) or standard therapy (A1C goal 7 - 8%)

---

• HEMOGLOBIN A1C

• Overview
• The Hemoglobin A1C test is widely used to diagnose diabetes and to measure the effectiveness of diabetes treatment
• See blood sugar 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
• The ADA recommends diabetics with good control have their A1C checked every 6 months, and those with suboptimal control should 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

---

• 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 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]
• ADA recommendations
• The ADA does not recommend race-adjusted values for A1C
• Summary
• For patients with identical average blood sugars, A1C values run higher in non-whites 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
• Summary
• 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 lifespan
• Shortened life span (falsely lowered A1C)
• The average life of a red blood cell (RBC) is 120 days
• Conditions that are associated with increased RBC turnover include blood loss, hemolytic anemia, erythropoietin therapy, splenomegaly, spherocytosis, sickle cell disease, pregnancy (second and third trimesters), glucose-6-phosphate dehydrogenase (G6PD) deficiency, and hemodialysis. These conditions may falsely lower A1C values because the circulating red blood cells' exposure to glycosylation has been reduced.
• In these patients, blood sugar values and/or other glycosylated proteins should be used to evaluate diabetes control [1,32,37,48]
• 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]

---

• EYE EXAM

• Overview
• 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]


• 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, 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 [48]

---

• 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 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]

• 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 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]

• 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 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]
• 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
• 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]

---

• 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.
• 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]

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 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

• ADA neuropathy screening recommendations
• Assessment 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
• 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

---

• 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]


• 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, 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

---

• BLOOD PRESSURE GOALS

• Overview
• The ideal blood pressure (BP) range in diabetics has not been completely determined
• The ACCORD study detailed below compared outcomes between diabetics who were treated to a target SBP of < 120 to those who were treated to a target of < 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 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 had been recommended that all diabetics be treated to a blood pressure goal of < 130/80. After the ACCORD trial, the recommendation was changed so that it incorporated individual CVD risk.

---

• IMMUNIZATIONS

• In addition to standard recommendations, the ADA recommends the following for diabetics:
• Yearly influenza vaccine
• 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.
• Two- or three-dose hepatitis B series if previously unvaccinated and aged 18 - 59 years. If ≥ 60 years, consider three-dose hepatitis B series.
• See screening and immunizations recommendations for healthy adults for more

---

• EXERCISE FOR DIABETES

• Overview
• Exercise is an important part of blood sugar control
• Two meta-analyses that looked at the effect 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 HbA(1c) 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 HbA(1c), 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 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 to be 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

---

• EXERCISE AND INSULIN

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

---

• 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 that the body secretes in response to hypoglycemia. Glucagon stimulates the liver to release glucose into the bloodstream. In cases of extreme hypoglycemia, glucagon can be given as an injection or nasal powder to raise glucose levels rapidly. Available glucagon products are described below.


• 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 of glucagon. The intranasal formulation may also cause nasal/facial irritation and headache. [49]
• The effects of intramuscular and intranasal glucagon on blood sugars were measured in a trial involving adults (N=75) with type 1 diabetes 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
• 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

---

• DAILY ASPIRIN IN DIABETES

• Reference [48]

ADA recommendations for daily aspirin 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 discussion with the patient on the benefits versus 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

• Straighthealthcare analysis
• Aspirin for the primary prevention of CVD is not supported by clinical trials. See primary prevention of CVD for more.
• See antiplatelet therapy in CAD for more on dual antiplatelet therapy

---

• BIBLIOGRAPHY

• 1 - PMID 21193625
• 2 - PMID 18779236
• 3 - PMID 19465231
• 4 - PMID 21502652
• 5 - PMID 17276798
• 6 - PMID 18347777
• 7 - PMID 17943769
• 8 - PMID 20228401
• 9 - PMID 20606150
• 10 - PMID 18945920
• 11 - PMID 18502299
• 12 - PMID 15504992
• 13 - PMID 21540423
• 14 - PMID 16855995
• 15 - PMID 1276613
• 16 - PMID 18165339
• 17 - Glucagon PI
• 18 - PMID 15644549
• 19 - PMID 12020336
• 20 - PMID 20508178
• 21 - PMID 10969821
• 22 - PMID 20413518
• 23 - PMID 8114857
• 24 - PMID 22517736
• 25 - PMID 24357209 - ADA 2014 GL
• 26 - ADA 2015 Standards of Medical Care in Diabetes
• 27 - NGSP website
• 28 - PMID 20032277
• 29 - PMID 15345893
• 30 - PMID 10453183
• 31 - PMID 16698007
• 32 - PMID 21617108
• 33 - PMID 20200384
• 34 - PMID 17536077
• 35 - PMID 18628569
• 36 - PMID 18540046
• 37 - PMID 26864415 - Factors affecting A1C
• 38 - PMID 26696680 - ADA 2016 exec summary
• 39 - PMID 26868137 - MA in DKD BMJ
• 40 - PMID 16338452 - MA in DKD Lancet
• 41 - PMID 12766131
• 42 - PMID 28223445 - Diabetic Retinopathy: A Position Statement by the American Diabetes Association, Diabetes Care 2017
• 43 - PMID 27999003 - Diabetic Neuropathy: A Position Statement by the American Diabetes Association, Diabetes Care 2017
• 44 - ADA 2018 Standards of Medical Care in Diabetes
• 45 - PMID 28605777 - Racial Differences in the Relationship of Glucose Concentrations and Hemoglobin A1c Levels, Ann Intern Med (2017)
• 46 - PMID 29222370 - ADA Standards of Medical Care in Diabetes (2018)
• 47 - PMID 29507945 - Hemoglobin A1c Targets for Glycemic Control With Pharmacologic Therapy for Nonpregnant Adults With Type 2 Diabetes Mellitus: A Guidance Statement Update From the American College of Physicians., Ann Intern Med (2018)
• 48 - ADA Standards of Medical Care in Diabetes (2020)
• 49 - PMID 26681725 - Intranasal Glucagon for Treatment of Insulin-Induced Hypoglycemia in Adults With Type 1 Diabetes: A Randomized Crossover Noninferiority Study, Diabetes Care (2016)
• 50 - PMID 26884472 - Glucagon Nasal Powder: A Promising Alternative to Intramuscular Glucagon in Youth With Type 1 Diabetes., Diabetes Care (2016)