Diabetes%20mellitus Diagnosis

• Diabetes mellitus (DM) is diagnosed without further testing in patients presenting with unequivocal hyperglycemia with acute metabolic decompensation (eg diabetic ketoacidosis [DKA], hyperosmolar non-ketotic hyperglycemic coma)
• Same tests are used for screening and diagnosis
• Diagnosis of diabetes mellitus is based either on fasting plasma glucose (FPG), 2-hour value in the 75-g oral glucose tolerance test (OGTT) or HbA1c
  • A single abnormal value is diagnostic for a symptomatic individual 
  • HbA1c levels may vary with patient’s ethnicity, presence of anemia or hemoglobinopathy
  • Diagnosis of diabetes mellitus should be based solely on plasma blood glucose criteria in patients with abnormal red cell turnover (eg pregnancy, recent blood loss or transfusion, sickle cell disease, hemodialysis)
  • Patients with established cardiovascular disease should be screened using FPG and/or HbA1c; an OGTT may be done if FPG and HbA1c are inconclusive

• Diabetes mellitus is diagnosed if any of the following is present:
  • HbA1c level ≥6.5% (48 mmol/mol)          
    • Test should be performed in a lab using a national glycohemoglobin standardization program (NGSP) certified method and standardized to Diabetes Control and Complications Trial (DCCT) assay
    • Recommendations for HbA1c level may vary between countries. Please refer to available guidelines from local health authorities
  • FPG ≥7 mmol/L (≥126 mg/dL)
    • Fasting is considered as no caloric intake for at least 8 hours
  • 2-hour plasma glucose ≥11.1 mmol/L (≥200 mg/dL) during OGTT
    • Performed using a glucose load that contains the equivalent of 75-g anhydrous glucose dissolved in water
  • Random plasma glucose ≥11.1 mmol/L (≥200 mg/dL) in a patient presenting with hyperglycemic crisis or classic symptoms of hyperglycemia

• If typical hyperglycemic symptoms are not present, diagnosis requires 2 abnormal test results from the same sample or in 2 separate test samples
  • If 2 different tests are available and are both above the diagnostic thresholds, the diagnosis of diabetes is made
  • If 2 different test results are discordant, the test whose result is above the cut-off point should be repeated and the diagnosis is made based on the result of the confirmatory test

• Pre-diabetes is considered in patients with:
  • Impaired Fasting Glucose (IFG): FPG 5.6-6.9 mmol/L (100-125 mg/dL)
  • Impaired Glucose Tolerance (IGT): 2-hour plasma glucose 7.8-11 mmol/L (140-199 mg/dL) in the 75-g OGTT
  • HbA1c 5.7-6.4% (39-47 mmol/mol)
    • HbA1c 6-6.5% have a 25-50% 5-year risk of developing diabetes mellitus
    • Baseline HbA1c is a stronger predictor of subsequent diabetes mellitus and cardiovascular events

Screening Asymptomatic Adult Patients for Diabetes Mellitus

• Screening for diabetes mellitus is recommended to all adults who are overweight (body mass index [BMI] ≥23 kg/m² for Asians) or with waist circumference of ≥80 cm for Asian women and  ≥90 cm for Asian men plus the following other risk factors:
  • Physical inactivity
  • Diabetes mellitus in 1st-degree relative
  • Female diagnosed with gestational diabetes mellitus (GDM) or who gave birth to a baby weighing >9 lb (>4 kg)
  • Females diagnosed with polycystic ovarian syndrome (PCOS)
  • With severe obesity, acanthosis nigricans or other conditions associated with insulin resistance
  • With hemoglobin A1c (HbA1c) ≥5.7%, impaired glucose tolerance (IGT), impaired fasting glucose (IFG) on previous testing
  • With high-density lipoprotein cholesterol (HDL-C) level of 0.9 mmol/L (<35 mg/dL) and/or triglyceride (TG) level of 2.82 mmol/L (>250 mg/dL)
  • Diagnosed with hypertension (≥140/90 mmHg or on antihypertensive drugs)
  • With history of cardiovascular disease (CVD)
  • Race/ethnicity that are in high risk (eg Chinese, Indians, Asian Americans, African Americans, Latino, Pacific Islander)
  • With schizophrenia and/or severe bipolar disease on antipsychotic therapy
  • Those receiving antiretroviral therapy or long-term systemic steroid therapy
  • Those born from mothers with GDM

• According to the American Diabetes Association (ADA) 2023 recommendations, screening for diabetes mellitus in all patients should begin at age 35 years*      
• HbA1c, FPG, or 2-hour 75-g OGTT may be used to diagnose diabetes mellitus or to identify future risk for diabetes mellitus
• Testing should be repeated every 3 years if results are normal; more frequent depending on initial result and risk status
  • Annual screening should be done in patients with pre-diabetes

*Recommendations may vary between countries. Please refer to available guidelines from local health authorities 

• Comprehensive medical evaluation should be performed to classify diabetes mellitus, identify presence of complications, review previous treatment and blood glucose control, and offer a basis for care plan

Important Components of Medical History

• Age and symptoms of diabetes mellitus at onset
• Lifestyle of patient (eg eating habits, physical activities, nutritional status and weight history)
• History of weight loss
• History of diabetes mellitus education
• History of recurrent hypoglycemia
• Treatment regimen currently and previously used, and corresponding response (based on HbA1c records)
  • Includes patient’s glucose monitoring result
• Frequency, severity or cause of diabetic ketoacidosis
• Incidence, cause and severity of hypoglycemia, and patient’s awareness
• History of diabetes mellitus-related complications including retinopathy, nephropathy, coronary heart disease (CHD), cerebrovascular disease, peripheral arterial disease 
• Current or history of skin, foot, dental and genitourinary (GU) infections
• History of drug or alcohol use
• Occupational history

Complete Physical Examination

• Height, weight, BMI and waist measurement
• Blood pressure (BP) including orthostatic measurement if appropriate
• Thyroid palpation/status
• Skin examination to check for acanthosis nigricans and insulin injection sites
• Neurological examination
• Cardiovascular system, chest and abdominal examinations
• Fundoscopic examination
• Complete foot examination
  •  Please see Screening and Management of DM Complications/Comorbidities discussion for further information

Laboratory Tests at First Visit

• Fasting plasma glucose, 2-hour postprandial or random plasma glucose
• HbA1c, if not yet done within the past 2-3 months
• If not done within the past year, include:
  • Fasting lipid profile (ie total cholesterol, HDL-C, LDL-C and triglycerides)
  • Liver function tests (LFTs)
  • Urine albumin excretion with spot urine albumin-to-creatinine ratio
  • Renal function tests (Na, K, urea, creatinine) with estimated glomerular filtration rate (eGFR)
  • Urinalysis: Ketones, glucose, protein, sediments
  • Electrocardiogram (ECG)
  • Thyroid stimulating hormone (TSH) in type 1 diabetes mellitus, patients with dyslipidemia, or women >50 years old

Referrals should be done for:

• Annual dilated fundoscopic examination
• Family planning in women of reproductive age
• Medical nutrition therapy (MNT)
• Diabetes self-management education (DSME)
• Dental examination
• Mental health assessment, if necessary
  • Screening for depression, diabetes mellitus-related distress, anxiety, eating disorder, and cognitive impairment should be considered in patients with poor self-management

Type 1 Diabetes Mellitus

• Caused by β-cell destruction which leads to complete insulin secretion deficiency
• May be immune-mediated or idiopathic
• Immune-mediated type 1 diabetes mellitus occurs more commonly in childhood or adolescence but may occur at any age
• Persistence of autoimmune markers like islet cell antibodies (ICA) or other islet autoantibodies (eg antibodiesto glutamic acid decarboxylase [GAD] 65, insulin, anti-tyrosine phosphatase-related islet antigen 2 [anti-IA-2] and IA-2 beta, and zinc transporter ZnT8) in serum may be helpful in establishing diagnosis of type 1 DM

Type 2 Diabetes Mellitus

• Most common form of diabetes
• Secondary to progressive loss of β-cell insulin secretion concomitant with insulin resistance
  • Insulin secretory defects are related to inflammation, metabolic stress and genetic factors
• Usually present in patients >30 years old who are overweight or obese and/or have a positive family history
• Does not have autoantibodies

Other Specific Types

• Uncommon causes of diabetes mellitus wherein underlying problem or disease process is identified
• Examples include genetic defects in β-cell function and insulin action, diseases of the exocrine pancreas, or secondary to drug or chemical use

Gestational Diabetes Mellitus (GDM)

• Diabetes diagnosed during pregnancy (2nd and 3rd trimester) that was not present prior to gestation
• Please see Gestational Diabetes Mellitus disease management chart for further information
  

• Complications are closely linked to control of blood glucose, BP and lipid of the patient
• Improvement of blood glucose control will decrease the risk and progression of these complications

Atherosclerotic Cardiovascular Diseases (ASCVD)

• Main cause of morbidity and mortality in diabetic patients
• Routine screening for coronary artery diseases (CAD) among asymptomatic patients is not recommended since it does not improve outcomes as long as atherosclerotic cardiovascular diseases risk factors are treated
• Hypertension and dyslipidemia are usual conditions that coexist with type 2 diabetes mellitus, which are risk factors for atherosclerotic cardiovascular diseases
• Cardiovascular disease risk factors should be assessed at least yearly in all patients with diabetes
• Cardiovascular disease risk categories in patients with diabetes according to the 2021 European Society of Cardiology (ESC) guidelines on cardiovascular disease prevention:  
  • Very high risk: Individuals with type 2 diabetes mellitus with established ASCVD and/or severe target organ damage 
  • High risk: Individuals with type 2 diabetes mellitus and/or severe target organ damage with moderate risk criteria not met 
  • Moderate risk: Individuals with <10 years of well-controlled type 2 diabetes mellitus without target organ damage or other ASCVD risk factors 
  • Patients >40 years old with type 1 diabetes mellitus may also be classified according to these criteria 

• Aspirin at low dose (75-162 mg/day) may be used for primary prevention in diabetic patients at high risk for atherosclerotic cardiovascular diseases (ie men and women ≥50 years old who have either family history of premature atherosclerotic cardiovascular diseases, hypertension, smoking, dyslipidemia or albuminuria) and are not at increased risk for bleeding
  • Aspirin has been shown to be effective when given as part of secondary prevention strategy in patients with diabetes and previous stroke or myocardial infarction
  • Concomitant use of proton pump inhibitor is recommended in patients on Aspirin monotherapy, dual antiplatelet therapy, or anticoagulant therapy and at high risk of gastrointestinal bleeding

• Clopidogrel (75 mg/day) is recommended as an add-on therapy to Aspirin in the 1st year after acute coronary syndrome or as an alternative to Aspirin-allergic patients
• Combination therapy with Aspirin and low-dose Rivaroxaban may be used to prevent major adverse cardiovascular and limb events in patients with stable coronary and/or peripheral artery disease
• All patients should be advised to stop smoking
  • Studies have shown that patients with diabetes who smoke have a higher risk for atherosclerotic cardiovascular diseases, premature death and microvascular complications of diabetes mellitus
    

Hypertension

• BP should be measured routinely at every visit; home BP self-monitoring should be considered in patients with diabetes mellitus and 24-hour ambulatory BP monitoring should be considered for BP assessment and adjustment of antihypertensive treatment
• Common comorbidity of diabetes mellitus and a major risk factor for both atherosclerotic cardiovascular diseases and microvascular complications
• Usually secondary to nephropathy in diabetes mellitus type 1 and frequently coexists with other cardiometabolic risk factors in diabetes mellitus type 2
• Measure BP at every routine check up
  • Systolic blood pressure (SBP) of ≥130 mmHg or diastolic blood pressure (DBP) of ≥80 mmHg or both, obtained on at least 2 separate days confirms the diagnosis of hypertension
  • Hypertension could be diagnosed in patients with cardiovascular disease and BP ≥180/110 mmHg at a single visit
  • In 2023 ADA guideline, 2018 American Association of Clinical Endocrinology (AACE) and the 2017 ACC/AHA hypertension guideline, it is recommended for patients with diabetes mellitus and hypertension to have an on-treatment target blood pressure of <130/80 mmHg
  • ESC 2021 cardiovascular disease prevention guidelines recommend individualized BP targets in patients with diabetes mellitus: SBP to 130 mmHg, and <130 mmHg but not <120 mmHg if well tolerated, but in patients ≥70 years, target SBP to 130-139 mmHg
    • Target DBP to <80 mmHg but not <70 mmHg

• Individuals with diabetes mellitus with BP ≥140/90 mmHg at diagnosis or follow-up should be advised on lifestyle modification and be given pharmacological agents immediately
• Multiple drugs are usually needed to reach target BP
  • Combination therapy with ACE inhibitors or angiotensin II receptor blockers (ARBs) plus calcium channel blockers or thiazide diuretics are the preferred initial treatment for patients with diabetes mellitus and hypertension
  • Thiazide diuretic should be added to the regimen of individuals with diabetes mellitus with uncontrolled hypertension and eGFR of ≥30 mL/min/1.73 m²
  • Loop diuretic should be added to the regimen of individuals with diabetes mellitus with uncontrolled hypertension and eGFR of <30 mL/min/1.73 m²
  • Addition of a mineralocorticoid receptor antagonist is considered in patients with diabetes and resistant hypertension 
  • For patients with diabetes and established coronary artery disease or albuminuria, ACE inhibitors or ARBs should be part of the regimen
  • Kidney function and serum potassium (K) levels should be monitored if ACE inhibitors, angiotensin II receptor blockers or diuretics are given
  • Consider other forms of hypertension in patients with unmanageable BP even with optimal doses of at least 3 antihypertensive agents, wherein one of which is a diuretic
• Please see Hypertension disease management chart for further information

Dyslipidemia

• Lipid profile, whether fasting or not, should be measured at least yearly in patients with diabetes to identify patients with dyslipidemia and to monitor treatment response
• Low HDL-C with high triglycerides (TG) is the most common pattern of dyslipidemia in patients with type 2 diabetes mellitus
• Lifestyle modification should be advised to all diabetic patients with dyslipidemia
  • Avoid trans fat, decrease saturated fat and cholesterol intake
  • Increase omega-3 fatty acids, viscous fiber (eg oats, legumes, citrus) and plant stanols/sterols in diet
  • Reduce weight, if overweight
  • Increase physical activity

• Pharmacological therapy should be added to lifestyle modification therapy in diabetic patients with cardiovascular disease, patients >40 years old with ≥1 cardiovascular disease risk factors, or in patients with LDL-C that remains >2.6 mmol/L (>100 mg/dL) even with lifestyle modification
  • Statins are the drug of choice in lowering LDL-C level and cardioprotection
  • Recommended to initiate statin therapy, in addition to lifestyle modification, for patients with diabetes mellitus aged 20-39 years with atherosclerotic cardiovascular disease

• Target LDL-C for patients with diabetes based on 2018 AACE and 2019 ESC guidelines
  • Young adults (type 1 diabetes mellitus ≤35 years; type 2 diabetes mellitus ≤50 years) with diabetes mellitus duration <10 years, without other risk factors: <3.0 mmol/L (<116 mg/dL)
  • Patients with diabetes mellitus without target organ damage with diabetes mellitus duration ≥10 years or with additional risk factor: <2.6 mmol/L (<100 mg/dL)
  • Patients with diabetes mellitus with target organ damage, with at least 3 major risk factors or early onset of type 1 diabetes mellitus (duration >20 years): <1.8 mmol/L (<70 mg/dL) or ≥50% reduction from the baseline
  • Drug-treated patients that did not reach the above targets on maximum tolerated statin therapy: Decrease of 30-40% from baseline

• Desirable levels of TG is <1.7 mmol/L (<150 mg/dL) and HDL-C are 1 mmol/L (>40 mg/dL) in men and 1.3 mmol/L (>50 mg/dL) in women
• Apolipoprotein B (secondary treatment goals) target in patients with high risk for cardiovascular disease is <90 mg/dL based on 2020 AACE guidelines
  
• Severe hypertriglyceridemia may necessitate urgent treatment with lifestyle therapy and drugs such as fibric acid derivative, Niacin or fish oil in order to decrease risk of acute pancreatitis
  • Icosapent ethyl, when added to statin in patients with ASCVD or elevated TG and high cardiovascular disease risk, has been shown to decrease cardiovascular disease risk
• In patients with HDL-C <1.03 mmol/L (<40 mg/dL) and LDL-C 2.6-3.3 mmol/L (100-129 mg/dL), Fenofibrate, Gemfibrozil or Niacin may be given
  • Niacin is the drug of choice in raising HDL-C, but high doses can increase blood glucose
• Fibrates, as an alternative to statins, are not recommended for primary prevention in diabetic patients without evidence of atherosclerotic cardiovascular disease

• Statins combined with other lipid-lowering agents may be given to patients whose targets are not achieved with maximum tolerated dose of statins based on 2020 AACE guidelines
  • Further decrease in LDL-C may be achieved through addition of Niacin, Fenofibrate, Ezetimibe, omega-3 fatty acids, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor or bile acid sequestrants to statin therapy
  • Combination of statin and Ezetimibe is recommended in patients with diabetes mellitus and a recent acute coronary syndrome, when statin monotherapy is not sufficient to reduce LDL-C levels to <1.4 mmol/L (<55 mg/dL)
  • PCSK9 inhibitor is recommended in patients with very high cardiovascular risk and with persistently elevated LDL-C despite maximal tolerated statin therapy plus Ezetimibe, or in patients with statin intolerance
  • Statin plus Fibrate or Niacin may be effective in treating all 3 lipid fractions but may increase the risk of abnormal transaminase level, myositis or rhabdomyolysis
    • Combination statin plus Fibrate or Niacin therapy should only be used if benefits outweigh the risks with careful toxicity monitoring
• Please see Dyslipidemia disease management chart for further information

Diabetic Foot

• Annual comprehensive foot examination should be done in all diabetic patients to identify risk conditions suggestive of ulcers and amputations
  • But for patients with insensate feet, foot deformities, or a history of foot ulcers, feet examination should be done at every visit
  • Vascular, dermatologic (eg assessment of skin appearance), neurologic, musculoskeletal, and footwear (ie type of shoe, fit, patterns of wear) examination should be done
  • Should include foot inspection of the skin, evaluation of foot pulses and testing of loss of protective sensation (LOPS) which utilizes 10-g monofilament plus either a test for vibration using 128-Hz tuning fork, pinprick sensation, vibration perception threshold, temperature or assessment of ankle reflex
    • LOPS is considered if ≥1 test is abnormal but ruled out if at least 2 tests are normal and no abnormal test
  • Ankle-brachial index (ABI) should be obtained in patients >50 years old or younger patients but with risk factors for peripheral arterial disease (eg smokers, hypertensive, with dyslipidemia, or diabetes mellitus for >10 years), or patients with claudication symptoms or pedal pulses that are decreased or absent
    • Patients with positive ankle-brachial index should be referred to a specialist for further assessment and management

• Foot ulceration and amputation are frequent causes of morbidity and disability in patients with diabetes, which are often a result of diabetic neuropathy and/or peripheral arterial disease
  • Usually secondary to loss of protective sensation, motor dysfunction, and decreased sweat production that causes dry and chapped skin due to autonomic involvement
  • Incidence of lower extremity ulcers in patients with diabetes is 4-10% and lifetime risk is 25%
  • Foot ulceration is the precursor to 85% of lower extremity amputations in diabetic patients
  • Patients who smoke cigarettes, with history of amputation or foot ulcer, with peripheral neuropathy, foot deformity, peripheral vascular disease (PVD), visual impairment, diabetic nephropathy or uncontrolled blood glucose level are at high risk for foot ulcers or amputations

• Foot infections are common in patients with diabetes mellitus and are often more severe than in patients with no diabetes mellitus
• Peripheral arterial disease is an important risk factor for amputation which occurs 4-7 times more in diabetic patients than in general population
  • Identified through history of claudication and assessment of pedal pulses
  • Early diagnosis, control of risk factors, medical management, and timely revascularization may help prevent amputation

• Imaging studies may help establish or confirm the diagnosis and direct the management for patient
  • Plain radiographs should be the 1st imaging study in diabetic patients with signs and symptoms of diabetic foot disorder
  • Magnetic resonance imaging is usually used in evaluating soft tissue and bone pathology, and aids in the diagnosis of osteomyelitis, deep abscesses, septic joint, and tendon rupture

• Patients should be advised on proper daily foot monitoring and care, and selection of appropriate footwear
  • General footwear recommendations include a broad and square toe box, laces with 3 or 4 eyes per side, padded tongue, quality lightweight materials and sufficient size to accommodate a cushioned sole
  • Well-fitted walking shoes or athletics shoes are recommended in patients with neuropathy or evidence of increased plantar pressures as they cushion the feet and redistribute the pressure
  • Custom-molded shoes are recommended in patients with bony deformities like Charcot foot while those with bony deformity like hammertoes and bunions, extrawide or deep shoes are recommended
  • Custom therapeutic footwear may aid in preventing future foot ulcers in high-risk patients

• Management of comorbidities, evaluation of vascular status and treatment, assessment of lifestyle factors, assessment of ulcer, management of tissues, and relief of pressure are important in treating diabetic foot ulcers
  • Management of tissues involves debridement, maintaining moisture through wound dressings, identification (through curettage or biopsy) and treatment of infection, and wound care through use of advanced modalities (eg therapeutic growth factors, bioengineered tissues, stem cell therapy)
    • Debridement is an important component of chronic wounds since it removes necrotic tissue and callus, reduces pressure, helps in evaluating wound bed, lowers bacterial burden, facilitates drainage and stimulates healing
    • Advanced modalities act through cellular and molecular-based mechanisms that actively promote wound angiogenesis to hasten the process of healing
    •  Recombinant platelet-derived growth factor has been used to stimulate the formation of granulation tissue and promote wound healing
    •  Recombinant epidermal growth factors are also available and have been shown to stimulate proliferation of fibroblasts, keratinocytes and endothelial cells in blood vessels contributing to cicatrization
• Please see Diabetic Foot Infection disease management chart for further information

Diabetic Kidney Disease (Nephropathy)

• Most important cause of end-stage renal disease (ESRD)
• Occurs in 20-40% of diabetic patients
  • Signs of diabetic microvascular complications, eg neuropathy and retinopathy, are usually seen in patients with diabetic kidney disease

• Persistent albuminuria at levels 30-299 mg/24 hours is the first stage of diabetic nephropathy in type 1 diabetes mellitus, and sign of nephropathy development in type 2 diabetes mellitus and increased cardiovascular disease risk
  • A spot urine albumin-to-creatinine ratio of >25 mg/mmol indicates diabetic nephropathy 
  • Development to persistent albuminuria at levels ≥300 mg/24 hours will likely progress to end-stage renal disease
  • Reduced eGFR without albuminuria is becoming more common with increased prevalence of diabetes and is often reported in both types 1 and 2 diabetes

• Should monitor urine albumin excretion with spot urine albumin-to-creatinine ratio values annually in patients with type 1 diabetes mellitus diagnosed for ≥5 years and in all type 2 diabetic patients starting at diagnosis
  • Used to assess treatment response and disease progression
  • Albuminuria can only be considered when 2-3 specimens collected within 3-6 months have shown abnormal results
    • Increased values may be secondary to exercise within 24 hours, infection, fever, congestive heart failure (HF), marked hyperglycemia and hypertension
  • Yearly serum creatinine measurement is also advised in all diabetic adults regardless of their urine albumin excretion level, to estimate glomerular filtration rate and to stage chronic kidney disease (CKD)

• Blood glucose and BP should be controlled to lower the risk or slow the progression of nephropathy
  • Consider SGLT2 inhibitors and GLP-1 receptor agonists as added drugs to Metformin to attain target A1c or in those who cannot use or tolerate Metformin
  •  SGLT2 inhibitors reduce risks of CKD progression, cardiovascular disease events and hypoglycemia while GLP-1 receptor agonists reduce risks of cardiovascular disease events and hypoglycemia and possibly slow progression of CKD
    • Empagliflozin and Dapagliflozin are approved for use in patients with eGFR 25-45 mL/min/1.73 m²  and more useful in patients at high risk of CKD progression
    • Canagliflozin is approved for use in patients with eGFR ≥30 mL/min/1.73 m²   
    • GLP-1 receptor agonists may be used in patients with lower eGFR but would require dose adjustment except for Dulaglutide, Liraglutide or Semaglutide
  • Metformin should not be initiated in patients with eGFR <30-45 mL/min/1.73 m²
• In patients with diabetes, hypertension, eGFR <60 mL/min/1.73 m², it is recommended to have ACE inhibitors or ARBs to prevent CKD progression

• Patients with persistent albuminuria should be treated with ACE inhibitors or angiotensin II receptor blockers, whichever is tolerated
  • ACE inhibitors have been shown to reduce major cardiovascular disease outcomes in patients with diabetes mellitus, thus supporting its use in patients with elevated albuminuria, which is also a cardiovascular disease risk factor
  • Angiotensin II receptor blockers have been shown to slow down the rate of albuminuria progression, and to end-stage renal disease in patients with type 2 diabetes mellitus
    • Angiotensin II receptor blockers were found to be superior to calcium channel blockers at heart failure reduction especially in patients with type 2 diabetes mellitus and significant diabetic kidney disease
  • May give diuretics, calcium channel blockers and beta-blockers to patients who need further decrease in BP in addition to ACE inhibitors or angiotensin II receptor blockers
    • Above agents may also be used as alternatives to patients who cannot tolerate ACE inhibitors or angiotensin II receptor blockers
  • Serum creatinine and K levels should be monitored periodically in patients who are managed with ACE inhibitors, angiotensin II receptor blockers or diuretics

• A nonsteroidal mineralocorticoid receptor antagonist (eg Finerenone) is recommended in patients with CKD with increased risk for cardiovascular events or CKD progression and not able to use SGLT2 inhibitors
• Dietary protein restriction may be considered in patients with progressive nephropathy even with good glucose and BP control
  • Helps slow progression of albuminuria, occurrence of end-stage renal disease and decline in glomerular filtration rate 

• Should screen complications of CKD in patients with eGFR <60 mL/min/1.73 m²
  • Monitor eGFR every 6 months in patients with GFR 45-60 mL/min/1.73 m², and every 3 months in patients with GFR 30-44 mL/min/1.73 m²

Neuropathy

• Screen for distal symmetric polyneuropathy (DPN) upon diagnosis of type 2 diabetes mellitus and 5 years after type 1 diabetes mellitus diagnosis, and at least yearly thereafter using simple clinical tests
  • Yearly screening should be performed including tests for pinprick sensation, vibration perception using a 128-Hz tuning fork, 10-g monofilament pressure sensation at the distal plantar aspect of both great toes and metatarsal joints, and ankle reflexes

• Screen for cardiovascular autonomic neuropathy (CAN) at diagnosis of type 2 diabetes mellitus and 5 years after type 1 diabetes mellitus is diagnosed
  • Cardiovascular autonomic neuropathy is the most studied and clinically significant form of diabetic autonomic neuropathy because it is associated with mortality risk independent of cardiovascular disease risk factors
  • It is asymptomatic in early stage while at advanced stage, it is associated with resting tachycardia and orthostatic hypotension
  • Treatment is generally focused on alleviating symptoms

• Peripheral nerve dysfunction in diabetic patients is considered only after other causes have been ruled out
• Chronic sensorimotor distal polyneuropathy and autonomic neuropathy are the most common among the neuropathies
• Associated with poor glycemic control, duration of diabetes, visceral obesity, height, hypertension, age, smoking, hypoinsulinemia and dyslipidemia
• Increases the risk of developing severe and potentially life-threatening foot complications (eg ulcers, osteoarthropathy, osteomyelitis), medial arterial calcification, and neuropathic edema
• Timely detection and proper treatment of neuropathy is important in diabetic patients
  • Treatable nondiabetic neuropathy may be present
  • Various treatments for symptomatic diabetic neuropathy are available
  • Risk of foot injury is increased due to insensitivity and being asymptomatic in 50% of distal symmetric polyneuropathy patients
  • Significant morbidity and mortality may result from autonomic neuropathy especially cardiovascular autonomic neuropathy

• Distal symmetric polyneuropathy (DPN)
  • Usually develops as a dying-back neuropathy, involving the most distal extremities 1st then extends proximally up the limbs, and later may also affect the anterior abdominal wall and trunk
    • Glove-and-stocking distribution (most common), pseudosyringomyelic syndromes and atactic syndrome (diabetic pseudotabes) (occasionally)
    • With insidious onset and has chronic and progressive course if no intervention will be given
  • Small unmyelinated (C) fiber, thinly myelinated (Aδ) fibers, and large myelinated (Aα, Aβ) fibers are commonly involved
    • Small-fiber function can be assessed by pinprick and temperature sensation; large-fiber function can be assessed by testing lower extremity reflexes, vibratory sense and 10-g monofilament testing
    • Protective sensation can be assessed by 10-g monofilament testing
  • Studies have shown that small fiber neuropathy occurs early (presenting with pain and hyperalgesia) before sensory deficits or nerve conduction slowing can be detected
  • Motor function is also involved but less prominently than sensory deficits, and are usually confined to the distal lower limbs which results in muscle atrophy and weakness
  • Ankle reflexes are frequently reduced or absent
  • Loss of protective sensation indicates distal sensorimotor polyneuropathy and is a risk factor for diabetic foot ulceration
  • Major contributory factor for diabetic foot ulcers and lower-limb amputation
  • Differential diagnosis for severe neuropathy: Neurotoxic medication use, heavy metal poisoning, alcohol abuse, vitamin B12 deficiency, kidney disease, chronic inflammatory demyelinating neuropathy, inherited neuropathies or vasculitis

• Autonomic neuropathy
  • Patients usually present with resting tachycardia, exercise intolerance, orthostatic hypotension, constipation, diarrhea, gastroparesis, erectile dysfunction, hypoglycemia unawareness, fecal incontinence, neurogenic bladder, sudomotor dysfunction, or neurovascular impairment
  • Management will depend on patient’s clinical manifestation
    • Change in diet and prokinetic drugs (eg Erythromycin) can improve gastroparesis
    • Phosphodiesterase type 5 inhibitors, intracorporeal or intraurethral prostaglandins, vacuum devices, or penile prostheses may be recommended in patients with erectile dysfunction

• Patients should maintain a stable and optimal blood sugar level, BP and lipid levels to slow down the progression, improve, retard or prevent neuropathic symptoms
  • In patients with type 1 diabetes mellitus, optimizing glucose control prevents or delays the development of neuropathy while in patients with type 2 diabetes mellitus, it slows the progression of neuropathy

• Therapy of patients may be aimed at symptomatic relief of pain or at the underlying neuropathic process
  • Recommended initial pharmacotherapy for neuropathic pain in patients with diabetes is either Pregabalin, Duloxetine or Gabapentin
  • Capsaicin cream, opioids (eg Tramadol, Oxycodone, Tapentadol), and tricyclic antidepressants (eg Amitriptyline, Desipramine, Imipramine, Clomipramine) may be given to patients for symptomatic treatment of painful neuropathy
  • α-lipoic acid (or thioctic acid) decreases oxygen free radicals thereby influencing the underlying neuropathic process
    • Studies have shown that it decreases pain, paresthesias and numbness, and has a favorable safety profile
  • Benfotiamine is a lipid-soluble thiamine derivative that study shows have improved neuropathic pain in patients with diabetic neuropathy as being a transketolase activator and inhibitor of alternative metabolic pathways implicated in the pathogenesis of hyperglycemia-induced vascular damage
  • Long-term Metformin use is associated with vitamin B12 deficiency and homocysteinemia; consider monitoring vitamin B12 levels and, if needed, Mecobalamin may be given to Metformin-treated patients who developed neuropathy
• Please see Neuropathic Pain disease management chart for further information

Retinopathy

• Microvasculature complication of diabetes mellitus which is linked to the duration of diabetes mellitus and level of glycemic control
• Most common cause of blindness in patients aged 20-74 years in developed countries
  • Glaucoma, cataracts, and other eye disorders occur earlier and more frequently in people with diabetes mellitus

• May be secondary to chronic elevated blood sugar, nephropathy, dyslipidemia and hypertension
  • 5 years to develop after the onset of hyperglycemia; may be present at time of diagnosis of diabetes mellitus

• Screening is done with an initial dilated and comprehensive eye exam by an ophthalmologist after diagnosis for individuals with type 2 diabetes mellitus and within 5 years for individuals with type 1 diabetes mellitus
  • Subsequent eye exams should be performed annually; if ≥1 eye exam is normal, the next eye exam may be repeated every 1-2 years
  • If retinopathy is present, subsequent examinations should be done yearly; more frequently, if progressing
  • May also use retinal photography for screening

• Blood glucose, serum lipid and BP should be controlled to lower the risk or slow the progression of retinopathy
  • Fenofibrate for patients with dyslipidemia and ACE inhibitors and ARBs for patients with hypertension are effective treatments in decreasing retinopathy progression

• Intravitreous injections of anti-vascular endothelial growth factor (anti-VEGF) agents help reduce the risk of vision loss in patients with proliferative diabetic retinopathy (PDR)
  • Aflibercept, Bevacizumab and Ranibizumab are anti-VEGF agents indicated for central-involved diabetic macular edema that occurs beneath the foveal center and may threaten reading vision

• Refer patients to ophthalmologist if pregnant or with sudden unexplained visual acuity changes; patients with macular edema, severe nonproliferative diabetic retinopathy (NPDR) or PDR should be referred immediately to an ophthalmologist for possible laser photocoagulation therapy to prevent loss of vision

Other Comorbidities Commonly Associated with Diabetes Mellitus

• Hearing impairment
  • May be secondary to neuropathy and/or vascular disease
  • Studies have shown significant association of high frequency impairment in those with history of coronary heart disease and peripheral neuropathy; low/mid frequency impairment in those with low HDL-C and poor health status

• Obstructive sleep apnea
  • Most common type of sleep apnea that causes physical obstruction of the airway during sleep
  • Referral for a home study in lower risk settings or to a sleep specialist for evaluation and treatment in higher risk settings is recommended

• Fatty liver disease
  • Studies have shown that diabetes mellitus is linked to incident nonalcoholic chronic liver disease and hepatocellular carcinoma
  • Advise weight loss, blood glucose control, and treatment with antidiabetic or dyslipidemic agents
  • Consider Pioglitazone and GLP-1 receptor agonists for patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) at high risk of fibrosis

• Decreased testosterone level
• Erectile dysfunction
• Pancreatitis
• Periodontal disease
• Cancer of the liver, pancreas, endometrium, colon, rectum, breast, or bladder
  • Increased risk in patients with type 2 diabetes mellitus possibly due to obesity, age, physical inactivity, hyperglycemia, or hyperinsulinemia

• Fractures
  • Type 1 diabetes mellitus is associated with osteoporosis
  • Type 2 diabetes mellitus has high risk of hip fracture despite higher bone mineral density (BMD) compared with non-diabetics
  • Patient’s fracture history and risk factors should be assessed and bone mineral density testing recommended, if appropriate
  • High-risk patients should be advised on how to reduce their risk for falls, importance of adequate calcium and vitamin D intake, and to avoid agents that may further decrease their bone mineral density level
  • Thiazolidinediones should be avoided by patients with type 2 diabetes mellitus and fracture risk factors

• Cognitive impairment
  • Patients with diabetes mellitus have increased risk for cognitive decline and dementia, and greater rate of cognitive decline especially with a history of severe hypoglycemia