Diabetes Mellitus Follow Up

Monitoring

Assessment of Glycemic Control  

Glycemic control is essential in the management of diabetes mellitus. Clinical trials have proven significant reduction of microvascular and macrovascular complications with improved glucose control. Patients’ blood glucose monitoring or interstitial glucose monitoring and HbA1c are used for assessing the effect on glycemic control.  

Blood Glucose Monitoring

The key component in blood glucose monitoring is to integrate information into clinical and self-management plans. Blood glucose monitoring permits patients to evaluate their response to therapy and check whether glucose targets are being achieved. It may be used as a guide to the success of therapy for patients using less insulin injections, oral antidiabetic agents, or medical nutrition therapy alone. The results may help prevent hypoglycemia and adjust medications (especially prandial insulin doses), medical nutrition therapy, and physical activity. Postprandial blood glucose monitoring may be performed to achieve postprandial glucose targets.  

Frequency and timing are dependent on the patient’s glucose status, needs and goals, and mode of treatment. It should be done by patients on multiple-dose insulin or insulin pump therapy at least prior to meals and snacks, occasionally postprandially, at bedtime, prior to exercise, when low blood glucose is suspected, after treating low blood glucose until normoglycemic, and prior to critical tasks such as driving. It is important for patients on insulin to monitor and prevent asymptomatic hypo- or hyperglycemia. For patients with type 2 diabetes mellitus on oral antidiabetic therapy, frequency and timing is unclear.  

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Complications

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

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• Very high risk: Individuals with type 2 diabetes mellitus with clinically established atherosclerotic cardiovascular disease or severe target organ damage or ≥20% 10-year cardiovascular disease risk using SCORE2-Diabetes
• High risk: Individuals with type 2 diabetes mellitus without clinically established atherosclerotic cardiovascular disease or severe target organ damage and 10-<20% 10-year cardiovascular disease risk using SCORE2-Diabetes
• Moderate risk: Individuals with type 2 diabetes mellitus without clinically established atherosclerotic cardiovascular disease or severe target organ damage and 5-<10% 10-year cardiovascular disease risk using SCORE2-Diabetes
• Low-risk: Individuals with type 2 diabetes mellitus without clinically established atherosclerotic heart disease or severe target organ damage and <5% 10-year cardiovascular disease risk using SCORE2-Diabetes
• Patients >40 years old with type 1 diabetes mellitus may also be classified according to these criteria

Aspirin at a low dose (75-162 mg/day) may be used for primary prevention in diabetic patients at high risk for atherosclerotic cardiovascular disease (ie men and women ≥50 years old who have either a family history of premature atherosclerotic cardiovascular disease, hypertension, smoking, dyslipidemia, or albuminuria) and are not at increased risk for bleeding. It has been shown to be effective when given as part of the secondary prevention strategy in patients with diabetes mellitus and previous stroke or myocardial infarction. It is recommended in patients with CKD and atherosclerotic cardiovascular disease. It may be given to patients with diabetes mellitus without a history of symptomatic atherosclerotic cardiovascular disease or revascularization to prevent the first severe vascular event in the absence of contraindications. Concomitant use of a 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 during the first year after acute coronary syndrome or as an alternative to Aspirin-allergic patients. It is also recommended as an add-on therapy to Aspirin for 6 months after coronary stenting in patients with chronic coronary syndromes, irrespective of stent type. 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.  

As SGLT2 inhibitor or SGLT1/2 inhibitor (eg Sotagliflozin) with proven benefit is recommended in patients with type 2 diabetes mellitus and established heart failure with preserved or reduced ejection fraction to reduce the risk of worsening heart failure and cardiovascular death. Sotagliflozin is a dual SGLT1 and SGLT2 inhibitor that is approved by the US FDA in patients with heart failure or type 2 diabetes mellitus, CKD, and other cardiovascular risk factors to reduce cardiovascular death, hospitalization for heart failure, and urgent heart failure. Sotagliflozin lowers glucose via delayed glucose absorption in the gut by inhibiting the cotransporter SGLT1 and increasing urinary glucose excretion.  

All patients should be advised to stop smoking. Studies have shown that patients with diabetes mellitus who smoke have a higher risk for atherosclerotic cardiovascular disease, premature death, and microvascular complications of diabetes mellitus.  

Hypertension  

Hypertension is a common comorbidity of diabetes mellitus and a major risk factor for both atherosclerotic cardiovascular disease and microvascular complications of diabetes mellitus. It is usually secondary to nephropathy in type 1 diabetes mellitus and frequently coexists with other cardiometabolic risk factors in type 2 diabetes mellitus.  

Notably, blood pressure is measured at every routine check-up. A systolic blood pressure (SBP) of ≥130 mmHg or diastolic blood pressure (DBP) of ≥80 mmHg or both, obtained from an average of ≥2 careful readings on at least two separate days confirms the diagnosis of hypertension. Hypertension could be diagnosed in patients with cardiovascular disease and blood pressure of ≥180/110 mmHg at a single visit. Antihypertensive drug treatment is initiated when the blood pressure is ≥130/80 mmHg. 

In the 2026 ADA guideline, the 2018 American Association of Clinical Endocrinology (AACE) and the 2025 American College of Cardiology/American Heart Association guidelines, it is recommended for patients with diabetes mellitus and hypertension to have an on-treatment target blood pressure of <130/80 mmHg. The 2024 ESC hypertension guideline recommends a treatment target of 120-129/70-79 mmHg if tolerated. 

Home blood pressure monitoring should be considered in patients with diabetes mellitus and 24-hour ambulatory blood pressure monitoring should be considered for blood pressure assessment and adjustment of antihypertensive treatment.
 
Multiple drugs are usually needed to reach the target blood pressure. Combination therapy with angiotensin-converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs), plus calcium channel blockers, or thiazide-type diuretics are the preferred initial treatment for patients with diabetes mellitus and hypertension. In individuals with diabetes mellitus and uncontrolled hypertension, a thiazide diuretic should be added to the regimen if eGFR is ≥30 mL/min/1.73 m². The addition of a mineralocorticoid receptor antagonist (MRA) is considered in patients with diabetes and resistant hypertension. ACE inhibitors or ARBs are recommended in patients with hypertension and diabetes when CKD is present (eGFR <60 mL/min/1.73 m² or albuminuria ≥30 mg/g) and should be considered with mild albuminuria (<30 mg/g) to slow diabetic kidney disease. Kidney function and serum potassium levels should be monitored if ACE inhibitors, ARBs, MRA or diuretics are given. Increases in creatinine in response to blood pressure-lowering treatment should not be concerning unless hyperkalemia develops or creatinine increases to >30% over the baseline levels. Consider other forms of hypertension in patients with unmanageable blood pressure even with optimal doses of at least three 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 mellitus to identify patients with dyslipidemia and to monitor treatment response. Low high-density lipoprotein-cholesterol (HDL-C) with high triglycerides 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 which includes avoidance of trans fat, a decrease in saturated fat and cholesterol intake, an increase in omega-3 fatty acids, viscous fiber (eg oats, legumes, citrus), and plant stanols or sterols intakes, reduction of weight if overweight, and increase in physical activity.  

Pharmacological therapy should be added to lifestyle modification therapy in diabetic patients with cardiovascular disease, patients >40 years old with ≥1 cardiovascular risk factor, or patients with low-density lipoprotein-cholesterol (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 levels and for cardioprotection. High-intensity statins (eg Atorvastatin, Rosuvastatin) are recommended in patients with diabetes mellitus with high or very high cardiovascular risk. Intensive LDL-C reduction with statins with or without Ezetimibe is recommended in patients with diabetes mellitus with CKD to reduce the risk of atherosclerotic events (eg coronary death, non-fatal myocardial infarction, ischemic stroke, coronary revascularization). In patients receiving statin therapy, it is not recommended to add fibrate; Niacin and supplements containing omega fatty acids as they do not provide additional cardiovascular risk reduction. It is recommended to initiate statin therapy, in addition to lifestyle modification, for patients with diabetes mellitus aged 20-39 years with atherosclerotic cardiovascular disease. It should also be considered in patients with type 1 diabetes mellitus who are >40 years old without history of cardiovascular disease, or <40 years old with other risk factors for cardiovascular disease or microvascular end-organ damage, or a 10-year cardiovascular disease risk of ≥10% to reduce cardiovascular risk.

The target LDL-C for patients with diabetes mellitus based on the 2018 AACE, 2023 ESC, and 2024 ADA guidelines are as follows:

• Adults with diabetes mellitus at higher atherosclerotic cardiovascular disease risk (≥1 additional risk factor): ≥50% reduction from baseline and <1.8 mmol/L (<70 mg/dL)
• Adults with diabetes mellitus and atherosclerotic cardiovascular disease: ≥50% reduction from baseline and <1.4 mmol/L (<55 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 with a duration of >20 years or with high cardiovascular risk: <1.8 mmol/L (<70 mg/dL) or ≥50% reduction from the baseline
• Patients with diabetes mellitus with very high cardiovascular risk: <1.4 mmol/L (<55 mg/dL) or ≥50% reduction from the baseline
• Drug-treated patients that did not reach the above targets on maximum tolerated statin therapy should target a decrease of 30-40% from baseline

Non-HDL-C target in patients with type 2 diabetes mellitus with very high cardiovascular risk is <2.2 mmol/L (<85 mg/dL) and <2.6 mmol/L (<100 mg/dL) in high cardiovascular risk patients. Desirable levels of TG are <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 the 2020 AACE guidelines. Severe hypertriglyceridemia may necessitate urgent treatment with lifestyle therapy and drugs such as fibric acid derivatives, Niacin, or fish oil in order to decrease the risk of acute pancreatitis. Icosapent ethyl, when added to statin in patients with atherosclerotic cardiovascular disease or elevated TG and high cardiovascular disease risk, has been shown to decrease cardiovascular disease risk. Secondary causes of hypertriglyceridemia are evaluated in patients with fasting TG levels of ≥500 mg/dL.  

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 patients with diabetes without evidence of atherosclerotic cardiovascular disease. Statins combined with other lipid-lowering agents may be given to patients whose targets are not achieved with the maximum tolerated dose of statins based on the 2020 AACE guidelines.  

Further decrease in LDL-C may be achieved through the addition of Niacin, Fenofibrate, Ezetimibe, omega-3 fatty acids, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, or bile acid sequestrants to statin therapy. The 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 maximally 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. The combination of statin plus Fibrate or Niacin therapy should only be used if the benefits outweigh the risks with careful toxicity monitoring. PCSK9 inhibitor (eg Alirocumab, Evolocumab) with monoclonal antibody treatment, Bempedoic acid or PCSK9 inhibitor with Inclisiran may be considered as alternatives to statins in patients with diabetes and atherosclerotic cardiovascular disease with intolerance to statins.  

Please see Dyslipidemia disease management chart for further information.

Diabetic Foot  

Annual comprehensive foot examinations should be done in all diabetic patients to identify risk conditions suggestive of ulcers and amputations. However, 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. 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 are ideally done. LOPS is considered if ≥1 test is abnormal, but it is 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, hypertension, 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 mellitus, which are often a result of diabetic neuropathy and/or peripheral arterial disease. It is usually secondary to loss of protective sensation, motor dysfunction, and decreased sweat production that causes dry and chapped skin due to autonomic involvement. The incidence of lower extremity ulcers in patients with diabetes mellitus is 4-10% and the lifetime risk is 25%. Foot ulceration is the precursor to 85% of lower extremity amputations in diabetic patients. Patients who smoke cigarettes, with a history of amputation or foot ulcers, 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 the general population. It is identified through a 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 in patients suspected of a diabetic foot. Plain radiographs should be the first 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 joints, and tendon ruptures.  

Patients should be advised on proper daily foot monitoring and care, and the selection of appropriate footwear. General footwear recommendations include a broad and square toe box, laces with three or four 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 deformities like hammertoes and bunions, extra-wide or deep shoes are recommended. In high-risk patients, custom therapeutic footwear may aid in preventing future foot ulcers.   Management of comorbidities, evaluation of vascular status and treatment, assessment of lifestyle factors, assessment of ulcers, 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 the 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 the 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 the proliferation of fibroblasts, keratinocytes, and endothelial cells in blood vessels which contributes to cicatrization.  

Please see Diabetic Foot disease management chart for further information.  

Diabetic Kidney Disease (DKD) or Nephropathy  

Diabetic nephropathy is the most important cause of end-stage renal disease. It occurs in 20-40% of diabetic patients. Signs of diabetic microvascular complications such as neuropathy and retinopathy are usually seen in patients with diabetic nephropathy. Screening for CKD in patients with diabetes mellitus is recommended to be done at least annually.  

Urine albumin excretion should be monitored with spot UACR values annually with patients with type 1 diabetes mellitus diagnosed for ≥5 years and in all patients with type 2 diabetes starting at diagnosis. It is 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, 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 CKD.    

Persistent albuminuria at levels 30-299 mg/24 hours is often the first stage of diabetic nephropathy in type 1 diabetes mellitus and is a sign of nephropathy development in type 2 diabetes mellitus and increased cardiovascular disease risk. A spot UACR 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. UACR should be repeated after 3 months in patients with albuminuria of ≥300 mg and/or eGFR of <60 mL/min/1.73 m². Monitoring of albuminuria and eGFR should be done at least every 6 months with established diabetic kidney disease. The aim is to reduce urinary albumin by ≥30% in patients with CKD and albuminuria of ≥300 mg/g to slow CKD progression. Reduced eGFR without albuminuria is becoming more common with the increased prevalence of diabetes and is often reported in both types 1 and 2 diabetes.

Risk of CKD Progression

Blood glucose and blood pressure should be controlled to lower the risk or slow the progression of nephropathy. 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 should be considered. SGLT2 inhibitors reduce the risks of CKD progression, cardiovascular disease events, and hypoglycemia while GLP-1 receptor agonists reduce the risks of cardiovascular disease events and hypoglycemia and possibly slow down the progression of CKD. Initiation of an SGLT2 inhibitor in combination with an ACE inhibitor or ARB is recommended in patients with type 2 diabetes mellitus and CKD with an eGFR of ≥20 mL/min/1.73 m² and urinary albumin of ≥200 mg/g creatinine to reduce cardiovascular and kidney failure risk. Empagliflozin and Dapagliflozin are approved for use in patients with eGFR 25-45 mL/min/1.73 m² and are 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 adjustments except for Dulaglutide, Liraglutide, or Semaglutide. Metformin should not be initiated in patients with eGFR <30-45 mL/min/1.73 m².  

The use of SGLT2 inhibitors if eGFR ≥20 mL/min/1.73 m² and GLP-1 receptor agonists or nonsteroidal MRA if eGFR is ≥25 mL/min/1.73 m² should be considered in patients with type 2 diabetes mellitus with CKD to reduce cardiovascular risk. Patients with eGFR <20 mL/min/1.73 m² and not on dialysis can be safely continued on SGLT2 inhibitors to reduce the risk of CKD progression and for cardiovascular benefits. In patients with diabetes mellitus and hypertension with an eGFR <60 mL/min/1.73 m², it is recommended to have ACE inhibitors or ARBs to prevent CKD progression. ACE inhibitors or ARBs are recommended in patients with diabetes mellitus as CKD is diagnosed to reduce kidney failure risk. Titration to a maximally tolerated dose is recommended to prevent the progression of kidney disease and reduce cardiovascular events. Patients with persistent albuminuria should likewise be treated with ACE inhibitors or ARBs, whichever is tolerated. ACE inhibitors have been shown to reduce major cardiovascular disease outcomes in patients with diabetes mellitus, thus supporting their use in patients with elevated albuminuria, which is also a cardiovascular disease risk factor. ARBs have been shown to slow down the rate of albuminuria progression to end-stage renal disease in patients with type 2 diabetes mellitus. ARBs were found to be superior to calcium channel blockers in heart failure risk reduction, especially in patients with type 2 diabetes mellitus and significant diabetic kidney disease. Initiation of treatment of an SGLT2 inhibitor with Finerenone may be considered in adults with type 2 diabetes mellitus and UACR ≥100 mg/g with EGFR of 30-90 mL/min/1.73 m² on ACE inhibitor or ARB due to evidence of safety and beneficial effects on albuminuria.   

If a further decrease in blood pressure is warranted, diuretics, calcium channel blockers, and beta-blockers in addition to ACE inhibitors or ARBs may be given. These agents may also be used as alternatives for patients who cannot tolerate ACE inhibitors or ARBs. Serum creatinine and potassium levels should be monitored periodically in patients who are managed with ACE inhibitors, ARBs, or diuretics. A nonsteroidal MRA (eg Finerenone) is recommended in patients with CKD with increased risk for cardiovascular events or CKD progression who were not able to use SGLT2 inhibitors. Finerenone is recommended as add-on therapy to an ACE inhibitor or ARB to reduce cardiovascular and kidney failure risk in patients with type 2 diabetes with an eGFR >60 mL/min/1.73 m² with UACR ≥300 mg/g (≥30 mg/mmol), or an eGFR of 25-60 mL/min/1.73 m² and UACR of ≥30 mg/g (≥3 mg/mmol) with appropriate monitoring.  

Dietary protein restriction may be considered in patients with progressive nephropathy even with good glucose and blood pressure control as it helps slow the progression of albuminuria, the occurrence of end-stage renal disease, and the decline in GFR. For patients with non-dialysis-dependent stage G3 or higher CKD, the protein intake should be 0.8 g/kg/day while for patients on dialysis, the protein intake of 1 to 1.2 g/kg/day should be considered.

Screening should be done for complications of CKD in patients with eGFR of <60 mL/min/1.73 m². eGFR should be monitored 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  

Screening for distal symmetric polyneuropathy (DPN) should be done upon the 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.  

Screening for cardiovascular autonomic neuropathy (CAN) is similarly done upon the 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 the early stage while at the 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. Neuropathy is associated with poor glycemic control, the duration of diabetes mellitus, visceral obesity, height, hypertension, age, smoking, hypoinsulinemia, and dyslipidemia. It 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 are important in diabetic patients and various treatments for symptomatic diabetic neuropathy are available. It should be noted that treatable nondiabetic neuropathy may also be present. The risk of foot injury is increased due to insensitivity and being asymptomatic in 50% of patients with distal symmetric polyneuropathy. Significant morbidity and mortality may result from autonomic neuropathy, especially cardiovascular autonomic neuropathy.  

In patients with any form of neuropathy, stable and optimal blood sugar level, blood pressure, and lipid levels should be maintained 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 mellitus includes gabapentenoids (eg Gabapentin, Pregabalin), serotonin-norepinephrine reuptake inhibitors (SNRIs) (eg Duloxetin, Desvenlafaxine, Venlafaxine), sodium channel blockers (eg Carbamazepine, Lacosamide, Lamotrigine, Oxcarbazepine, Valproic acid), and tricyclic antidepressants (eg Amitriptyline). It must be noted that combination therapy with these medications may provide additional relief for neuropathic pain. Capsaicin cream, opioids (eg Tramadol, Oxycodone, Tapentadol), 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 a study shows has 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, therefore, monitoring vitamin B12 levels should be considered and, if needed, Mecobalamin may be given to Metformin-treated patients who developed neuropathy.

Distal symmetric polyneuropathy (DPN)  

Distal symmetric polyneuropathy usually develops as a dying-back neuropathy, involving the most distal extremities first then extending proximally up the limbs, and later may also affect the anterior abdominal wall and trunk. It most commonly presents as a glove-and-stocking distribution, although pseudosyringomyelic syndromes and atactic syndrome (diabetic pseudotabes) may occasionally happen. It has an insidious onset and has a chronic and progressive course if no intervention is given.  

Small unmyelinated (C) fibers, thinly myelinated (Aδ) fibers, and large myelinated (Aα, Aβ) fibers are commonly involved. Smaller function can be assessed by pinprick and temperature sensation while large-fiber function can be assessed by testing the lower extremity reflexes, vibratory sense, and 10-g monofilament testing. The protective sensation can be assessed by 10-g monofilament testing.  

Studies have shown that small fiber neuropathy occurs early, presenting as 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. The loss of protective sensation indicates distal sensorimotor polyneuropathy and is a risk factor for diabetic foot ulceration. It is a major contributory factor for diabetic foot ulcers and lower-limb amputation.  

The differential diagnosis for severe neuropathy that should be ruled out includes neurotoxic medication use, heavy metal poisoning, alcohol abuse, vitamin B12 deficiency, kidney disease, chronic inflammatory demyelinating neuropathy, hypothyroidism, inherited neuropathies, or vasculitis.    

Autonomic Neuropathy  

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 the patient’s clinical manifestation. Change in diet and prokinetic drugs (eg Erythromycin, Metoclopramide) can improve gastroparesis. Phosphodiesterase type 5 inhibitors, intracorporeal or intraurethral prostaglandins, vacuum devices, or penile prostheses may be recommended in patients with erectile dysfunction.  

Please see Neuropathic Pain disease management chart for further information.

Retinopathy  

Retinopathy is a microvascular complication of diabetes mellitus which is linked to the duration of the diabetes and level of glycemic control. Diabetic retinopathy is the 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. It may be secondary to chronic elevated blood sugar, nephropathy, dyslipidemia, and hypertension. It takes 5 years to develop after the onset of hyperglycemia but may be present at the 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. Progressive or sight-threatening retinopathy warrants frequent examinations by an ophthalmologist. Retinal photography may also be used for screening.  

Blood glucose, serum lipid, and blood pressure should all 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, Brolucizumab, Faricimab, 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 an ophthalmologist if pregnant or with sudden unexplained visual acuity changes. Patients with macular edema, severe non-proliferative diabetic retinopathy (NPDR), or proliferative diabetic retinopathy should be referred immediately to an ophthalmologist for possible laser photocoagulation therapy to prevent loss of vision.  

Other Comorbidities Commonly Associated with Diabetes Mellitus  

Aside from the macrovascular and microvascular complications of diabetes mellitus, other comorbidities that are associated with diabetes mellitus include hearing impairment, obstructive sleep apnea, fatty liver disease, decreased testosterone level, erectile dysfunction, pancreatitis, periodontal disease, risk of cancer development, fractures, and cognitive impairment.  

Hearing impairment  

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

Obstructive sleep apnea  

Obstructive sleep apnea is the 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.  

Metabolic dysfunction-associated steatotic liver disease (MASLD)  

Studies have shown that diabetes mellitus is linked to incident non-alcoholic chronic liver disease and hepatocellular carcinoma. Weight loss, blood glucose control and treatment with antidiabetic or agents for dyslipidemia are advised. Pioglitazone and GLP-1 receptor agonists may be considered for patients with MASLD or metabolic dysfunction-associated steatohepatitis (MASH) who are at high risk of developing fibrosis.  

Decreased Testosterone Level  

Erectile Dysfunction  

Pancreatitis  

Patients with recurrent or long-term use of glucocorticoids represent a significant risk factor for developing type 2 diabetes mellitus. Hence, postprandial or random blood glucose levels should be monitored in these patients.  

Periodontal disease

Cancer of the liver, pancreas, endometrium, colon, rectum, breast, or bladder  

There is an increased risk for the development of cancer in patients with type 2 diabetes mellitus possibly due to obesity, age, physical inactivity, hyperglycemia, or hyperinsulinemia. In patients treated with an immune checkpoint inhibitor (ICI), PI3Kα inhibitor or mammalian target of rapamycin (mTOR) inhibitor, fasting or random plasma glucose should be tested before initiating treatment. Patients being treated with PI3Kα inhibitors should also be tested weekly for the first 2 weeks and then every 4 weeks during treatment. A1c may be tested every 3 months during treatment for patients with a PI3Kα inhibitor or mTOR inhibitor.   

Fractures  

Type 1 diabetes mellitus is associated with osteoporosis while type 2 diabetes mellitus has a high risk of hip fracture despite higher bone mineral density (BMD) compared with non-diabetics. The patient’s fracture history and risk factors should be assessed, and bone mineral density testing recommended, if appropriate. Diabetic specific risk factors for fracture include a HbA1c >8%, diabetes duration of >10 years, medication with insulin, sulfonylureas or thiazolidinediones, frequent hypoglycemic events, lumbar spine or hip T-score ≤-2.0, presence of peripheral and autonomic neuropathy, and presence of retinopathy and nephropathy. High-risk patients should be advised on how to reduce their risk for falls, the importance of adequate calcium and vitamin D intake through diet or supplementation, and the avoidance of agents that may further decrease their bone mineral density level. Osteoporosis drug therapy may be considered in older adults with diabetes with increased fracture risk (T-score ≤-2.5) and in adults with diabetes with a T-score between -2.0 and -2.5 and additional risk factors for fracture. Thiazolidinediones should be avoided by patients with type 2 diabetes mellitus and fracture risk factors.  

Cognitive impairment  

Patients with diabetes mellitus have an increased risk for cognitive decline and dementia, and a greater rate of cognitive decline, especially if with a history of severe hypoglycemia.