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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 (BGM)
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.
Diabetes Mellitus_Follow Up 1Continuous Glucose Monitoring (CGM)
Continuous glucose monitoring is helpful in identifying glucose variations in patients with poorly controlled diabetes mellitus. It is a valuable tool when used in conjunction with intensive insulin regimens to lower HbA1c in patients with type 1 diabetes mellitus. It is essential in creating an ambulatory glucose profile as it provides data on time in range, percentage of time spent above and below range, and variability. Real-time CGM or intermittently scanned CGM is recommended to monitor DM on any type of insulin therapy. Intermittently scanned CGM devices should be scanned at a minimum once every 8 hours to avoid gaps in the data. Early use in patients with type 1 diabetes mellitus is recommended to improve glycemic outcomes and quality of life, and to minimize hypoglycemia. It may be a supplemental tool to blood glucose monitoring in patients with frequent hypoglycemia and/or those with hypoglycemia unawareness and it has alarms for hypo- or hyperglycemic excursions. The results are accurate, similar to blood glucose monitoring when properly calibrated.
Glycosylated Hemoglobin A1c (HbA1c)
Glycosylated HbA1c is formed by the non-enzymatic glycation of hemoglobin. It reflects average glycemia over 3 months and has strong predictive value for diabetes mellitus complications.
It is recommended to be done at the initial assessment and then as part of continuing care. Every 3 months measurement may determine whether the patient’s glucose targets have been achieved and maintained. Frequency should be based on the individual’s clinical situation and treatment regimen used, and the physician’s judgment. It should be performed at least two times per year in patients who are meeting treatment goals and have stable glucose control. It should be done four times per year in patients whose therapy has changed or those not reaching glycemic goals.
When used in a point-of-care setting, results in increased intensification of therapy and improvement in glycemic control. One may check the accuracy of the patient’s continuous glucose monitoring or meter or the reported results of blood glucose monitoring, and the sufficiency of the timing or frequency of blood glucose monitoring.
It does not measure glycemic variability or hypoglycemia. Glycemic control is best evaluated by blood glucose monitoring or continuous glucose monitoring plus HbA1c in patients with type 1 diabetes mellitus and type 2 diabetes mellitus with severe insulin deficiency. It may be affected by conditions that affect erythrocyte turnover (eg anemia, hemolysis, blood loss, blood transfusion, or hemoglobinopathy) as well as renal impairment and pregnancy.
Glycemic Goals
Glycemic goals are individualized based on the duration of diabetes mellitus, age or life expectancy, comorbid conditions, cardiovascular disease, advanced microvascular complications, hypoglycemia unawareness, and individual patient preference.
An HbA1c of <7% has been shown to reduce microvascular and neuropathic complications of diabetes mellitus and is associated with long-term reduction in macrovascular disease if implemented right after diagnosis has been made. An HbA1c of ≤6.5% may be advised in patients with diabetes mellitus of short duration, with long life expectancy, and no significant cardiovascular disease; given that this can be achieved without causing significant hypoglycemia. An HbA1c goal of <8% may be allowed in patients with a history of severe hypoglycemia, limited life expectancy, advanced micro- or macrovascular complications, extensive comorbid conditions, and to those with long-standing diabetes mellitus who did not reach their target glucose level despite treatment and appropriate monitoring.
The preprandial capillary plasma glucose goal is set at 4.4-7.2 mmol/L (80 to 130 mg/dL). Whereas the peak postprandial capillary plasma glucose goal is set at <10 mmol/L (<180 mg/dL) and is monitored 1 to 2 hours after the start of a meal. Peak postprandial capillary plasma glucose monitoring is recommended in patients with acceptable fasting plasma glucose but has HbA1c values above target. Studies have shown that Insulin regimens targeting postprandial glucose have no cardiovascular disease benefit as compared to those targeting preprandial glucose.
Severe or frequent hypoglycemia is an absolute indication for adjusting the treatment regimen which includes higher glycemic goals.
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.
Diabetes Mellitus_Follow Up 2Atherosclerotic Cardiovascular Diseases (ASCVD)
Atherosclerotic cardiovascular disease is the main cause of morbidity and mortality in diabetes mellitus patients. In the assessment of cardiovascular disease risk in patients with type 2 diabetes mellitus, several factors should be considered including medical and family history, symptoms, physical examination findings, other diagnostic test results, and the presence of atherosclerotic cardiovascular disease or severe target organ damage. Severe target organ damage is defined as an eGFR of <45 mL/min/1.73 m2 irrespective of albuminuria, or an eGFR or 45-59 mL/min/1.73 m2 and microalbuminuria (UACR 30-300 mg/g, stage A2), or proteinuria (UACR >300 mg/g, stage A3), or presence of microvascular disease in ≥3 different sites (eg microalbuminuria [stage A2] plus retinopathy plus neuropathy). However, routine screening for coronary artery diseases (CAD) among asymptomatic patients is not recommended since it does not improve outcomes if atherosclerotic cardiovascular disease risk factors are treated.
Screening for heart failure by measuring natriuretic peptide (B-type natriuretic peptide [BNP] or N-terminal pro-BNP [NT-proBNP]) should be considered in patients with diabetes to prevent stage C heart failure. Asymptomatic patients with diabetes with abnormal natriuretic peptide levels are recommended to undergo echocardiography to identify stage B heart failure (asymptomatic with evidence of structural heart disease or functional cardiac abnormalities including elevated biomarkers of myocardial strain or increased filling pressures).
Estimation of the 10-year cardiovascular disease risk using type 2 diabetes-specific 10-year cardiovascular disease score (SCORE2-Diabetes) is recommended for patients with type 2 diabetes mellitus ≥40 years old without symptomatic atherosclerotic cardiovascular disease or severe target organ damage. SCORE2-Diabetes combines information on conventional cardiovascular disease risk factors (eg age, systolic blood pressure, smoking status, total HDL-C) with diabetes-specific information (eg age at diabetes diagnosis, HbA1c, eGFR) and is able to estimate an individual's 10-year risk of fatal and non-fatal cardiovascular events (eg myocardial infarction, stroke).
Hypertension and dyslipidemia are usual conditions that coexist with type 2 diabetes mellitus which are risk factors for atherosclerotic cardiovascular disease. Cardiovascular risk factors should be assessed at least yearly in all patients with diabetes mellitus.
Cardiovascular disease risk categories in patients with diabetes according to the 2023 European Society of Cardiology (ESC) guidelines on cardiovascular disease management:
- 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.
Blood pressure should be measured routinely at every check-up. Home
blood pressure self-monitoring should be considered in patients with diabetes
and 24-hour ambulatory blood pressure monitoring should be considered for blood
pressure assessment and adjustment of antihypertensive treatment.
A systolic blood pressure (SBP) of ≥130 mmHg or diastolic blood
pressure (DBP) of ≥80 mmHg or both, obtained 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.
According to the 2024 American Diabetes
Association (ADA) guideline, the 2018 American Association of Clinical
Endocrinology (AACE) guideline, 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. According to the European Society of Cardiology (ESC)
2021 Cardiovascular Disease prevention guidelines, the recommended
individualized blood pressure targets in patients with diabetes
mellitus were set to a systolic blood pressure of 130 mmHg, or <130
mmHg but not <120 mmHg if well tolerated, or 130-139 mmHg in patients ≥70
years old. Meanwhile, the target diastolic blood pressure was set to <80
mmHg but not <70 mmHg. Individuals with diabetes mellitus with a blood
pressure of ≥150/90 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 the target blood pressure.
Combination therapy with ACE inhibitors or angiotensin II receptor blockers, plus
calcium channel blockers, or thiazide diuretics is the preferred initial
treatment for patients with diabetes mellitus and hypertension. Thiazide
diuretic should be added to the regimen in individuals with diabetes mellitus with
uncontrolled hypertension and eGFR of ≥30 mL/min/1.73 m2. Loop
diuretics should be added to the regimen of individuals with diabetes mellitus with
uncontrolled hypertension and eGFR of <30 mL/min/1.73 m2. The
addition of a mineralocorticoid receptor antagonist is considered in patients
with diabetes mellitus and resistant hypertension. For patients with diabetes
mellitus and established coronary artery disease or albuminuria, ACE inhibitors
or angiotensin II receptor blockers should be part of the regimen. Kidney
function and serum potassium levels should be monitored if ACE inhibitors,
angiotensin II receptor blockers, or diuretics are given. Increases in creatinine in response to BP-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 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 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). 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 2018 AACE, 2023 ESC,
and 2024 ADA guidelines are as follows:
- Young adults with either type 1 diabetes mellitus with an age of ≤35 years or type 2 diabetes mellitus with an age of ≤50 years, with diabetes mellitus duration of <10 years, without other risk factors: <3.0 mmol/L (<116 mg/dL)
- Patients with diabetes mellitus without target organ damage with diabetes mellitus with a duration of ≥10 years or with additional risk factor or with moderate cardiovascular risk: <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 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. The aim is to reduce urinary albumin by ≥30% in patients with chronic kidney disease and
albuminuria of ≥300 mg/g to slow chronic kidney disease 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
mellitus.
Risk of CKD Progression
| Persistent Albuminuria Categories |
|||||||
| A1 Normal to mildly increased |
A2 Moderately increased |
A3 Severely increased |
|||||
| GFR Categories | GFR (mL/min/1.73 m2) | <30 mg/g <3 mg/mmol |
30-300 mg/g 3-30 mg/mmol |
>300 mg/g >30 mg/mmol |
|||
| G1 Normal or high |
≥90 |
Low risk | Moderately increased risk | High risk | |||
| G2 Mildly decreased |
60-89 | Low risk | Moderately increased risk | High risk | |||
| G3a Mildly to moderately decreased |
45-59 | Moderately increased risk | High risk | Very high risk | |||
| G3b Moderately to severely decreased |
30-44 | High risk | Very high risk | Very high risk | |||
| G4 Severely decreased |
15-29 | Very high risk | Very high risk | Very high risk | |||
| G5 Kidney failure |
<15 | Very high risk | Very high risk | Very high risk | |||
| Reference: Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Inter Suppl. 2013 Jan;3(1):18. | |||||||
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. 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.
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). 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 nonalcoholic 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.
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.
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 an 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. Thiazolidinediones should be avoided by patients with type 2 diabetes mellitus and those with 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.