Diabetic Complications

The terms that are used to discuss the renal damage caused by DM are used interchangeably and in a way that can be confusing.

• Diabetic nephropathy refers to the structural changes and changes in renal function caused by DM (Suneja, 2021). Diabetic nephropathy causes chronic kidney disease (CKD). CKD refers to a gradual loss of kidney function (Bargman & Skorecki, 2018). There are many causes of CKD; in the US, DM is the most common cause of CKD (Bargman & Skorecki, 2018), and this pathology is called diabetic kidney disease (DKD).
• DKD can progress to end-stage renal disease (ESRD). ESRD is the stage of CKD in which renal function has declined to a point at which the patient will not survive without renal replacement therapy, such as dialysis (Bargman & Skorecki, 2018).
• Kidney failure: Kidney failure is another term for ESRD.
• Albuminuria: Large molecules like albumin do not easily pass through the glomeruli. (Maddukuri, 2022b). Diabetic nephropathy causes structural damage to the kidneys, allowing abnormally high amounts of albumin to be filtered through the glomeruli and excreted in the urine (Maddukuri, 2022b). Albuminuria is commonly used as a marker of renal damage, and it is the earliest detectable sign of DKD (McGrath & Edi, 2019).
• Albuminuria can be measured by the urinary albumin to creatinine ratio or by measuring the amount of albumin in a 24-hour urine sample (Brutsaert, 2022; Navaneethan et al., 2023). Urine albumin-creatinine ratio is preferred (Navaneethan et al., 2023). A normal urinary albumin-creatine ratio is < 30 mg, and a high level is ≥ 30 mg/g to 300 mg/g (Brutsaert, 2022; Navaneethan et al., 2023). There can be significant variation in the result of this test over any given period - a > 20% difference between measurements - so two or three specimens must be collected within three to six months to confirm that the patient has high albuminuria (ElSayed et al., 2023a).
• Estimated glomerular filtration rate (eGFR): The eGFR indirectly measures the volume of blood filtered by the kidney (Maddukuri, 2022a). The eGFR is expressed in mL per minute, and because eGFR can vary with body size, the body surface area (BSA) is used as a correcting factor; this is the m² in the test result. An eGFR of < 60 mL/min/1.72 m² is abnormal and is diagnostic for CKD (Maddukuri, 2022a; Powers et al., 2022).

The pathophysiologic mechanisms that cause DKD involve three basic factors: chronic hyperglycemia, genetics, and lifestyle factors (Guedes & Pecoits-Filho, 2022; Natarajan, 2021; Powers et al., 2022; Wu et al., 2021).

1. Chronic hyperglycemia is the most important cause of DKD. Persistently elevated blood sugar, along with lifestyle factors of hyperlipidemia, hypertension, insulin resistance, and obesity, cause an accumulation of advanced glycation end products (AGEs), inflammation, and oxidative stress (Guedes & Pecoits-Filho, 2022; Natarajan, 2021; Powers et al., 2022; Wu et al., 2021). These processes, in turn, cause damage to the kidneys and the renal vasculature. Damage is evidenced by hyperfiltration (albuminuria) and decreased eGFR (A/L B Vasanth Rao et al., 2019). Eventually, the stress the kidneys experience as they attempt to compensate for and correct the excess urinary excretion of albumin causes glomerular damage and the loss of nephrons (Barrera-Chimal et al., 2022).
2. Between 20% to 40% of patients with DM develop DKD, and a genetic predisposition to DKD is likely (Natarajan, 2021; Powers et al., 2022).
3. Advanced glycation end-products are a byproduct of glycation. Glycation is a process by which a sugar, usually glucose, becomes attached to a lipid or a protein like hemoglobin, i.e., glycated hemoglobin. Glycation in DM is caused by chronic hyperglycemia (Brownlee, 2005). Glycation is more likely to happen in specific cells and tissues like the Schwann cells of the peripheral nervous system because they are unable to handle a chronic, high glucose concentration, i.e., hyperglycemia, and glycation (and other alternative pathways) is initiated to handle the excess glucose (Brownlee, 2005; James et al., 2022). Advanced glycation end-products are a byproduct of glycation; AGEs produce reactive oxygen species (ROS), which cause oxidative stress and tissue damage in vulnerable tissues. AGEs may also increase AGE production (Rhee & Kim, 2018; Yang et al., 2019). In addition, AGEs may contribute to the development of a phenomenon called metabolic memory, a condition in which periods of hyperglycemia can continue to be a risk factor for DKD even after glycemic control is attained, possibly because AGEs accumulate and are very slowly metabolized (Aranyi & Susztak, 2019; Lee et al., 2022; Rhee & Kim, 2018.

DKD occurs in 20-40% of patients who have diabetes (ElSayed et al., 2023a). Diabetes is the most common cause of CKD (Guedes & Pecoits-Filho, 2022), and in the US, DM is the leading cause of kidney failure or ESRD (Limonte et al., 2022). In addition, CKD caused by DM significantly increases the risk of developing cardiovascular disease and mortality from cardiovascular disease (Limonte et al., 2022). The risk increases as albuminuria and reduced eGFR worsen, and DM-associated CKD increases the risk of developing peripheral vascular disease and stroke (Limonte et al., 2022).

American Indian, Asian, Black, and Hispanic Americans have a higher prevalence of DM than white Americans (Limonte et al., 2022; Ngo-Metzger, 2022; Owoyemi & Balogun, 2022). Diabetic members of these populations have a higher risk of developing DKD, and the prevalence of DKD and kidney failure is higher (Limonte et al., 2022). Diabetes and hypertension, the two primary causes of CKD, and lifestyle factors contributing to CKD are more prevalent among Black Americans (CDC, 2020; CDC, 2022a; CDC, 2022b). However, the comparatively higher risk for DKD, ESRD, and other diabetic complications in Black Americans is not fully explained by these factors (Owoyemi & Balogun, 2022).

Risk factors for DKD and all DM microvascular complications are considered modifiable or non-modifiable (Pelle et al., 2022).

Modifiable risk factors for DKD include cigarette smoking, hyperglycemia, hyperlipidemia, hypertension, and obesity (Guedes & Pecoits-Filho, 2022; Pelle et al., 2022). Non-modifiable risk factors include age, genetic susceptibility, ethnicity, and male gender (Pelle et al., 2022).

Gender differences that may affect the risk of developing DKD are still being researched. Giandalia et al. (2021) wrote that although the available information is still inconclusive, the overall epidemiological data indicate that the risk of developing DKD is higher in men with DM, who also have a higher risk of DKD progression (Giandalia et al., 2021).

Modifiable risk factors are very common in people with diabetes (CDC, 2022b). For example, it has been estimated that in US adults aged 18 years or older diagnosed with diabetes, 13.8% smoked cigarettes, 69.0% had hypertension, 89.8% were overweight or obese, and 49.4% had a glycated hemoglobin or A1C level ≥ 7.0 (CDC, 2022b).

Note: Hypertension can help cause diabetic nephropathy, and diabetic nephropathy can cause hypertension.

The American Diabetes Association recommends that at least once a year:

1. Patients who have had T1DM for ≥ five years should have a measurement of urinary albumin-creatinine ratio and eGFR (ElSayed et al. 2023a).
2. All patients with T2DM should have a urinary albumin-creatinine ratio and eGFR measurement, regardless of the treatment they receive (ElSayed et al., 2023a).

DKD disease is a clinical diagnosis based on the following:

1. albuminuria and an abnormally low eGFR and
2. the absence of signs and symptoms of other causes of kidney disease that can cause renal damage (ElSayed et al., 2023a).

The albuminuria and the low eGFR are persistent, and the albuminuria is 30 mg to 300 mg albumin per g of creatine, and eGFR is <60 mL/min/1.73 m²(Brutsaert, 2022; Maddukuri, 2022b; Selby & Taal, 2020; Suneja, 2021). The albumin level and the eGFR are used to diagnose DKD, and they are also used to help guide treatment decisions (ElSayed et al., 2023a).

Diabetic nephropathy causes structural damage to the glomeruli, resulting in hyperfiltration and reduced blood flow through the glomeruli (A/L B Vasanth Rao et al., 2019). Hyperfiltration is detected and measured by comparing the amount of urinary albumin to the amount of urinary creatinine. Reduced blood flow is detected and measured by the eGFR.

Treatment of DKD is intended to slow and hopefully stop the progression of the disease, and treatment of DKD includes glycemic control, blood pressure control, and nutritional modifications. Regarding the prevention of DKD, exercise, lipid control, weight loss, and smoking cessation can help prevent diabetic complications, but the “. . . only proven primary prevention interventions for CKD are blood glucose and blood pressure control” (ElSayed et al. 2023a).

The pharmacological treatment of DKD for glycemic control is discussed in the next section.

• Glycemic control: Intensive glucose control and attaining near-normoglycemia has been shown to delay the onset and progression of albuminuria and decrease eGFR (Agrawal et al., 2018; ElSayed et al., 2023a). For patients who have DM, the recommended A1C level is < 7% (ElSayed et al., 2023c). However, CKD changes the benefits and risks of intensive glucose control, increasing the risk of adverse effects. It can take at least two years in T1DM patients and more than ten years in T2DM patients to see the renal benefits of intensive glucose control (ElSayed et al., 2023a). Given those factors, an A1C of < 8% may be appropriate for a diabetic patient with CKD (ElSayed et al., 2023a; ElSayed et al., 2023c).
• Blood pressure control: The American Diabetes Association Professional Practice Committee recommends optimizing blood pressure control and minimizing blood pressure variability to reduce the risk of CKD and/or slow its progression (ElSayed et al., 2023a). Antihypertensives have been shown to reduce the risk of albuminuria. In patients with an eGFR <60 mL/min/1.73 m² and a urinary albumin/creatinine ratio ≥300, antihypertensive therapy can reduce the risk of the progression of CKD to ESRD. (ElSayed et al., 2023a). The target blood pressure level for diabetic patients is < 130/80 mm; a lower level can be considered if the patient has CKD (ElSayed et al., 2023a).
• Nutrition: Patients with DKD who are not dialysis-dependent should restrict their protein intake to approximately 0.8 grams/kg/day (ElSayed et al., 2023a). Compared to higher amounts, a protein intake of 0.8 g/kg/day has been associated with a slower decline in eGFR. A protein intake >20% of the daily caloric intake has been associated with increased albuminuria and an increased rate of decline of kidney function (ElSayed et al., 2023a; Yue et al., 2020). A low-protein diet is considered protective/therapeutic by reducing glomerular hyperfiltration, one of the pathophysiologic mechanisms that cause glomerular injury (Schrauben et al., 2022). Restricting dietary sodium to < 2300 mg/day can help control hypertension. For patients with DKD and a low eGFR, renal excretion of sodium can be impaired, so a sodium-restricted diet may be advisable (ElSayed et al., 2023a). A sodium-restricted diet may also decrease albuminuria (Schrauben et al., 2022).

Two classes of antidiabetic medications are used for glycemic control and have been shown to decrease the progression of CKD (ElSayed et al., 2023b). Sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1-RAs) lower blood glucose, slow CKD progression, and prevent cardiovascular complications caused by DM and CKD.

• SGLT2 inhibitors: SGLT2 is a protein that increases glucose reabsorption from the renal tubules, and SGLT2 accounts for approximately 90% of reabsorbed glucose (Katzung et al., 2021). The SGLT2 inhibitors, canagliflozin, dapagliflozin, empagliflozin, and ertugliflozin, increase the urinary excretion of glucose and lower plasma glucose (Katzung et al., 2021). These drugs are labeled for treating T2DM,  and canagliflozin and dapagliflozin are labeled for treating CKD to reduce the risk of sustained decrease in eGFR and ESRD. The SGLT2 inhibitors have been shown to slow the progression of CKD, reduce the risk of kidney failure, and they can provide significant cardiovascular benefits in patients who have T2DM (ElSayed et al., 2023a; ElSayed et al., 2023b; Limonte et al., 2022; Navaneethan et al., 2023).
• GLP-1-RAs: These are analogs of the incretin hormone glucagon-like-peptide-1 (GLP-1). GLP-1 decreases blood glucose by decreasing glucagon secretion and increasing insulin secretion (Powers & D’ Alessio, 2017). The GLP-1-RAs, dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide, are injectable antidiabetics with a labeled use for treating T2DM. The 2022 Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend GLP-1-RAs as a second-line treatment for glucose control in patients who have T2DM and CKD (Navaneethan et al., 2023). The GLP-1-RAs reduce the risk of cardiovascular complications in this patient population (ElSayed et al., 2023c; Limonte et al., 2022; Tong & Adler, 2022), and there is good, albeit inconclusive, evidence that the GLP-1-RAs can slow the progression of DKD (ElSayed et al., 2023a; Navaneethan et al., 2023; Tong & Adler, 2022).

Angiotensin-converting-enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) are the first-line treatment for diabetic patients who have hypertension, an eGFR <60 mL/min/1.73 m², and a urinary albumin/creatinine ratio  ≥300 mg/g (ElSayed et al., 2023a). The ACEs and the ARBs can prevent the progression of CKD, and they seem equally effective at doing so (ElSayed et al., 2023d). The American Diabetes Association Standard of Care recommends that in nonpregnant patients with diabetes and hypertension, either an ACE inhibitor or an ARB is recommended for those with modestly elevated urinary albumin-to-creatinine ratio (30–299 mg/g creatinine) and is strongly recommended for those with urinary albumin-to-creatinine ratio ≥ 300 mg/g creatinine and/or an eGFR <60 mL/min/1.73 m²” (ElSayed et al., 2023a).

Metformin is the first-line drug for patients who have T2DM. Metformin is mostly excreted (90%) in the urine, and decreased renal function decreases renal clearance of the drug and increases peak and systemic exposure to metformin. In addition, renal impairment increases the risk of developing lactic acidosis, a potentially deadly adverse effect of metformin (Bosse, 2019). Metformin can be safely used for diabetic patients with DKD (Boddepalli et al., 2022; ElSayed et al., 2023a), but to avoid putting patients at risk, these recommendations below must be followed(Boddepalli et al., 2022; ElSayed et al., 2023a).

1. Metformin is contraindicated if the patient’s eGFR is <30 mL/min/1.73 m².
2. The eGFR should be monitored during treatment with metformin. The eGFR, not serum creatinine, should guide treatment with metformin.
3. If the patient’s eGFR becomes <45 mL/min/1.73 m², clinicians should consider the benefits and risks of continuing the use of metformin.
4. Treatment with metformin should not be initiated if a patient’s eGFR is <45 mL/min/1.73 m².
5. If a patient’s eGFR is 30 to 60 mL/min/1.73 m², the use of metformin should be temporarily stopped before or at the time of the use of iodinated contrast dye.

There are interventions and lifestyle changes that can help prevent the progression of DKD, which will be discussed in a separate section.

The only interventions proven to prevent the development of DKD are glucose control and blood pressure control (ElSayed et al., 2023a). “There is no evidence that renin-angiotensin-aldosterone system (RAAS) inhibitors or any other interventions prevent the development” of DKD (ElSayed et al., 2023a)

A patient who has DKD should be closely monitored for changes in serum potassium, the dose of medications that need to be adjusted according to a patient’s eGFR should be periodically checked, nephrotoxic drugs should be avoided, and urinary albumin excretion and eGFR should periodically be measured (ElSayed et al., 2023a). In addition, these patients should be monitored for complications of CKD, such as anemia, electrolyte abnormalities, hypertension, metabolic acidosis, metabolic bone disease, and volume overload (ElSayed et al., 2023a).

DSPN is considered the most common chronic complication of T1DM and T2DM (Ang et al., 2022). The lifetime prevalence of DSPN has been estimated to be > 50% (Ang et al., 2022), and because 20% to 50% of patients who have DSPN do not have pain or other symptoms, the prevalence is likely higher (Ang et al., 2022; Powers et al., 2022). Distal symmetrical polyneuropathy appears to be more common in patients who have T2DM (Ang et al., 2022).

Note: Distal symmetrical polyneuropathy is sometimes referred to as diabetic peripheral neuropathy or DPN; however, DSPN is the preferred term.

Three primary causes of DSPN initiate and sustain the mechanisms of injury by which DSPN affect the peripheral nerves and include elevated glucose, changes in insulin signaling, and dyslipidemia (Ang et al., 2022; James et al., 2022). These three factors cause multiple pathologic processes, including (but not limited to) decreased blood flow to the nerves and ischemic stress, inflammation, oxidative stress, changes in cell function, and DNA damage (Ang et al., 2022; Fan & Gordon Smith, 2022). Ang et al. (2022) wrote: “The most common form of nerve injury is a progressive distal-to-proximal peripheral nerve loss that typically presents as sensory predominant.” As with other diabetic microvascular complications, the nerves are “. . . susceptible to hyperglycemia due to their shared inability to balance intracellular glucose levels, resulting in diabetic neuropathy” (James et al., 2022; Smith et al., 2022a).

The American Diabetes Association defines DSPN as “. . . the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes.” (Pop-Busui et al., 2017).

Approximately 30% to 50% of patients who have DSPN are asymptomatic (Ang et al., 2022; Powers et al., 2022), and DSPN is often diagnosed many years after its onset when irreversible sensory damage has already occurred (James et al., 2022).

Sensory symptoms typically start first. Common signs and symptoms of DSPN include burning, decreased perception of temperature, numbness, pain, and tingling, usually bilateral and beginning in the feet and spreading proximally, moving up to the level of the calves and sometimes affecting the hands((ElSayed et al., 2023e; Pop-Busui et al., 2017; Powers et al., 2022; Smith et al., 2022a). The symptoms usually worsen at night (Pop-Busui et al., 2017). Some patients complain of hyperalgesia, an increased/exaggerated response to pain, and allodynia, pain caused by innocuous stimuli like putting on shoes or socks (Pop-Busui et al., 2017). Pain caused by DSPN can range from mild to very intense.

A physical examination usually reveals a decreased perception of vibration and temperature. The patient may have foot drop and muscular atrophy, unsteady gait, and the ankle deep-tendon reflexes may be absent (Powers et al., 2022; Smith et al., 2022b). The signs and symptoms of DSPN are considered chronic when they have been present for greater than three to six months (Bönhof et al., 2019).

The American Diabetes Association recommends that everyone who has T2DM should be screened for the presence of DSPN when the diagnosis is made, and everyone who has T1DM should be screened for DSPN five years after the diagnosis is made; after the initial screening, annual screening should be done for both groups (ElSayed et al., 2023e). Screening for DSPN is very important: “Up to 50% of diabetic peripheral neuropathy may be asymptomatic. If not recognized and preventive foot care is not implemented, people with diabetes are at risk for injuries and diabetic foot ulcers and amputations”(ElSayed et al., 2023e).

Everyone who has DM should be screened with a 10-g monofilament test once a year to determine if their feet are at risk for diabetic foot ulcers (DFU) and/or amputation (ElSayed et al., 2023e).

DSPN is a clinical diagnosis and a diagnosis of exclusion (Pop-Busui et al., 2017). The criteria for the diagnosis include the following:

1. The presence of signs and symptoms that are typical for DSPN
2. Characteristic findings during the physical examination (Po-Busui et al., 2017)

The American Diabetes Association states that a combination of typical symptomatology and symmetrical distal sensory loss or typical signs in the absence of symptoms in a patient with diabetes is highly suggestive of DSPN and may not require additional evaluation or referral. A diagnosis may only be made on examination or, in some cases, when the patient presents with a painless foot ulcer (Pop-Busui et al., 2017).

Physical examination may include the following:

• Ankle reflex: Absent or reduced
• Balance difficulties
• Pinprick sensation: Absent or reduced
• Proprioception: Absent or reduced
• Thermal discrimination: Absent or reduced
• Vibration perception: Absent or reduced
• 10 g monofilament: Absent or reduced. In the 10 g monofilament test, the clinician lightly brushes the soles of a patient’s feet with a very light, thin nylon strand to determine the patient’s sensitivity to touch. 

Symptoms may include burning, electric shock sensations, loss of balance, numbness, pain, stabbing sensation, and tingling.

If a patient has signs and symptoms of DSPN, but the clinician is unsure if DSPN is the cause, a consultation with a neurologist and nerve conduction studies can be done (Mishriky et al., 2022).

Factors that increase the risk of developing DSPN are listed in Table 1.

The importance of these risk factors in the progression to DSPN differs between T1DM and T2DM (Gibbons, 2020). For patients who have T1DM, hyperglycemia is the primary factor in DSPN development and progression. For patients who have T2DM, the risk factors for disease development and progression are hyperlipidemia, hyperglycemia, hypertension, insulin resistance, smoking, and body weight (Fan & Gordon Smith, 2022; Gibbons, 2020). In addition, research suggests that metabolic syndrome and obesity by themselves, independent of a patient’s level of glucose control, increase the risk of developing DSPN (Fan & Gordon Smith, 2022).

DFU is a very common and potentially dangerous complication of diabetic peripheral neuropathy. Charcot neuroarthropathy can also occur but is much less common than DFU.

Note: A discussion of the assessment and grading of DFU and the treatment of DFU would be long, complex, and beyond the scope of this module.

• Glycemic control: Glycemic control can prevent the occurrence of DSPN and slow its progression in patients with T1DM (Fan & Gordon Smith, 2022), but it is uncertain if glycemic control provides these benefits for T2DM patients. However, glycemic control is a cornerstone of DM treatment. Regarding its benefits for T2DM patients and the development of DSPN, Pop-Busui et al. (2022) wrote: “Although there has not been, nor will there ever be, a randomized trial to test the hypothesis, an early step in the management of painful DPN should be to achieve optimal and stable glycemic control.”
• Exercise: There is no conclusive evidence that exercise can prevent or slow the progression of DSPN (Pop-Busui et al., 2022).
• Hyperlipidemia correction and weight loss: Hyperlipidemia is a significant risk factor for DSPN, especially in patients who have T2DM (James et al., 2022), and obesity is a significant risk factor for the development of DSPN. When needed, weight loss and correcting hyperlipidemia are basic interventions for people with DM, and there is evidence (limited) that they may help prevent and/or reduce the progression of DSPN (ElSayed et al., 2023e; Look Ahead Research Group, 2017).
• Diet: A healthy diet has benefits like glycemic control, anti-inflammatory effects, and the prevention of dyslipidemia. There is no evidence that a specific diet or dietary interventions can prevent or slow the progression of DSPN (ElSayed et al., 2023e; Pop-Busui et al., 2022), “. . . but eating pattern modifications may prove effective as part of a more comprehensive lifestyle treatment regimen” (Pop-Busui et al., 2022).
• Hypertension: Hypertension appears to be one of the most important modifiable risk factors for developing diabetic neuropathy, especially DSPN (Bashir et al., 2021; Sethi et al., 2022). Blood pressure control can aid in preventing the progression of DSPN in T2DM and may reduce disease progression in T2DM (ElSayed et al., 2023e).

Three medications are FDA-approved as a treatment for painful diabetic peripheral neuropathy and include duloxetine (Cymbalta®), pregabalin (Lyrica®), and tapentadol (Nucynta®). 

• Duloxetine: Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI), and duloxetine, alone or in combination with pregabalin, is effective at relieving neuropathic pain (James et al., 2022; Pop-Busui et al., 2022). Adverse effects of duloxetine include (but are not limited to) dizziness, nausea, and somnolence (James et al., 2022).
• Pregabalin: Pregabalin and gabapentin (Neurontin®) are γ-aminobutyric acid (GABA) analogs. GABA is a major inhibitory neurotransmitter. Pregabalin has FDA approval as a treatment for painful diabetic peripheral neuropathy, but gabapentin does not. Still, GABA analogs are the first-choice medications for this application (James et al., 2022), effectively relieving diabetic neuropathic pain. The drugs are almost exclusively excreted unchanged in the urine, so the dose must be lowered in patients with abnormally low eGFR.
• Tapentadol: Tapentadol is an opioid analgesic. Tapentadol binds to mu-opioid receptors in the CNS and inhibits norepinephrine reuptake (Collegium Pharmaceutical, Inc., 2019; Pop-Busui et al., 2022). Tapentadol has limited effectiveness in treating painful diabetic neuropathy (James et al., 2022; Pop-Busui et al., 2022), it has abuse and addiction potential, and its adverse effects, e.g., reduced GI motility and sedation, can be harmful to elderly patients (James et al., 2022; Pop-Busui et al., 2022).

Other medications that are used successfully to treat painful peripheral neuropathy include the SNRI venlafaxine (Effexor®), tricyclic antidepressants (TCAs) like amitriptyline, other opioids, and topical therapy with capsaicin or lidocaine cream (James et al., 2022; Pop-Busui et al., 2022).

These medications can be effective, but they have limitations.

1. The TCAs must be used cautiously if a patient has ischemic heart disease and other medical conditions like glaucoma. They cause unpleasant adverse effects like blurred vision, dry mouth, sedation, and urinary retention (Pop-Busui et al., 2022).
2. The disadvantages of opioids include abuse potential.
3. Topical therapies have limited usefulness because a large BSA may be painful, and capsaicin cream needs to be applied multiple times a day (Pop-Busui et al., 2022). In addition, repeated use of capsaicin cream can desensitize the skin, a potentially dangerous adverse for patients at risk for DFU (James et al., 2022). An 8% long-acting capsaicin patch is available. It has FDA approval as a treatment for painful diabetic neuropathy of the feet. Unlike capsaicin cream, which needs to be applied four times a day, the capsaicin patch (Qutenza®) is applied once every three months or longer.

Nutraceutical is an informal term, a combination of nutrition and pharmaceuticals. Nutraceutical was initially defined as a dietary supplement or food that can prevent or treat disease (Aronson, 2017), and many dietary supplements, including (but not limited to) alpha-lipoic acid, vitamin B compounds, and other vitamins, have been used to try and prevent or treat DSPN (Pop-Busui et al., 2022).

Diabetic autonomic neuropathy is a common complication of DM, and in the US, DM is the most common cause of autonomic neuropathy (Pop-Busui et al., 2018). The incidence and prevalence of diabetic autonomic neuropathy are difficult to determine because:

1. there are at least seven sub-types of this disorder,
2. most of the published literature is about cardiovascular autonomic neuropathy, and
3. many cases of diabetic autonomic neuropathy are initially subclinical, and the onset of symptoms is often significantly delayed (Verrotti et al., 2014).

However, for some of the sub-types, there is good documentation. For example, the prevalence of autonomic disorders in DM increases with the age of the patient (Lamotte & Sandroni, 2022), and 35% of patients who have T1DM and 65% of patients who have T2DM for > 20 years will have cardiovascular autonomic neuropathy (Pop-Busui et al., 2018). Diabetic autonomic neuropathy can be present alone, or a patient can have other diabetic neuropathies (Agochukwu-Mmonu et al., 2020; Lamotte & Sandroni, 2022), and > 50% of patients who have DSPN will develop CAN (Sudo et al., 2022). Symptoms of genitourinary dysfunction caused by diabetic neuropathy can affect as many as 50% of all patients with DM (Sharma et al., 2020).

The pathophysiologic mechanisms that cause diabetic autonomic neuropathy are the same as those that cause DSPN (Sharma et al., 2020; Sudo et al., 2022; Williams et al., 2022), i.e., oxidative stress, inflammation, and accumulation of AGEs. These pathophysiologic processes damage the parasympathetic and sympathetic branches of the autonomic nervous system, disrupting the normal balance between them and affecting the involuntary central nervous control of the cardiovascular, gastrointestinal, and genitourinary systems tract, and other organ systems (Lamotte & Sandroni, 2022).

Cardiovascular autonomic neuropathy is caused by damage to the autonomic nerve fibers that innervate the heart and vasculature (Duque et al., 2021), resulting in an imbalance of parasympathetic and sympathetic tone and impaired autonomic control of the cardiovascular system (Duque et al., 2021; Sudo et al., 2022; Williams et al., 2022). The pathophysiologic mechanisms that cause cardiovascular autonomic neuropathy are the same as those that cause DSPN (Duque et al., 2021; Sharma et al., 2020; Sudo et al., 2022; Williams et al., 2022).

Gastric: Diabetic gastrointestinal autonomic neuropathy is characterized by constipation or diarrhea, dysphagia, fecal incontinence, nausea, reflux, and vomiting.

Genitourinary: Genitourinary autonomic neuropathy is characterized by male and female sexual dysfunction and urinary dysfunction, e.g., neurogenic bladder (Agochukwu-Mmonu et al., 2020; Pop-Busui et al., 2017).

Sudomotor dysfunction: Sudomotor refers to the autonomic nerves that stimulate the production of sweat and perspiration (Cheshire, 2020). DM is the most common cause of autonomic sudomotor dysfunction (Cheshire, 2020), and this diabetic complication is characterized by anhidrosis, hypohidrosis (Pop-Busui et al., 2017), dry skin, and skin fissures (Shivaprasad et al., 2018).

The prevalence of diabetic retinopathy in patients with T1DM has been estimated to be > 33% (Bebu et al., 2023; Surowiec et al., 2022). The prevalence of diabetic retinopathy in patients who have T2DM has been estimated to be 13.1% (Cai et al., 2023). It should be noted that these are estimates, and Drinkwater et al. (2022) noted that recent (2018 to 2021) estimates of the prevalence of diabetic retinopathy have varied significantly, from 5% to 40%. The risk of developing diabetic retinopathy increases with age (Cai et al., 2023).

The pathophysiology of diabetic retinopathy is, like the other DM microvascular complications, very complex (Whitehead et al. 2018), and it involves multiple pathophysiological processes that cause inflammation, oxidative stress, and mitochondrial dysfunction that damage the retinal vasculature (Cai et al., 2023; Whitehead et al., 2018). The primary driver of diabetic retinopathy is chronic hyperglycemia (Powers et al., 2022; Whitehead et al., 2018).

The onset of diabetic retinopathy in patients who have T1DM  has been estimated to be at least five years after hyperglycemia has begun (ElSayed et al., 2023e). The onset of diabetic retinopathy in patients with T2DM is likely to be much later (Cai et al., 2023), as many patients with T2DM  have asymptomatic hyperglycemia late after the onset of the disease (ElSayed et al., 2023f).

Diabetic retinopathy can present with many ocular pathologies and is categorized into two stages, non-proliferative and proliferative (Mehta, 2022; Powers et al., 2022).

• Non-proliferative: Non-proliferative diabetic retinopathy develops first (Mehta, 2022), and it typically begins late in the first decade or early in the second decade of hyperglycemia (Powers et al., 2022). Non-proliferative diabetic retinopathy is characterized by retinal ischemia (Mehta, 2022; Powers et al., 2022), and if the patient has symptoms - and they may not (Drinkwater et al., 2022; Mehta, 2022) - the symptoms are mild and non-specific and/or can easily be ignored like blurred vision, difficulty reading, or difficulty seeing far away objects (Mondal et al., 2022). Non-proliferative diabetic retinopathy moves slowly from the mild to moderate stage of the disease, and the patient is usually asymptomatic during this time (Marques et al., 2023). However, the progression of non-proliferative diabetic retinopathy and the development of serious complications varies significantly from patient to patient (Marques et al., 2021). Some patients never develop the second stage of diabetic retinopathy (Powers et al., 2022). The more severe non-proliferative diabetic retinopathy is, the more likely it is to progress (Powers et al., 2022). Intraocularly, this stage of diabetic retinopathy is characterized by exudates, microaneurysms, and retinal hemorrhages (Mehta, 2022). Macular edema (discussed below) can develop during the non-proliferative phase (Al Zabadi et al., 2022; Mehta, 2022). Note: An exudate is a fluid that leaks from a blood vessel into the tissue.
• Proliferative: Proliferative diabetic retinopathy is characterized by neovascularization, i.e., the formation of new blood vessels (Mehta, 2022; Powers et al., 2022), and these blood vessels can rupture, causing hemorrhages and retinal detachment (Powers et al., 2022). Symptoms of proliferative diabetic retinopathy include (but are not limited to) blurred vision, floaters, and sudden vision loss (Mehta, 2022).
• Macular edema: Diabetic maculopathy, or diabetic macular edema (DME), is an accumulation of fluid in the retina (Sorour et al., 2023). DME can occur in both stages of diabetic retinopathy (Mehta, 2022; Powers et al., 2022). It is one of the leading causes of vision loss in people with diabetic retinopathy (Sorour et al., 2023). Note: The macula is the section of the retina that is responsible for central vision (seeing objects in the direct foreground), color vision, and seeing small details in the visual field.

Factors that increase the risk of developing diabetic retinopathy include chronic hyperglycemia, hyperlipidemia, a high mean A1C, a high urinary albumin-creatinine ratio, hypertension, the duration of diabetic retinopathy (longer duration increases the risk), and nephropathy (Chou et al., 2020; Drinkwater et al., 2022; ElSayed et al., 2023e; Mehta, 2022; Powers et al., 2022; Whitehead et al., 2018). Factors that may increase the risk of diabetic retinopathy progressing include an elevated A1C, elevated systolic blood pressure, and total cholesterol (Tarasewicz et al., 2023).

These recommendations for diabetic retinopathy screening are from the American Diabetes Association.

• Adults with T1DM should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within five years after the onset of diabetes.
• People with T2DM should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist at the time of the diabetes diagnosis.
• If there is no evidence of diabetic retinopathy for one or more annual eye exams and glycemia is well controlled, screening every 1–2 years may be considered. If any diabetic retinopathy is present, an ophthalmologist or optometrist should repeat subsequent dilated retinal examinations at least annually. If retinopathy is progressing or sight-threatening, examinations will be required more frequently.
• Programs that use retinal photography (with remote reading or a validated assessment tool) to improve access to diabetic retinopathy screening can be appropriate strategies for diabetic retinopathy. Such programs must provide pathways for timely referral for a comprehensive eye examination when indicated (ElSayed et al., 2023e).

Powers et al. (2022) wrote: “Most diabetic eye disease can be successfully treated if detected early. Routine, nondilated eye examinations by the primary care provider or diabetes specialist are inadequate to detect diabetic eye disease, which requires a dilated eye exam performed by an optometrist or ophthalmologist, and subsequent management by a retinal specialist.”

Aggressive and early control of hyperglycemia has been proven to prevent, delay the onset, and slow the progression of diabetic retinopathy(ElSayed et al., 2023e; Powers et al., 2022; Surowiec et al., 2022). Glycemic control can also decrease the need for ocular surgeries and may improve patient-reported visual function (ElSayed et al., 2023e). Blood pressure control can also help delay the development of diabetic retinopathy and slow its progression (Powers et al., 2022).

Hyperlipidemia (elevated low-density lipoprotein cholesterol [LDL-C], low high-density lipoprotein cholesterol [HDL-C], and very-low-density lipoprotein cholesterol [VLDL-C]) has been identified as a risk factor for developing diabetic retinopathy (Bryl et al., 2022; Chou et al., 2020). Treatment of hyperlipidemia with a statin and fenofibrate has been shown to reduce the incidence and progression of diabetic retinopathy (Bryl et al., 2022; Chou et al., 2020). Bryl et al. (2022) wrote that the relationship between lipids and diabetic retinopathy is not entirely understood, but “. . . lipid-reducing therapies can be considered one of the potential therapeutic agents with a beneficial effect on the course of diabetic retinopathy.”

Choosing a treatment, or treatments, for a patient who has diabetic retinopathy depends on what type the patient has, the presence of complications, risk factors for progression, and a patient’s signs and symptoms.

The four commonly used and effective therapies for treating diabetic retinopathy and macular edema are intravitreal anti-vascular endothelial growth factor (VEGF) inhibitor drugs, laser photocoagulation, intravitreal glucocorticoids, and vitrectomy. These can be used alone or as adjuncts to each other. The choice of treatment depends on the type of diabetic retinopathy, the severity of the disease, and whether there is macular damage.

1. Vascular endothelial growth factor inhibitors: VEGF is a protein that stimulates angiogenesis, the growth of new blood vessels. Production of VEGF increases when the retinal tissues are hypoxic, and the new blood vessels that are formed cause edema, increase capillary permeability, and can rupture. Excess VEGF production is a crucial part of the pathogenesis of diabetic retinopathy and DME (Zhang et al., 2022). Intra-ocular injections of VEGF inhibitors, also known as anti-VEGFs, are the first-choice medication for treating DME because of their effectiveness and the relative convenience and ease of the treatment protocols (Lundeen et al., 2022; Sun & Jampol, 2019; Sun & Qi, 2023; Wirkkala et al., 2022; Zhang et al., 2022).
   • Two VEGF inhibitors have FDA approval for treating diabetic retinopathy and DME: Aflibercept (Eylea®) and ranibizumab (Lucentis®). Bevacizumab (Avastin®) is a VEGF inhibitor used to treat DME; however, this is an off-label use of this drug (Sun & Qi, 2023; Sun et al., 2022).
   • VEGF inhibitors are very effective for treating DME, but approximately 30% to 50% of patients do not respond well to a VEGF inhibitor (Sun & Jampol, 2019; Zhang et al., 2022). Treatment with VEGF inhibitors is a long-term therapy (Cao et al., 2023), a challenging prospect for many patients. Common adverse effects include pain, conjunctival hemorrhage, increased intraocular pressure, and floaters (Regeneron, 2022; Genentech, 2018).
   • Note: A floater is a dark spot in the visual field that moves when a patient tries to focus on it. Floaters are often caused by age-related changes in the vitreous humor, and they are also caused by retinal detachment or an intraocular hemorrhage. 
2.  Laser photocoagulation: Laser photocoagulation, also known as pan-retinal photocoagulation, can be used alone or in combination with a VEGF inhibitor. The therapeutic mechanisms of laser photocoagulation are complex. They include increased oxygenation of ischemic areas and improved blood flow to the macula (Hoshiyama et al., 2022). It is a painless and effective treatment for proliferative diabetic retinopathy and DME (Everett & Paulus, 2021; Lundeen et al., 2022; Sun & Qi, 2023). VEGF inhibitor injection treatment involves multiple injections over time. Failure to complete the therapy protocol can have serious adverse effects (Everett & Paulus, 2021), and laser photocoagulation therapy is less lengthy and involved, a significant advantage (Everett & Paulus, 2021). Some complications of laser photocoagulation include sub-retinal and vitreous bleeding, retinal detachment, retinal traction, and visual field defects (Pande & Tidake, 2022).
3. Intravitreal glucocorticoids: Intravitreal injections and implants of glucocorticoids like dexamethasone, fluocinolone acetonide, and triamcinolone acetonide are effective treatments for DME (Gao et al., 2021; Lin et al., 2022;  ), and they are a reasonable option for patients who have not responded to VEGF inhibitor therapy (Gao et al., 2021; Lin et al., 2022). Intravitreal injections and implants can increase intraocular pressure and/or glaucoma (Gao et al., 2021).
4. Vitrectomy: Vitrectomy is done by removing the vitreous humor and replacing it with another fluid/solution. Vitrectomy is used if a patient has serious DME with persistent vitreal hemorrhage, vitreomacular traction (Fraser et al., 2023; Mehta, 2022) and if the patient has not responded to VEGF inhibitors and/or laser photocoagulation treatments (Fraser et al., 2023). Complications of vitrectomy include recurrence of DME, retinal detachment, neovascular glaucoma, and vitreous hemorrhage (Liao et al., 2020; Nawrocka & Nawrocki, 2022).
   • Note: Vitreomacular traction is a condition in which the vitreous cortex, the membranous shell that encapsulates and contains the vitreous humor, pulls away from the retina, causing a force (traction) that can damage the macula.