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BACKGROUND

Diabetes is a growing global health concern that affects all age groups and genders. Analysts predict a worldwide prevalence of 552 million people with diabetes by 2030.¹ According to the 2017 National Diabetes Statistics Report there are an estimated 30.3 million individuals with diabetes in the United States (U.S.), which approximates 9.4% of the population. Of these people, 8.1 million (27.8%) are undiagnosed.² This increased diabetes prevalence is attributed, in part, to an aging population with increased obesity.³

The damaging effects of hyperglycemia on the vasculature contribute to diabetes complications and comorbidities and between 30% and 50% of all people with diabetes have some organ damage, which can potentially progress to long-term complications.⁴ Studies show that two or more complications are diagnosed in almost one-fifth of people with diabetes.⁴ Life expectancy is also shorter for the diabetes community. For example, in the United Kingdom Prospective Diabetes Study (UKPDS) Outcomes Model, men with diabetes aged 55 years were predicted to live 3.6 to 11.5 years less than their age-matched peers.⁵

In addition to the societal and humanistic effects, the management of diabetes and its complications has substantial economic impact. The estimated total direct and indirect cost of diabetes in 2012 in the U.S. is $245 billion.² If diabetes is undetected or its complications are poorly managed, patients can experience a poor health-related quality of life (QoL) with significant morbidity and mortality, so optimal prevention and treatment strategies are necessary. Therefore, the purpose of this activity is to provide an overview of the complications and comorbidities affecting those with diabetes and describe some of the proposed treatment options.

COMPLICATIONS OF DIABETES: MICROVASCULAR VERSUS MACROVASCULAR

Patients with either type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D) are at potential risk for long-term microvascular and/or macrovascular complications. Those at greatest risk are patients whose diabetes is uncontrolled.⁶ Microvascular diseases occur in small blood vessel tissues, such as the kidney, the retina of the eyes, and the nerves, where exposure to glucose correlates closely with plasma glucose levels. The resulting complications include nephropathy, retinopathy, and neuropathy.⁶

Diabetic retinopathy (DR) is one of the most common microvascular complications and the leading cause of vision loss among patients with diabetes.^6,7 DR is the most common cause of new cases of blindness among adults aged 20-74 years in developed countries.⁸ A mechanism postulated for the development of DR is the conversion of glucose to sorbitol by the enzyme aldose reductase. Hyperglycemia increases the uptake of glucose molecules via the sorbitol pathway, which accumulate in the cells and result in osmotic stress, microaneurysm formation, thickening of the basement membrane, and pericyte loss.⁶ In addition, vascular endothelial growth factor (VEGF) production increases in response to hypoxia.⁶ VEGF normally creates new blood vessels, but it can overexpress and lead to disease and increased oxidative stress. Because oxidative stress plays a role in cell injury from hyperglycemia, suppression of VEGF has been shown to reduce the progression of retinopathy.⁶

DR can be divided into nonproliferative (NPDR) and proliferative diabetic retinopathy (PDR), which is a progression of NPDR.⁷ DR risk factors include poor glycemic control and long-standing disease.^7,9 NPDR involves the development of microaneurysms, venous loops, retinal hemorrhages, and hard and soft exudates, while PDR involves neovascularization or the development of new blood vessels on the retinal surface with or without vitreous hemorrhage.^6,9 According to the Centers for Disease Control and Prevention (CDC), from 2005 to 2008, there were 4.2 million (28.5%) patients with DR aged 40 years and older in the U.S.² Without therapeutic intervention, blindness can occur, so it is incumbent on the health care provider to stress the importance of good blood glucose control to the patient as a method of helping to delay or prevent diabetes complications.^6,9

Another microvascular complication is diabetic neuropathy (DN), which is a group of conditions that involves nerve damage.⁹ The pathophysiology of neuropathy is complex and unclear. Dyslipidemia, hyperglycemia, insulin resistance, and growth factors are associated with nerve glycation. Excess glucose interacts with reactive oxygen species, proteins, and lipids to form free radical byproducts that contribute to oxidative stress. This oxidative stress creates inflammation in the nerves. The polyol pathway also assists in the metabolic processes to promote intracellular variability and deterioration.^9-11 DN is classified according to the affected nerves such as peripheral, proximal, focal, or autonomic.⁹ Age, height, metabolic control, duration of diabetes, and/or a presence of nephropathy or retinopathy are potential risk factors that have been correlated with the presence of DN in clinical studies.^10,11 Most patients that present with symptoms of diabetic peripheral neuropathy (DPN) describe burning and tingling of the feet or hands, or numbness with pain worsening at night.⁶ With no intervention, people may be subject to amputation after foot ulceration or injury.² Even though DPN is the most common form of DN for patients with diabetes, it is important to exclude other diagnostic causes of neuropathy in this population, such as alcoholism, vitamin B12 deficiency from metformin, hypothyroidism, or uremia.^6-11 In 2010, the CDC reported about 73,000 nontraumatic lower limb amputations in patients with diabetes 20 years of age and older.³ In general, 60% of all nontraumatic lower limb amputations in that age group occur in those with diabetes.³

Proximal neuropathy is the second most common form of neuropathy, potentially affecting the muscles of the legs, buttocks, and hips and leading to muscle weakness. This can make it difficult for the individual to stand from a sitting position.¹² Focal neuropathy (FN) results in the sudden weakness of 1 nerve or a group of nerves, causing muscle weakness or pain. This malady occurs suddenly, but generally resolves in 6 to 8 weeks for patients with long-standing diabetes. Unlike the other types of neuropathy, the focal kind usually occurs in a single limited area, such as the wrist, and can involve nerve entrapment the likes of carpal tunnel syndrome.¹² Patients with diabetes and FN can develop double vision, aching behind one eye, Bell’s palsy, an inability to focus the eye; and severe pain in the pelvis, back, thigh, chest, stomach, or shin.¹² Diabetic autonomic neuropathy (DAN) can occur in a variety of organ systems and might be manifested by gastroparesis, hypoglycemic unawareness, constipation, diarrhea, erectile dysfunction, exercise intolerance, resting tachycardia, silent myocardial ischemia, and even sudden death.¹²

Diabetic nephropathy is the most common cause of end-stage renal disease (ESRD) in the nation and is a risk factor for coronary artery disease (CAD) and potentially mortality.¹³ The CDC cited diabetes as the primary cause of kidney failure in 44% of all new cases diagnosed in 2011.² Both the Diabetes Control and Complications Trial (DCCT) and the UKPDS trial demonstrated that improving hyperglycemia and reducing elevated glycated hemoglobin (A1C) decrease the risk of microvascular complications for those with T1D and T2D, respectively.^7,14

Unlike microvascular complications, macrovascular complications affect large blood vessels of the heart, brain, and arteries, thereby contributing to atherosclerosis, CAD, peripheral vascular disease (PVD) and cerebrovascular disease.⁶ The risk of patients with diabetes dying from cardiovascular (CV) complications is twice that of people without diabetes.¹⁵ Cardiovascular disease (CVD) accounts for 70% of overall mortality in patients with diabetes and is the most common cause of death.¹⁵

The benefit of blood glucose (BG) lowering in mitigating macrovascular disorders is unclear.^6,7 The lack of clarity was fueled by more recent trials, such as the ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial, the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation) trial, and the VADT (Veterans Affairs Diabetes Trial), which all sought to determine the effect of lowering BG to near-normal levels on CV risk in those with T2D.^16-18 Results of the ACCORD and ADVANCE trials concluded that that near-normal glycemic control for a median of 3.5 to 5 years does not reduce CV events and substantially increased the risks of death from all causes as well as CV disease.^16,17 The VADT concluded that intensive BG control in patients with poorly controlled T2D had no substantial effect on the rates of major CV events, death, or microvascular complications, except for the progression of proteinuria.¹⁸ In addition, the complications of CVD, PVD, and stroke also occur in patients without diabetes, but with risk factors of hypertension (HTN), dyslipidemia, and insulin resistance, which indicate that hyperglycemia may not necessarily be involved.¹⁹ Because the risk of macrovascular disease is increased in individuals with diabetes and obesity, the management of dyslipidemia, HTN, obesity, and/or tobacco cessation is quite urgent.²

COMMON COMORBIDITIES IN DIABETIC PATIENTS

Most people with diabetes have at least one comorbidity, but approximately 40% have at least three of them.²⁰ Patients with diabetes are at increased risk for comorbidities at higher rates than individuals the same age but without diabetes.²⁰ Comorbidities with worse outcomes are highly prevalent for those with diabetes and are listed in Table 1.^20,21 Comorbid disorders can be classified into clinically dominant conditions—concordant versus discordant chronic conditions, and symptomatic versus asymptomatic chronic conditions.²⁰ Clinically dominant comorbid conditions, such as severe depression, stage IV cancer, or newly diagnosed breast cancer, are serious conditions and clinicians may potentially focus more on the comorbidity, sometimes at the expense of diabetes management.²⁰ Concordant comorbid maladies that include diabetes and HTN have a related pathology and therapeutic management plan, while a discordant comorbidity, such as irritable bowel syndrome, is unrelated both in its pathology and in its treatment strategies.²⁰ Studies show that having comorbidities increases patients’ exposure to the health care system, thereby allowing for increased opportunities for foot inspections, eye examinations, and A1C testing, which leads to better glycemic control.²⁰ Interestingly, symptomatic comorbidities, such as back pain, are not always of greater concern to patients than managing their hyperglycemia, and patients may forgo analgesics to focus on diabetes therapy.²⁰ Asymptomatic conditions, such as HTN or dyslipidemia, might not present symptoms; so, treatment would highlight the prevention of mortality, improving patient functioning, halting medications’ adverse effects, and improving health-related QoL.²⁰

Because of the mortality risk seen with intensive BG lowering in the ACCORD and ADVANCE trials and the VADT to achieve near-normal BG levels, the American Diabetes Association (ADA) recommends selecting patients with few comorbidities and a long life expectancy to benefit from tighter glycemic goals (e.g., an A1C of less than 6.5%).²¹

THE IMPACT ON DIABETES TREATMENT GOALS ACCORDING TO THE DCCT AND THE UKPDS TRIALS

Large, randomized, controlled trials such as the DCCT and the UKPDS trial, had significant impact on diabetes treatment goals and guidelines in those with T1D and T2D, respectively.^7,14 The DCCT was a major clinical trial conducted involving patients with T1D in the U.S. and Canada to compare the effects of conventional versus intensive BG control with A1C as close as possible to the norm on diabetes-related complications.¹⁴ The goal A1C was less than 6.0% (within the normal range).¹⁴

The study results show that a statistically significant difference in the average A1C value was maintained between the intensive-therapy and the conventional-therapy groups (P < 0.001). Although 44% of patients in the study’s intensive-therapy arm achieved an A1C of less than 6.0% at least once during the study, fewer than 5% were able to maintain this value.¹⁴ Tight glycemic control reduced microvascular complications of retinopathy by 76%, microalbuminuria (defined as urinary albumin excretion of 40 mg or more per 24 hours) by 39%, albuminuria (defined as urinary albumin excretion of 300 mg or more per 24 hours) by 54%, and neuropathy by 60%. In fact, any prolonged BG lowering benefited the patient, even if he or she had a history of poor control.¹⁴ The chief adverse effect, though, was a 2- to 3-fold increase in severe hypoglycemia in the intensive-treatment group.¹⁴

The UKPDS was a large, randomized trial that recruited patients with T2D in the UK to determine whether intensive BG therapy reduced CV and microvascular complications and assess the advantage of sulfonylureas, metformin, or insulin.^7,22 Results of the UKPDS study show that as a result of tight glycemic control in the intensively treated group, participants experienced a decrease in microvascular but not macrovascular complications when compared with the conventionally treated group.⁷ There was a decrease, however, in all-cause mortality in overweight T2D patients who were on metformin therapy.²² Individuals randomized to metformin in the intensive-treated group had statistically significant risk reductions of 32% for any diabetes-related endpoint, 42% for diabetes-related death, and 36% for all-cause mortality compared with sulfonylurea and insulin.²²

The UKPDS 38 also evaluated patients with T2D and HTN, with a mean blood pressure (BP) at study entry of 160/94 mm Hg. Participants receiving treatment for tight BP control were compared with participants receiving BP treatment that was not as tightly controlled.²³ The main objective was to determine whether tight control of BP prevents microvascular and macrovascular complications in patients with T2D.²³ Mean BP during follow-up was significantly reduced in the group assigned to tight BP control (144/82 mm Hg) compared with the group assigned to less tight control (154/87 mm Hg) (P < 0.0001).²³ In summary, the UKPDS results demonstrated that reasonably tight treatment goals for BG combined with tight BP control, ultimately, achieved reductions in diabetes-related deaths, progression of retinopathy, and deterioration in visual acuity.²³

Therefore, several goals, guidelines, and management strategies emerged from these major findings, which include the following:

• The ADA recommends a general A1C goal of less than 7.0% to reduce complications. The A1C goal should be individualized, however, for patients in whom the benefits would outweigh the risks of severe hypoglycemia.²¹
• As a result of mortality findings and severe hypoglycemia observed in the ACCORD and ADVANCE trials and the VADT, the ADA guidelines suggest less stringent goals for patients with long-standing diabetes, advanced atherosclerosis, a history of severe hypoglycemia, advanced age with significant comorbidities, and a short life expectancy.²¹
• Both the UKPDS trial and the DCCT demonstrate that patients with T1D and those with T2D can realize benefits of decreased microvascular events with improved glycemic control.^7,14
• Hyperglycemia is toxic whether occurring early in life or later and regardless of its etiology and, in turn, causes a resulting inflammatory process contributing to microvascular complications.²⁴
• There was no long-term significant reduction in CVD with tight glycemic control, except in the UKPDS trial, where a risk reduction in both myocardial infarction (MI), of 15%, (P = 0.01) and in death from any cause, of 13% (P = 0.007) after 10 years of follow-up, were observed.^16-18,24-26
• Metformin significantly decreases the risk of diabetes-related endpoints for patients who are overweight with diabetes, including those with MI (33%; P = 0.005), and contributes to less weight gain and fewer hypoglycemic episodes.
• Long after the trials’ conclusions, there was a sustained benefit in patients with microvascular complications, indicating that early treatment is beneficial.²⁵
• Sulfonylurea and metformin did not provide sustained BG control over time; studies show that control worsened. So, as diabetes progresses, clinicians have to intensify therapy to regain glycemic control.^21,24,25
• Based on findings from the ACCORD, ADVANCE, and VADT studies, it is prudent to caution against excessively intensive BG goals because aggressive A1C targets (less than 6.5%) were associated with a 3-fold increased risk of hypoglycemia.^16-18

To effectively prevent and treat the complications experienced by a patient with diabetes, the clinician should target diabetes-specific therapeutic goals, as is recommended by organizations such as the ADA and others. It is important to implement prevention and treatment strategies for complications, as well as manage comorbid chronic conditions, incorporate the patient’s priorities and goals, and integrate diabetes self-management education and support (DSMES). Anything less may result in ineffective diabetes control, increased morbidity and, in the worst-case scenario, mortality.^20,21

PREVENTION AND TREATMENT OPTIONS FOR COMMON DIABETES COMPLICATIONS

Diabetic Retinopathy (DR)

Both the AACE/ACE guidelines and those of the ADA suggest optimizing glycemic and BP control to reduce or slow the progression of retinopathy.^21,27 The ADA recommends that adults with T1D should have an initial dilated and comprehensive eye examination by an ophthalmologist or optometrist within 5 years after the onset of diabetes.²¹ In the case of people with T2D, it is recommended that they receive an evaluation at the time of diagnosis.²¹ If upon examination there is no evidence of retinopathy for one or more annual eye exams and the patient has reasonable glycemic control, then follow-up exams every 1-2 years may be considered. If retinopathy is present, however, dilated retinal examinations should be repeated at least annually, with more frequent examinations potentially warranted in people with progressing retinopathy.^20,27

The ADA recommends panretinal laser photocoagulation therapy to reduce the risk of vision loss in patients with high-risk PDR, and in some cases, severe NPDR.²¹ Laser photocoagulation increases the oxygen tension in the retina, relieves hypoxia, improves retinal circulation, and reduces vision loss.²⁶

Enhancement of the retina’s oxygenation also lessens neovascularization and edema formation by reducing VEGF production. The anti-VEGF agents improve vision, cut down on vessel leakage, and reduce the necessity for laser photocoagulation in patients with ME.²⁸ The U.S. Food and Drug Administration (FDA) approved anti-VEGF therapies, such as aflibercept and ranibizumab, for the treatment of macular edema (ME) and other diabetic retinopathy complications.^28-30 The ADA recommends the use of anti-VEGF agents, such as ranibizumab, as an option to reduce the risk of vision loss in patients with PDR, and for the treatment of central-involved ME.²¹ A recent position statement from the ADA notes that there are three anti-VEGF treatments used for ME in diabetes – aflibercept, ranibizumab, and bevacizumab.³¹ At the time of this writing, bevacizumab does not carry an FDA indication for this purpose, but is used clinically. Additional information on aflibercept and ranibizumab, which do carry indications for the treatment of diabetic eye disease, follows.

Aflibercept (Eylea) is a recombinant fusion protein that serves as a receptor decoy to prevent the binding and subsequent activation of the VEGF receptors.²⁹ This agent is indicated for neovascular age-related macular degeneration, ME following retinal vein occlusion, diabetic macular edema (DME), or DR in patients with DME.²⁹ It is dosed at 2 mg (0.05 mL) once monthly by intravitreal administration for the first 5 injections, followed by once every 2 months.²⁹ The most common side effects associated with aflibercept include conjunctival hemorrhage, eye pain, cataracts, vitreous floaters, increased intraocular pressure (IOP), and vitreous detachment. Patients should immediately contact their ophthalmologist if they experience vision changes or develop red, painful eyes that are sensitive to light.²⁹ Serious adverse reactions include endophthalmitis and retinal detachment. Clinicians should advise patients that they may experience temporary visual disturbances after the injection, so they should avoid driving or operating machinery until they regain visual acuity.²⁹

Ranibizumab (Lucentis) is a humanized monoclonal antibody fragment indicated as an intravitreal injection for the treatment of patients with DR with DME.³⁰ It is dosed at 0.3 mg (0.05 mL) monthly by intravitreal administration, after which the retina is evaluated for further treatment.³⁰ The main adverse events are similar to those of aflibercept, which include conjunctival hemorrhage, eye pain, vitreous floaters, and elevated IOP.³⁰ Ranibizumab alone or as an adjunct to laser therapy has been shown to decrease mean retinal thickness, as well as improve vision and QoL in addition to substantially correcting visual acuity when compared with laser therapy.²⁸

Diabetic Peripheral Neuropathy (DPN)

There is no cure for DPN, but the standard of treatment includes optimization of glycemic control, proper foot care, use of supportive footwear, and pain control.^7,14,21,27 Patients must be taught to inspect their feet on a daily basis and look for any signs of dry cracking skin, callus formations, fissures, cuts, and bruises, as well as infections between the toes and near the toenails.^21,32 Individuals with diabetes should be educated about foot injury prevention.³³ Because as many as 50% of DPN cases are asymptomatic, comprehensive annual foot examinations to detect any signs of early DPN are warranted.²¹ The ADA recommends that all patients be screened for DPN at the time of diagnosis of T2D and, then, 5 years after diagnosis for those with T1D and yearly thereafter.²¹

Pharmacologic treatment for DPN is primarily for pain control. There are many agents used for the treatment of DPN, but only 2 medications have U.S. FDA approval—pregabalin and duloxetine.^32-34 Other examples of drugs used in DPN therapy include venlafaxine, carbamazepine, topiramate, amitriptyline, imipramine, paroxetine, citalopram, gabapentin, sodium valproate, dextromethorphan, morphine sulfate, tramadol, oxycodone, transdermal lidocaine, and capsaicin.³² Although approved for the treatment of DPN in Europe, capsaicin is approved in the U.S. only for neuropathic pain associated with postherpetic neuralgia, which does not include patients with diabetes.³³⁵The ADA provides the following recommendations for the treatment of painful DPN: ²¹

• Optimize glucose control to prevent or delay the development of neuropathy in patients with T1D and to slow the progression of neuropathy in patients with T2D
• Pregabalin, duloxetine, or gabapentin are recommended as initial pharmacologic treatment for neuropathic pain in diabetes

A systematic review and network meta-analysis concluded that selective serotonin reuptake inhibitors (SSRIs), topical capsaicin, tricyclic antidepressants (TCAs), and anticonvulsants were associated with statistically meaningful reductions in pain.³³ Selective norepinephrine reuptake inhibitors (SNRIs) had exhibited a greater effect on pain control than anticonvulsants and opioids did.³³ Amitriptyline, though commonly used for painful DPN, is limited by such adverse events as sedation, urinary retention, and orthostatic hypotension.³⁶ Both amitriptyline and desipramine showed similar pain relief in 1 study, regardless of whether patients had a diagnosis of depression or not.³⁶ Therefore, desipramine is an option for DPN because of its safety profile if patients are unable to tolerate amitriptyline.

Duloxetine is an SNRI that is FDA-approved for painful DPN.³⁴ The drug’s exact mechanism of action is unknown, but it is thought to potentiate serotonergic and noradrenergic activity in the central nervous system (CNS) to inhibit central pain and anxiety.³⁴ Duloxetine has a black box warning for suicidal thoughts and behaviors; so, patients have to be monitored.³⁴ The dosage for the treatment of DPN is 60 mg once daily, but in those with renal impairment, a lower dose is suggested at the outset and then a gradual increase or titration. Duloxetine is a delayed-release capsule and should not be sprinkled onto food. This agent’s serious adverse effects include orthostasis, hepatoxicity, suicidal thoughts, abnormal bleeding, and serotonin syndrome (SS). SS can occur alone or in combination with other serotonergic drugs that encompass triptans, TCAs, fentanyl, lithium, tramadol, buspirone, St John’s Wort, tryptophan, monoamine oxidase inhibitors (MAOIs), linezolid, and intravenous (IV) methylene blue.³⁴

A Cochrane review was designed to assess the benefit and harm of duloxetine use for the treatment of painful DPN or chronic pain.³⁷ The study results show that duloxetine at 60 mg daily was effective for treating painful DPNin the short-term, with a risk ratio (RR) for 50% or greater pain reduction at 12 weeks. The related number needed to treat to benefit (NNTB) was 5 (95% confidence interval [CI], 4 to 7). Adverse events were common in both the treatment and placebo groups, but more common in the former group. Authors concluded that doses of 60 mg and 120 mg of duloxetine were efficacious for treating painful DPN, but lower doses were ineffective.³⁷

Pregabalin is an anticonvulsant therapy used for a variety of conditions that include the management of neuropathic pain associated with DPN, postherpetic neuralgia, fibromyalgia, and partial-onset seizures.³⁸ The mechanism of action is not fully understood, but is thought to bind to the alpha₂-delta subunit of calcium channels in the CNS tissues, thereby resulting in antinociceptive effects.³⁸ Pregabalin is given at a maximum daily dose of 100 mg 3 times daily for the treatment of DN in patients with a creatinine clearance of 60 mL/minute or more.³⁸ The most common negative side effects are dizziness, somnolence, dry mouth, edema, blurred vision, weight gain, and abnormal concentration or attention.³⁸ Pregabalin has warnings of angioedema, hypersensitivity reactions, and an increased risk of suicidal thoughts or behavior.³⁸ Results of a meta-analysis show that pregabalin substantially lessened the pain associated with DPN by more than 50% and boosted patients’ global impression of change.³⁹ While not FDA-approved for DPN, recent evidence shows that gabapentin is efficacious (and affordable).⁴⁰

A significant challenge with the use of pregabalin and duloxetine is the potential for major drug-drug interactions (DDIs), especially for older adults. Naproxen and ketorolac reduce pregabalin effectiveness, eventually resulting in potentially major DDIs.⁴¹ Duloxetine is a highly protein-bound agent that undergoes hepatic metabolism and inhibits the isoenzymes CYP450 (2D6 and 1A2).^38,39 Many drugs are contraindicated or have potentially major DDIs with duloxetine therapy, in turn, causing CNS toxicity, SS, neuroleptic malignant syndrome (NMS), QT prolongation, and/or an increased risk of bleeding.^38,39 A recent retrospective, matched cohort study was conducted using medical and pharmacy claims data to examine the impact of DDIs on newly initiated treatment with pregabalin or duloxetine for patients with painful DPN.⁴¹ A total of 1,320 individuals met the criteria for inclusion in the study, with 570 patients given pregabalin and 750 prescribed duloxetine. Results show that the percentage of patients with a potential DDI was statistically greater (P < 0.001) in the duloxetine group (56.7%, n = 253) compared with the pregabalin group (2.9%, n = 13).⁴¹ There were 17 potentially major DDIs involving pregabalin, most of them incorporating the use of naproxen. On the other hand, there were 649 potentially major and moderate DDIs with duloxetine, including 11 contraindicated interactions.⁴¹ Precisely 91 of those interactions involved clopidogrel, while more than 25 interactions occurred with tramadol, sertraline, trazodone, cyclobenzaprine; meloxicam, citalopram, and/or fluoxetine.⁴¹ As a result of this study, pharmacists should screen patients on multiple therapies for potential DDIs when completing a medication review.

Given the risk of ulceration and other complications in patients with DPN, foot care education is an essential component of treatment. The risk of ulcers or amputations is increased in people who have the following risk factors: ²¹

• Poor glycemic control
• Peripheral neuropathy with loss of protective sensation
• Cigarette smoking
• Foot deformities
• Preulcerative callus or corn
• Peripheral arterial disease
• History of foot ulcer
• Amputation history
• Visual impairment
• CKD

Diabetic Autonomic Neuropathy (DAN)

As diabetes progresses, patients should be assessed for signs and symptoms of diabetic autonomic neuropathy (DAN), including orthostasis, resting tachycardia, hypoglycemic unawareness, and cardiovascular autonomic neuropathy (CAN), which is the most important and concerning DAN in terms of mortality.²³ In the early stages of CAN, people may be asymptomatic; but, as the disease progresses, there can be changes in heart-rate variability with deep breathing and abnormal CV reflex. Advanced disease is indicated by resting tachycardia and orthostasis.²³ CAN is best prevented by targeting BG, BP, and lipid control, tobacco cessation, and physical activity to reduce its progression and development among those with T2D. Patients who develop CAN should be referred to a cardiologist.²³

Hypoglycemic unawareness is a progressive loss of the autonomic symptoms of sweating, tremors, and palpitations traceable to reduced counter-regulatory responses to glucagon and epinephrine.⁴² The patient is unaware of hypoglycemia and unable to respond appropriately, thus leading to seizures, coma, and even death. This vicious cycle leads to further decreases in counter-regulatory responses to hypoglycemia.⁴² Risk factors include tight glycemic control, low A1C, and a history of T1D or T2D in those with long-standing disease. Patients should be educated to strictly avoid hypoglycemia. The 2 types of effective patient-education strategies include a psychological instructional program to improve the person’s ability to detect hypoglycemia and teaching him or her the proper strategies to help avoid hypoglycemia through dietary education and flexible insulin dosing strategies in response to exercise and a reduced diet.⁴² Studies show symptom improvement by 3 days and normalization of hypoglycemic awareness in as little as 3 weeks.

Diabetic Nephropathy

The ADA recommends optimizing both BG and BP control to reduce the risk or slow the progression of chronic kidney disease (CKD) in the presence of diabetes.²¹ CKD is diagnosed by the persistent presence of elevated urinary albumin excretion (albuminuria), low estimated glomerular filtration rate (eGFR), or other manifestations of kidney damage.²¹ Screening for albuminuria is most easily and commonly performed by measuring urinary albumin-to-creatinine ratio (UACR). A normal UACR is considered a value <30 mg/g creatinine, while increased urinary albumin excretion is defined as a UACR of ≥30 mg/g.²¹ The ADA recommends that all patients with T2D and those who have T1D for a duration of 5 or more years should be screened and assessed at least once a year using UACR and estimated glomerular filtration rate (eGFR).²¹ The guidelines do not recommend an angiotensin converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) for the primary prevention of CKD in patients with diabetes who have normal BP and UACR.²¹ Either an ACE inhibitor or an ARB is suggested for the treatment of patients who are not pregnant who have a moderately elevated UACR (30 to 299 mg/g); they are also strongly recommended for the treatment of those with a UACR of more than 300 mg/g.²¹ When treatment with ACE inhibitors, ARBs, or diuretics is initiated, clinicians should monitor the patient’s serum creatinine and potassium levels. They should also be vigilant, especially in patients with an eGFR of less than 60 mL/minute or with albuminuria, to evaluate, manage, and monitor for the potential complications and progression of CKD. The combination of ACE inhibitors and ARBs should be avoided because combining them therapeutically has no additional benefit on CVD or CKD and leads to higher rates of hyperkalemia and acute kidney injuries.²¹ Because the goal for managing CKD involves optimal BP control, the ADA recommends the use of antihypertensive mediations that have been shown to reduce cardiovascular events in people with diabetes, inclusive of ACE inhibitors, ARBs, thiazide-like diuretics, and dihydropyridine calcium channel blockers.²¹

As discussed in Module 4, several SGLT-2 inhibitors and GLP-1 receptor agonists have demonstrated benefits on renal outcomes in dedicated cardiovascular outcome trials. Accordingly, the ADA recommends the following for patients with diabetes and CKD: ²¹

• For patients with T2D and CKD, consider use of a SGLT2 inhibitor or GLP-1 receptor agonist shown to reduce risk of chronic kidney disease progression, cardiovascular events, or both.

In patients who have adequate kidney function (eGFR above 45 mL/min/1.73m²), the ADA gives preference to use of SGLT2 inhibitors for this purpose. Currently, the SGLT2 inhibitors recommended include canagliflozin (Invokana), empagliflozin (Jardiance), and dapagliflozin (Farxiga).²¹ Ertugliflozin is currently not included in this recommendation because cardiovascular outcomes data is not yet available with this agent.

Cardiovascular Disease (CVD)

CVD risk management involves managing HTN, controlling dyslipidemia, using antiplatelet therapy, and treating obesity, where applicable.²¹ The ADA provides the following recommendations related to BP goals: ²¹

• For individuals with diabetes and HTN at higher cardiovascular risk (existing atherosclerotic cardiovascular disease [ASCVD] or 10-year ASCVD risk >15%), a BP target of <130/80 mmHg may be appropriate, if it can be safely attained.
• For individuals with diabetes and HTN at lower risk for cardiovascular disease (10-year ASCVD risk <15%), treat to a BP target <140/90 mmHg.

For those patients with a BP of more than 120/80 mmHg, the ADA further recommends that health care practitioners advise patients to lose weight if they are overweight or obese, using the Dietary Approaches to Stop Hypertension (DASH) diet. The DASH diet regimen includes reducing sodium and increasing potassium intake, along with moderating alcohol use and increasing physical activity. In terms of pharmacotherapy recommendations, it is recommended that drug classes that have been demonstrated to reduce CV events in patients with diabetes – ACE inhibitors, ARBs, thiazide-like diuretics, or dihydropyridine calcium channel blockers – be used. The ADA recommends initial dual antihypertensive therapy including two agents from the classes previously listed in those with a baseline BP ≥160/100 mmHg. ²¹

The ADA recommends reducing saturated fat, trans-fat, and cholesterol and increasing omega fatty acids, viscous fiber, and plant stanols and sterols. Add to that, more physical activity and weight loss if indicated to improve the lipid profile in patients with diabetes.²¹ Table 2 provides a summary of recommendations from the ADA regarding statin and combination treatment in adults with diabetes. ²¹

The ADA currently states that antiplatelet therapy, such as an aspirin dose of 75 to 162 mg per day, may be considered as a primary prevention strategy in those with diabetes who are at increased cardiovascular risk, after a discussion with the patient on the benefits versus increased risk of bleeding.²¹ While the ADA says aspirin can be considered for primary prevention, the American College of Cardiology (ACC) and the American Heart Association (AHA) updated their guidelines in 2019 to state that aspirin should not be used in the routine primary prevention of ASCVD due to lack of net benefit.⁴³ In the setting of secondary prevention, however, current guidelines from both organizations agree that aspirin is recommended.^21,43 If these individuals are allergic to aspirin, though, clopidogrel at 75 mg a day can be substituted.²¹

Obesity is diagnosed according to a body mass index (BMI) of 30 kg/m² or greater.²⁷ Measurement of waist circumference may be considered for individuals with a BMI between 25 and 35 kg/m². Men with a waist circumference of 40 inches or more or women with a waist circumference of 35 inches or more are at a higher risk for metabolic disease and should be evaluated for such obesity-related complications as sleep apnea and osteoarthritis.²⁷ Nonpharmacologic strategies should include lifestyle modifications, such as behavioral change, reduced-calorie diets, and physical therapy. Weight-loss therapies, inclusive of pharmacotherapy or metabolic surgery, may be considered if these approaches fail to achieve the target goals.²¹

CONCLUSIONS

Patients with either T1D or T2D are at risk for long-term microvascular and macrovascular complications. Optimization of glycemic control remains the main strategy for the prevention of retinopathy, neuropathy, and nephropathy, while the treatment of HTN and dyslipidemia and the cessation of tobacco use can reduce CV risk. It is important to manage people with a patient-centered communication and approach to care. They should be taught about self-care management to prevent complications and that, in turn, may well lead to a good health-related QoL. Therefore, providers should aggressively focus on the therapeutic goals of both the prevention and treatment of diabetes and its complications by incorporating both pharmacologic and nonpharmacologic therapeutic plans of action.

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