CREDIT:
2.0
Continuing Education
EARN CE CREDIT FOR THIS ACTIVITY AT WWW.DRUGTOPICS.COM
AN ONGOING CE PROGRAM OF THE UNIVERSITY OF CONNECTICUT SCHOOL OF PHARMACY AND DRUG TOPICS
educationaL oBJectiVeS Goal: To assist pharmacists in recognizing significant complications associated with diabetes to help prevent the development or progression of complications and improve diabetes care.
After participating in this activity, pharmacists will be able to: ●
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Recognize macrovascular and microvascular complications associated with diabetes mellitus Identify goals of therapy and drug and non-drug treatment options to decrease the risk of macrovascular and microvascular complications in patients with diabetes mellitus Recommend appropriate medications for treating macrovascular and microvascular complications of uncontrolled diabetes
The University of Connecticut School of Pharmacy is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Pharmacists are eligible to participate in the knowledge-based activity, and will receive up to 0.2 CEUs (2 contact hours) for completing the activity, passing the quiz with a grade of 70% or better, and completing an online evaluation. Statement of credit is available via the online system.
Macrovascular and microvascular complications of diabetes mellitus Jiehyun Lee, PharmD
MEDICATION MANAGEMENT ClINIC SUPERVISOR, BACKUS HOSPITAl, NORWICH, CONN. ADJUNCT ASSISTANT ClINICAl PROFESSOR, UNIVERSITY OF CONNECTICUT SCHOOl OF PHARMACY, STORRS, CONN.
Devra K. Dang, PharmD, BCPS, CDE, FNAP ASSOCIATE ClINICAl PROFESSOR, UNIVERSITY OF CONNECTICUT SCHOOl OF PHARMACY, STORRS, CONN.
Abstract
ACPE #0009-9999-15-021-H01-P
Diabetes causes acute complications, such as hyperglycemic crises. It is, however, the progressive long-term complications of diabetes that bring devastating and life-threatening consequences to patients with diabetes. The long-term complications are divided into microvascular and macrovascular complications, both resulting from cellular damages inflicted by chronic hyperglycemia. Appropriate screenings and treatment of these complications must take place in a timely manner to prevent worsening of the complications.
Grant Funding: Merck Sharp & Dohme Corp.
Activity Fee: There is no fee for this activity. Initial release date: 7/1/2015 Expiration date: 7/1/2018
To obtain CPE credit, visit www.drugtopics.com/cpe and click on the “Take a Quiz” link. This will direct you to the UConn/Drug Topics website, where you will click on the Online CE Center. Use your NABP E-Profile ID and the session code 15DT21-TJJ84. First-time users must pre-register in the Online CE Center. Test results will be displayed immediately and your participation will be recorded with CPE Monitor within 72 hours of completing the requirements.
Faculty: Jiehyun Lee, Pharmd, and devra K. dang, Pharmd, BcPS, cde, FnaP
For questions concerning the online CPE activities, e-mail:
[email protected].
Dr. lee is medication management clinic supervisor at Backus Hospital in Norwich, Conn., and adjunct assistant clinical professor at the University of Connecticut School of Pharmacy, Storrs, Conn. Dr. Dang is associate clinical professor at the University of Connecticut School of Pharmacy, Storrs, Conn. Faculty Disclosure: Dr. lee and Dr. Dang have not actual or potential conflict of interest associated with this article. Disclosure of Discussions of Off-Label and Investigational Uses of Drugs: This activity may contain discussion of unlabeled/unapproved use of drugs in the Unitd States and will be noted if it occurs. The content and views presented in this educational program are those of the faculty and do not necessarily represent those of Drug Topics or University of Connecticut School of Pharmacy. Please refer to the official information for each product for discussion or approved indications, contraindications, and warnings.
IMAGE: GETTY IMAGES / E+ / JAMESBENET
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continuing education
MEDicAtioN tHErApY MANAgEMENt (MtM) iN pAtiENts WitH DiABEtEs cpE sEriEs Welcome to the Medication Therapy Management (MTM) in Patients with Diabetes CPE Series, which has been designed for pharmacists who take care of patients with diabetes. This series has 7 monthly knowledge-based activities from the University of Connecticut School of Pharmacy and Drug Topics. The first activity covers the pathophysiology, diagnosis, screening, and risk factors associated with diabetes mellitus. In the second activity, pharmacists will learn about medical nutrition therapy, physical activity, and health maintenance considerations for diabetic patients. The
D
iabetes is the 7th leading cause of death in the United States.1 The rates of death from all causes were about 1.5 times higher among patients with diabetes than persons of similar age without diabetes.1 Severely uncontrolled hyperglycemia can lead to acute complications of diabetes, such as diabetic ketoacidosis or hyperosmolar hyperglycemic state. It is more commonly however, the long-term complications of uncontrolled hyperglycemia, which put patients with diabetes at significant risk for death. The long-term complications of diabetes are divided into microvascular and macrovascular complications. The microvascular complications include retinopathy, nephropathy, and neuropathy. Macrovascular complications include cardiovascular disease (CVD) such as ischemic heart disease, cerebrovascular disease, peripheral arterial disease, chronic heart failure, and cardiomyopathy. The damaging effects of chronic hyperglycemia on human vasculature are the underlying causes for morbidity and mortality in patients with diabetes. It is crucial for healthcare professionals to understand the close relationship between diabetes and its vascular complications to prevent or slow the progression of them.
third and fourth activities focus on therapeutic considerations, including oral and injectable agents for diabetes care and management. The fifth CPE article covers macrovascular and microvascularcomplications of diabetes, and the sixth focuses on psychosocial considerations in the management of the disease. The last knowledge-based activity enables greater understanding of drug-induced hyper- and hypoglycemia, nonprescription medications, and complementary and alternative medicine for diabetes care. The MTM CPE Series also offers application-based and practice-based
glycemia triggers proinflammatory responses and other forms of cellular activation from endothelial cells, leading to overall vasculature damage. Several biochemical pathways have been postulated to trigger the cellular responses and cause the microvascular complications. These include polyol accumulation, formation of advanced glycation end products, oxidative stress, and activation of protein kinase C. Future treatment options for diabetes may target these pathways.2,3 Diabetic retinopathy. In the United States, 4.2 million (28.5%) adults with diabetes aged 40 years or older had diabetic retinopathy between 2005 and 2008.1 It is the most common vascular complication of diabetes, contributing to over 10,000 cases of blindness per year.4 Almost all patients with type 1 diabetes and approximately 60% of those with type 2 diabetes will develop some degree of retinopathy within 20 years of diagnosis.5 The prevalence of retinopathy at clinical diagnosis of type 2 diabetes is approximately 21% in the United States, and clinically significant retinopathy may have occurred as early as 7 years before the diagnosis.6 Diabetic retinopathy results from microangiopathy affecting retinal vasculature. Two underlying pathologic mechanisms are microvascular leakage and microvascular Microvascular occlusion.5 Diabetic retinopathy is clinically complications Hyperglycemia is closely associated with divided into 2 major stages: nonproliferative cellular dysfunction and activation. Hyper- diabetic retinopathy (NPDR), also known as DrugTopics .c om
activities for an additional CPE credits. Online interactive case-based studies are available for 1 hour of CPE credit each. The series concludes with live meetings, which are delivered at various locations throughout the year, offering application of MTM concepts to the patient with diabetes and motivational interviewing skills development for health behavior change in diabetes management. Check the website frequently for live meeting offerings. http://pharmacy.uconn.edu/academics/ce/ drug-topics-and-uconn-ce/mtmfor-patients-with-dm/
background retinopathy, and proliferative diabetic retinopathy (PDR). NPDR is further subdivided into mild, moderate, and severe levels. The retinopathy stages correspond to certain findings on dilated ophthalmoscopy (Table 1).4 Intravitreous vascular endothelial growth factor (VEGF) inhibitors, such as aflibercept, bevacizumab, or ranibizumab, have been studied as treatment of diabetic macular edema. Although the relative efficacy depended on baseline visual acuity, these anti-VEGF agents improved vision in eyes with center-involved diabetic macular edema.7 Diabetes patients with clinically significant macular edema and PDR generally require laser photocoagulation therapy to prevent progression to blindness. In some cases, diabetes patients with severe NPDR can also benefit from laser photocoagulation therapy.8 For vitreous hemorrhage and active progressive PDR, vitrectomy surgery may be required to improve visual acuity.4 Most diabetes patients with detectable retinopathy are asymptomatic until the damage to their eyes is severe enough to cause vision changes. Symptomatic patients may complain of blurry vision, floaters, nighttime vision impairment, and partial vision loss, all indicating clinically significant retinal damage.4 Because of the asymptomatic nature of diabetic retinopathy and the varying effectiveness of laser photocoagulation therapy at different stages of retinopathy, the American Diabetes Association (ADA) recommends an initial dilated and comprehensive July 2015
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MacRoVaScuLaR and MicRoVaScuLaR coMPLicationS
TABlE 1
DiAbetic retinopAthY DiseAse seVeritY scAle Disease severity level
Findings observable on dilated ophthalmoscopy
No apparent retinopathy
No abnormalities
Mild NPDR
Microaneurysms only
Moderate NPDR
More than just microaneurysms but less than severe NPDR
Severe NPDR
Any of the following: more than 20 intraretinal hemorrhages in each of 4 quadrants; definite venous beading in 2+ quadrants; prominent intraretinal microvascular abnormalities in 1+ quadrant And no signs of PDR
PDR
One or more of the following: neovascularization, vitreous/preretinal hemorrhage
Abbreviations: NPDR, nonproliferative diabetic retinopathy; PDR, proliferative diabetic retinopathy. Source: Ref 4
eye examination by an ophthalmologist or optometrist within 5 years after the onset of diabetes for patients with type 1 diabetes and shortly after the diagnosis of diabetes for patients with type 2 diabetes.8 This eye exam then should be repeated annually.8 It can also help detect other ophthalmic complications that are more common in older patients, such as cataract, glaucoma, and age-related macular degeneration.4 Medical management of diabetic retinopathy also includes glycemic control and blood pressure control. Two randomized clinical trials, the United Kingdom Prospective Diabetes Study (UKPDS) and the Diabetes Control and Complications Trial (DCCT), demonstrated the importance of glycemic control in preventing diabetic retinopathy.9-11 In UKPDS, newly diagnosed patients with type 2 diabetes were randomized to intensive treatment with a sulfonylurea or insulin or to conventional treatment with dietary therapy. Over 10 years the patients receiving intensive treatment showed a significant 25% risk reduction in microvascular end points, mostly due to fewer cases of retinal photocoagulation, when compared to those who received conventional treatment.9 In addition, a prospective observational study of UKPDS found that each 1% reduction in glycosylated hemoglobin (A1C) level was associated with a 37% decrease in microvascular end points.12 DCCT compared intensive insulin treatment (injection 3 or 4 times daily) to conventional insulin treatment (twice-daily injection) in patients with type 1 diabetes. During a mean follow-up of 6 years, the in-
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tensive treatment group showed a 76% reduction in the mean risk of retinopathy and a 54% reduction in the risk of progression.10 The Epidemiology of Diabetes Interventions and Complications (EDIC) study found that the benefits of the intensive diabetes control persisted in the patients followed for 10 years after conclusion of the DCCT, despite the fact that the A1C difference between the intensive treatment group and the conventional treatment group was lost within 1 year after the end of the study.11 The UKPDS also looked at the effectiveness of blood pressure control and found that tight blood pressure control (goal <150/85 mm Hg) was associated with a 34% reduction in progression of retinopathy and a 47% reduced risk of deterioration in visual acuity when compared to a blood pressure target of less than 180/105 mm Hg.13 Other clinical trials have demonstrated the association between blood pressure control and reduction in the incidence or progression of diabetic retinopathy.14,15 Diabetic nephropathy. Diabetes was the primary cause of kidney failure in the United States, accounting for 44% of all new cases of kidney failure in 2011.1 In the UKPDS the incidence of microalbuminuria was 2.0% per year and the prevalence of microalbuminuria was 24.9% 10 years after the diagnosis of type 2 diabetes. In addition, approximately 7% of patients with type 2 diabetes already had microalbuminuria at the time of diagnosis.16 The cumulative incidence of microalbuminuria in patients with type 1 diabetes was 12.6% over 7.3 years, according to the European
Diabetes (EURODIAB) Prospective Complications Study.17 A prospective, populationbased study also suggested that diabetic nephropathy was significantly associated with cardiovascular mortality.18 Pathogenic mechanism of diabetic nephropathy involves glomerular basement membrane thickening, diffuse mesangial sclerosis, microaneurysm, hyaline degeneration, and hyaline arteriosclerosis. Mesangial expansion and glomerular basement membrane thickening are commonly seen in diabetes patients with varying degrees of nephropathy.19 In the past, diabetic nephropathy was categorized into 2 stages based on urinary albumin excretion: microalbuminuria and macroalbuminuria, also known as proteinuria or overt diabetic nephropathy. These terms were mistakenly interpreted as the differing sizes of albumin molecules, when in fact, the terms microalbuminuria and macroalbuminuria were referring to the quantity of urinary albumin excreted. To prevent this confusion and for a more accurate description, the ADA recommends the term “increased urinary albumin excretion” over the terms microalbuminuria and macroalbuminuria (Table 2).8
Clinically significant retinopathy may have occurred as early as 7 years before the diagnosis. The ADA recommends albumin measurement in a spot urine sample to obtain urinary albumin-to-creatinine ratio (UACR), which should be done annually in patients with type 1 diabetes with a duration of 5 years or longer and in all patients with type 2 diabetes starting at the time of diagnosis.8 Although the increased urinary albumin excretion may detect early signs of diabetic nephropathy, the risk for developing diabetic nephropathy and CVD can begin even at normal urinary albumin excretion.19 DrugTopics .c om
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Albuminuria (UACR ≥30 mg/g) is a sign of diabetic kidney disease and a wellestablished marker of increased CVD risk. However, up to 40% of patients with type 1 diabetes can have spontaneous remission of elevated UACR. Also, factors such as exercise, fever, and marked hypertension may elevate UACR. Thus, the diagnosis of increased urinary albumin excretion should only be made based on a positive reading for 2 out of 3 samples collected over a 3- to 6-month period.8 Similar to diabetic retinopathy, glycemic control and blood pressure control are the main ways to prevent diabetic nephropathy. In the DCCT, the intensive insulin treatment group experienced a 39% and 54% reduction in the incidence of increased UACR 30-299 mg/g (formerly known as microalbuminuria) and UACR ≥300 mg/g (formerly known as macroalbuminuria), respectively, compared to the conventional insulin treatment group.10 The EDIC study also demonstrated that benefits of the intensive treatment on preventing diabetic nephropathy persisted 8 years after the end of DCCT even though the difference in A1C was no longer significant between the intensive treatment group and the conventional treatment group.11 The UKPDS also showed a 34% risk reduction in the progression of albuminuria for the intensive therapy group.9 Other prospective randomized studies have also demonstrated that glycemic control can delay the rate of progression from increased UACR 30-299 mg/g to UACR ≥300 mg/g in patients with type 1 or type 2 diabetes.20,21 Thus, strict glycemic control (A1C <7%) is still recommended for most patients with diabetes to prevent microvascular complications. However, as will be discussed later in this article, the A1C goal needs to be individualized according to patient characteristics, and a less-stringent A1C goal may be appropriate in certain patients. In the UKPDS, blood pressure control also reduced the risk for the development of albuminuria in patients with type 2 diabetes.13 Other numerous studies showed that treatment of hypertension, irrespective of the agent used, produced beneficial effects on albuminuria in patients with type 1 and type 2 diabetes.19 In particular, renin-angiotensin-aldosterone system (RAAS) blockade plays an important role DrugTopics .c om
in the prevention and treatment of diabetic nephropathy. In patients with type 2 diabetes, both angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARB) have been shown to reduce the risk of development and progression of diabetic nephropathy significantly by up to 70%.22-24 In addition, ACE inhibitors increase the chances of regression to normal urinary albumin excretion.19 The renoprotective effects of ACE inhibitors and ARBs are independent of their blood pressure-lowering effects and related to decreased intraglomerular pressure and passage of proteins into the proximal tubule.19 ACE inhibitors provide a selective benefit over other antihypertensive agents in preventing and delaying the progression of increased urinary albumin excretion, slowing the decline in glomerular filtration rate (GFR), and reducing the risk of major CVD outcomes in patients with diabetes.8 ARBs do not have the same benefit as ACE inhibitors on CVD risk in diabetes patients or prevention of the onset of albuminuria in diabetes patients with normal blood pressure. However, ARBs do reduce the progression of albuminuria in patients with type 2 diabetes and are potentially associated with a smaller increase in serum potassium levels compared to ACE inhibitors.8 Thus, the ADA recommends an ACE inhibitor or ARB for diabetes patients with hypertension and elevated urinary albumin excretion, but recommends against the table 3
table 2
Definitions of Abnormalities in URINARY Albumin Excretion Category
Spot urine collection (µg/mg creatinine)
Normal
<30
Increased urinary albumin excretion
≥30
Diagnosis of increased urinary albumin excretion should only be made based on a positive reading for 2 out of 3 samples collected over a 3- to 6-month period as other factors such as exercise, fever, and marked hypertension may elevate urinary albumin excretion. Source: Ref 8
use of ACE inhibitor or ARB as the primary prevention of diabetic nephropathy in diabetes patients with normal blood pressure and normal UACR (<30 mg/g).8 Combination treatment of an ACE inhibitor plus an ARB has been shown to produce synergistic effects on urinary albumin excretion in some studies.19,25 However, the National Kidney Foundation’s 2012 Kidney Disease Outcomes Quality Initiative Clinical Practice Guidelines for Diabetes and Chronic Kidney Disease recommend against dual therapy with an ACE inhibitor and an ARB in diabetes due to the risk of increased adverse events (e.g. hyperkalemia, impaired kidney function), despite a reduction in observed albuminuria. Combination therapy
Criteria for Clinical Diagnosis of the Metabolic Syndrome
Measure
Categorical Cut Points
Elevated waist circumference
Population- and country-specific definitionsa
Elevated triglycerides (drug treatment for elevated triglycerides is an alternate indicator)
≥150 mg/dL (1.7 mmol/L)
Reduced HDL-C (drug treatment for reduced HDL-C is an alternate indicator)
<40 mg/dL (1.0 mmol/L) in males; <50 mg/dL (1.3 mmol/L) in females
Elevated blood pressure (antihypertensive drug treatment in a patient with a history of hypertension is an alternate indicator)
Systolic ≥130 and/or diastolic ≥85 mm Hg
Elevated fasting glucose (drug treatment ≥100 mg/dL (5.55 mmol/L) of elevated glucose is an alternate indicator) Abbreviations: HDL-C, high-density lipoprotein cholesterol. a
Accepted U.S. definition for elevated waist circumference is > 40 inches (102 cm) in men and > 35 inches (88 cm) in women Source: Ref 45
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TABlE 4
MacRoVaScuLaR and MicRoVaScuLaR coMPLicationS
blooD pressUre mAnAgement for pAtients With DiAbetes
Blood pressure
Management
>120/80 mmHg
Initiate lifestyle changes
>140/90 mmHg
Prompt initiation and timely subsequent titration of pharmacological therapy in addition to lifestyle therapy Source: Ref 8
with an ACE inhibitor or ARB with the renin inhibitor aliskiren is also contraindicated in diabetes patients according to the FDA due to the risk of renal impairment, hypotension, and hyperkalemia.25 Also, the combinations of RAAS inhibitors (e.g. ACE inhibitor plus ARB, mineralocorticoid antagonist, or direct renin inhibitor) provided no additional benefit on CVD or diabetic kidney disease compared to monotherapy. Thus, the combined use of different RAAS inhibitors should be avoided in patients with diabetes.8 Reduction in dietary protein intake was once considered for diabetes patients with diabetic kidney disease, but it did not alter glycemic measures, CVD risk measures, or the course of GFR decline. Thus, reducing the amount of dietary protein below the recommended daily allowance of 0.8 g/kg/day is not recommended.8 Diabetic neuropathy. Diabetic neuropathy is characterized by progressive nerve damage affecting both divisions of the peripheral nervous system, the somatic and autonomic systems. A prospective study of patients with type 1 diabetes reported that the overall prevalence of diabetic neuropathy ranged from 18% to 58% at baseline.26 In patients with type 2 diabetes the overall prevalence of diabetic peripheral neuropathy was 28% according to a populationbased study.27 Numerous classifications of diabetic neuropathy are available for the variety of syndromes within the peripheral nervous system. The most common are DPN and autonomic neuropathy.8 Diabetic peripheral neuropathy (DPN) is defined as “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes.”28 It carries considerable morbidity and mortality. DPN is the leading cause of lower-extremity amputations, and approximately 60% of non-traumatic lowerlimb amputations occurs in patients with
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diabetes.1 More than 80% of amputations follow a foot ulcer or injury, which may be due to nerve damages from diabetes.29 Up to 50% of patients with DPN may complain of burning, tingling, stabbing, deep aching, or electrical pain, which often worsens at night.29 The symptoms commonly manifest in the feet and lower limbs, but can also be present in the hands. This classic pattern of symmetrical sensory loss is called the “stocking-glove” distribution.30 In more advanced cases of DPN, patients may simply feel numbness, which then can potentially lead to painless foot injury or ulceration.29 Other forms of neuropathy, such as heavy metal poisoning, alcohol abuse, neurotoxic medications, chronic inflammatory demyelinating polyneuropathy, vitamin B12 deficiency, hypothyroidism, vasculitis, and uremia, must be ruled out first before making a diagnosis of DPN. Of note, longterm use of metformin can cause vitamin B12 deficiency, which may be confused with painful diabetic peripheral neuropathy.31 A careful clinical examination should be done for all patients with diabetes to diagnose DPN. Comprehensive foot examination including inspection and assessment of foot pulses should be performed annually to identify predictive risk factors for ulcers and amputation.8 Simple clinical tests for foot exam include pinprick sensation, vibration perception tests with a 128-Hz tuning fork or a biothesiometer, 10-g monofilament pressure sensation, and ankle reflex assessment.8,29 These neurological exams are to identify loss of protective sensation, rather than early neuropathy. Abnormalities in more than 1 of these tests have greater than 87% sensitivity in detecting DPN.29 In particular, the 10-g monofilament sensation test is a strong predictor of future foot ulcer risk.32 Examination of the feet for ulcers, calluses, and deformity should also be performed.29 In addition, all patients with diabetes should be educated on how to
perform daily self-monitoring of their feet, proper selection of footwear, and proper skin and nail care for foot.8 Foot ulcers and wound care may require a referral to a podiatrist, orthopedic or vascular surgeon, or rehabilitation specialist. Further information on the diagnosis and treatment of diabetic foot ulcers and infections can be found in the clinical practice guideline of Infectious Diseases Society of America.33 Motor (focal and multifocal) neuropathies represent another category of diabetic neuropathy and are more common in older patients with type 2 diabetes.30 This category includes focal limb, cranial, truncal, and proximal motor neuropathy. 29 Focal limb neuropathy (mononeuropathy) is often, but not always, due to nerve entrapment. 30 Carpal tunnel syndrome, an example of nerve entrapment, occur in up 20% of diabetes patients.34 Cranial neuropathies are rare. Truncal neuropathies (thoracolumbar radiculoneuropathy) may present with girdle-like pain over the abdominal wall with spontaneous resolution within 4-6 months. Proximal motor neuropathy (amyotrophy) is characterized by relatively acute onset of unilateral or asymmetrically bilateral, severe pain with muscle wasting and weakness in the thighs.30 Autonomic neuropathy carries significant morbidity and even mortality in diabetes patients. Three common organ systems affected by diabetic autonomic neuropathy are the gastrointestinal, genitourinary, and cardiovascular systems. Neurologic dysfunction can manifest as gastroparesis, constipation, erectile dysfunction, bladder dysfunction, exercise intolerance, resting tachycardia, and orthostatic hypotension. Cardiovascular autonomic neuropathy may bring life-threatening consequences to diabetes patients such as silent myocardial ischemia and even sudden cardiac death.29 Tight glycemic control is the only way to prevent the development and progression of diabetic neuropathy. The DCCT study showed that improved glycemic control reduced the risk of diabetic neuropathy in patients with type 1 diabetes.10 Many epidemiologic studies have suggested that glycemic control helps prevent diabetic neuropathy in patients with type 2 diabetes as well.29 Many drugs have been studied for the treatment of the symptoms of DPN. DrugTopics .c om
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Tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, anticonvulsants, opioids, topical capsaicin, and the lidocaine patch have been clinically used to provide symptomatic relief from DPN pain. Only duloxetine, tapentadol, and pregabalin, however, have FDA’s approved indication for the treatment of DPN. Multiple national and international guidelines on the pharmacological treatment of painful DPN exist, and with various differences in their recommendations. The majority of the guidelines do recommend serotonin norepinephrine reuptake inhibitors (either duloxetine only or both duloxetine and venlafaxine), tricyclic antidepressants, or the alpha2-delta ligands pregabalin and gabapentin as firstor second-line treatment.35 In 2012, tapentadol extended-release was approved by the FDA for DPN pain severe enough to require around-the-clock opioid treatment, for which alternative analgesics have failed. It is a centrally-acting analgesic that has mu-opioid receptor agonist and norepinephrine reuptake inhibition activity and is classified as a Schedule II drug. It is the first and only opioid approved by the FDA for this indication at the time of writing. Pharmacologic treatment options for painful DPN should be carefully chosen and evaluated as these can cause significant side effects and drug interactions. For example, even though some guidelines recommend tricyclic antidepressants as a first-line treatment option, significant cardiac and anticholinergic side effects as well as weight gain can occur with this drug class. No pharmacologic agent currently available can modify the natural history of DPN. Thus, treatment should focus on glycemic control to prevent the onset and progression of diabetic neuropathy.29,30
TABlE 5
Age <40 years
40-75 years
>75 years
AmericAn DiAbetes AssociAtion’s recommenDAtions for stAtin therApY in pAtients With DiAbetes Risk factors
with lipid Recommended statin dose* Monitoring panel
None
None
CVD risk factor(s)α
Moderate or high
Overt CVDβ
High
None
Moderate
CVD risk factor(s)
High
Overt CVD
High
As needed to monitor adherence
None
Moderate
CVD risk factor(s)
Moderate or high
Overt CVD
High
As needed to monitor adherence
Abbreviations: CVD, cardiovascular disease. * In addition to therapeutic lifestyle modifications α Include low-density lipoprotein cholesterol ≥100 mg/dL, high blood pressure, smoking, and overweight and obesity β Includes those with previous cardiovascular events or acute coronary syndromes
Macrovascular complications Macrovascular complications such as myocardial infarction (MI), stroke, and peripheral artery disease are major consequences of diabetes. Patients with diabetes are at 2- to 4-fold increased risk for developing CVD.2 Patients with diabetes have 1.7 times higher rates of CVD death, 1.8 times higher rates of heart attack, and 1.5 times higher rates of stroke than adults without diabetes.1 The macrovascular complications are responsible for approximately 80% of mortality in diabetes patients. Although patients with diabetes commonly experience and complain of microvascular complications, the greatest cause of death in people with diabetes is CVD.36 The main pathologic mechanism of diabetic macrovascular complications is the development of atherosclerosis – the excessive accumulation of lipids, inflammatory cells, and connective tissue in the vessel wall. Ath-
pause&ponder Patients may better realize the importance of treatment adherence when you point out that their current symptoms (e.g. painful peripheral neuropathy or erectile dysfunction) are likely due to uncontrolled hyperglycemia. think of patients whom you can help to connect their current symptoms with complications of diabetes. DrugTopics .c om
Annually or as needed to monitor for adherence
Source: Ref 8
erosclerotic plaques are formed in response to endothelial cell dysfunction and activation as described previously. The plaques grow silently over decades and eventually occlude the vessel lumen causing ischemia to target tissues. Although this form of vessel occlusion causes considerable discomfort (eg, angina pectoris), clinical cardiovascular events commonly occur when a thrombus (blood clot) is formed due to the plaque deterioration or rupture, leading to rapid and complete cessation of blood supply to target tissues.2 Glycemic Control. Subsequent observational follow-up data of the landmark studies DCCT and UKPDS showed significant benefits of intensive therapy over conventional therapy on CVD. The DCCT/EDIC study research group followed 93% of the original cohort from DCCT for a mean duration of 17 years and found that intensive treatment reduced the risk of any CVD event by 42% and the risk of nonfatal MI, stroke, or death from CVD by 57%.37 The UKPDS demonstrated a nonsignificant 16% reduction in the risk of MI.9 In post-trial monitoring of 3,277 patients from UKPDS over 10 years, the intensive therapy group was associated with significant risk reductions for MI (15%, sulfonylurea-insulin group; 33%, metformin group) compared to the conventional therapy group.38 It should be noted that baseline differences in mean A1C levels between the intensive therapy group and the conventional therapy group were lost by 1 year. A prospective observaJuly 2015
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TABlE 6
MacRoVaScuLaR and MicRoVaScuLaR coMPLicationS
loW-DensitY lipoprotein cholesterol loWering potentiAl of stAtin therApY
High-intensity
Moderate-intensity
Low-intensity
Daily dose lowers LDL-C on average, by approximately ≥50%
Daily dose lowers LDL-C on average, by approximately 30% to <50%
Daily dose lowers LDL-C on average, by <30%
Atorvastatin 40-80 mg Rosuvastatin 20-40 mg
Atorvastatin 10-20 mg Rosuvastatin 5-10 mg Simvastatin 20-40 mg Pravastatin 40-80 mg Lovastatin 40 mg Fluvastatin XL 80 mg Fluvastatin 40 mg BID Pitavastatin 2-4 mg
Simvastatin 10 mg Pravastatin 10-20 mg Lovastatin 20 mg Fluvastatin 20-40 mg Pitavastatin 1 mg
Abbreviations: LDL-C, low-density lipoprotein cholesterol; XL, extended release; BID, twice daily.
tional study of UKPDS also found that each 1% reduction in A1C was associated with a 14% reduction in MI and a 12% reduction in stroke.12 The benefits of metformin in CVD were also observed in UKPDS, with a 39% reduction in MI in the metformin group compared to the dietary therapy group.39
The renoprotective effects of ACE inhibitors and ARBs are independent of their blood pressure-lowering effects. As these 2 landmark studies had no glycemic threshold further research was warranted, especially in patients with type 2 diabetes. Several large, long-term trials took place in response, including Action to Control Cardiovascular Risk in Diabetes (ACCORD), Action in Diabetes and Vascular Disease: Preterax and Diamicron ModifiedRelease Controlled Evaluation (ADVANCE), and Veterans Affairs Diabetes Trial (VADT). All of these studies enrolled older type 2 diabetes patients with long duration of type 2 diabetes.40 The ACCORD study looked at over 10,000 type 2 diabetes patients with ei-
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Source: Ref 49
ther history of CVD or significant CVD risk and randomized them to intensive glycemic control (goal A1C <6%) or standard glycemic control (goal A1C 7.0%-7.9%). Both groups were treated with multiple diabetes medications, but 35% of the participants were already treated with insulin at baseline. The mean duration of diabetes was 10 years. The glycemic control portion of the ACCORD study was stopped early due to an increased rate of all-cause mortality and cardiovascular deaths in the intensive control group. A clear explanation for the mortality findings could not be found.41 Severe hypoglycemia was associated with higher mortality than those without it in both groups.36 The ADVANCE study looked at over 11,000 patients with type 2 diabetes from Europe, Australia/New Zealand, Canada, and Asia. The participants were randomized to intensive glycemic control (primary therapy with gliclazide [a sulfonylurea] and additional medications with a target A1C ≤6.5%) or standard therapy (any diabetes medications except gliclazide with a target set according to “local guidelines”). Baseline characteristics of the patient population were similar to those of the ACCORD study, except that the participants of ADVANCE were slightly older and had an average duration of diabetes 2 years shorter, lower baseline A1C, and almost no use of insulin at baseline. The median A1C was 6.3% in the intensive therapy group and 7.0% in the standard therapy group. Despite the difference in A1C levels, no significant difference was found between the 2 groups in the macrovascular out-
come (hazard ratio 0.94, 95% confidence interval 0.84-1.06; P=.32).42 The VADT was a much smaller randomized, controlled trial compared to ACCORD and ADVANCE, including 1,791 military veterans. Participants of VADT were randomized to intensive glycemic control (goal <6%) or standard glycemic control (planned A1C difference of 1.5% between the 2 groups). Both groups used multiple and similar diabetes medications to achieve the glycemic goals. Median A1C level within the first 6 months of the study was 6.9% in the intensive group and 8.4% in the standard group. However, the intensive group showed no significant reduction in CVD events. In fact, more CVD deaths were found in the intensive group compared to the standard group, although the difference was not statistically significant.43 Exploratory analyses of VADT also found a close association between severe hypoglycemia and CVD mortality.36 A subsequent meta-analysis, including these 3 trials and 2 others, found that intensive glycemic control was associated with a statistically significant 17% risk reduction in nonfatal MI and 15% risk reduction in coronary heart disease but not in the risk of stroke or all-cause mortality.44 It has been suggested that, based on subgroup analyses from the 3 studies described above, clinicians can consider a more intensive glycemic goal than the general goal of A1C <7% in certain patients. These include those with short duration of diabetes, long life expectancy, and no significant CVD because intensive glycemic control may lower their CVD risk, provided that this can be achieved without significant hypoglycemia or other adverse effects of treatment. For patients who have a history of severe hypoglycemia, limited life expectancy, advanced microvascular or macrovascular complications, or extensive comorbid conditions, less-stringent A1C goals than the general goal of <7% may be appropriate.36 CVD risk factors. Management of macrovascular complications not only involves achieving glycemic control but also needs to include management of other CVD risk factors such as hypertension, dyslipidemia, and obesity. Collectively these CVD risk factors have been called the metabolic syndrome. The DrugTopics .c om
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components of metabolic syndrome are elevated blood glucose level, raised blood pressure, elevated triglyceride levels, low high-density lipoprotein cholesterol levels, and central obesity (Table 3).45 The metabolic syndrome has direct correlation to CVD outcomes and increases the risk for CVD by 2-fold over the next 5 to 10 years.45 The benefits of lipid and blood pressure lowering in decreasing CVD risk have been substantiated by many studies in patients with diabetes. Early detection and management of these CVD risk factors are crucial in diabetes management to prevent macrovascular events. In the ACCORD study, intensive systolic blood pressure (SBP) target (<120 mmHg) was compared to a less stringent SBP target (130-140 mmHg).46 The intensive SBP arm achieved a mean blood pressure of 119/64 mmHg while the less stringent SBP arm achieved a mean blood pressure of 143/70 mmHg. Despite the lower blood pressure achieved by the intensive SBP target arm, there was no difference in the rate of a composite outcome of fatal and nonfatal major cardiovascular events.46 In the ADVANCE-BP (blood pressure) study, the active blood pressure intervention arm (a single-pill, fixed-dose combination of perindopril and indapamide) was compared to the placebo group.47 A significant risk reduction was seen in major vascular events including death. The final blood pressure in the treatment arm was 136/73 mmHg, which was not as low as the blood pressure achieved by the intensive SBP target group in the ACCORD. Given these results, the ADA recommends a blood pressure goal of <140/90 mmHg in patients with diabetes. This is also in line with the recent hypertension guideline published by the 8th Joint National Committee.48 Tighter blood pressure goal (<130/80 mmHg) may still be considered for patients with long life expectancy, high risk for stroke, and chronic kidney disease.8 In terms of blood pressure management (Table 4), the ADA recommends that an ACE inhibitor or an ARB should be included in the antihypertensive regimen as these agents have been shown to be more effective in reducing CVD risk for diabetes patients than any other antihypertensive agents.8 Patients on these medications should have their kidney function and serum potassium level monitored.
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table 7
American Diabetes Association Aspirin Therapy Criteria
Consider aspirin therapy (75–162 mg/day) as primary prevention strategy in those with type 1 or type 2 diabetes at increased cardiovascular risk (10-year risk >10%) • Men >50 years or women >60 years of age AND at least 1 additional major CVD risk factor: ❍ Family history of CVD ❍ Hypertension ❍ Smoking ❍ Dyslipidemia ❍ Albuminuria Avoid aspirin therapy in patients at low CVD risk (10-year risk < 5%): men <50 years or women <60 years of age and no major additional CVD risk factors For men <50 years or women <60 years of age with multiple other CVD risk factors (10-year CVD risk 5-10%), clinical judgment is required. Abbreviations: CVD, cardiovascular disease.
Lipid management has been dramatically changed after the publication of the lipid guideline by the American College of Cardiology/American Heart Association.49 This lipid guideline no longer supports the use of low-density lipoprotein cholesterol (LDL-C) targets, but focuses on statin therapy and its potency because most trials of statins and CVD outcomes looked at specific doses of statins, rather than aiming at specific LDL-C goal. The ADA recommendations for statin therapy and the potency of various statins are summarized in Tables 5 and 6.8,49 Of all the medications for dyslipidemia, statins are the only agents that have clinical evidence for decreasing CVD mortality in diabetes patients.8 Addition of non-statin therapy (fibrate or niacin) to statin therapy provides no additional cardiovascular benefit and is not generally recommended.8 Of note, the bile acid sequestrant colesevelam has an FDAapproved indication for type 2 diabetes.50 Because of plaque erosion and rupture, patients with diabetes are at increased risk of thrombotic CVD.2 Aspirin therapy decreases the risk for CVD events but only in certain diabetes patients.8 The recommendation for aspirin therapy was changed with the 2010 ADA Standards of Care guideline. The recommendation was based on more recent research data that cast doubts on the efficacy of aspirin for primary prevention in diabetes patients. The efficacy depends on a patient’s underlying CVD risk, which must be weighted against the risk of gastrointestinal bleeding.51 The current (2015) criteria for aspirin therapy are
Source: Ref 8
listed in Table 7.8 In addition, patients with diabetes are encouraged to stop smoking or not begin smoking given that smoking increases the risk of CVD dramatically. Patients should be educated to know their “diabetes ABCs” – their A1C, blood pressure, and cholesterol goal and current values.52 Nonpharmacologic treatments such as dietary therapy, weight management, and physical activity can lead to the achievement of glycemic, blood pressure, and lipid goals and help prevent diabetic complications.
Conclusion Clinical evidence and science have proved clear relationships between diabetes and vascular complications. The impact of vascular complications is well understood among healthcare professionals. As a complex metabolic disease, diabetes requires more than just glycemic control to prevent and manage vascular complications.• Editor’s Note: This CE activity, which was first published in January 2013 for Drug Topics (print edition and online), has been updated and reaccredited in 2015. Dr. Lee updated the article. For immediate CPE credit, take the test now online at
www.drugtopics.com/cpe Once there, click on the link below Free CPE Activities
July 2015
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MacRoVaScuLaR and MicRoVaScuLaR coMPLicationS
test QUestions 1.
Which is NOT a microvascular complication of diabetes?
8.
a. Retinopathy b. Myopathy c. Nephropathy d. Neuropathy 2.
a. Pregabalin, tapentadol, and duloxetine b. Pregabalin, tapentadol, and amitriptyline c. Gabapentin, pregabalin, and duloxetine d. Gabapentin, tapentadol, and fluoxetine
Which is NOT an example of diabetic macrovascular complications? a. Peripheral artery disease b. Myocardial infarction (MI) c. Stroke d. Chronic kidney disease
3.
How early may clinically significant diabetic retinopathy be detected in a patient with diabetes? a. 5 years before diagnosis of diabetes b. 6 years before diagnosis of diabetes c. 7 years before diagnosis of diabetes d. 8 years before diagnosis of diabetes
4.
How often does a patient with diabetes need a dilated eye exam? a. Twice a year b. Once a year c. Every other year d. Every 5 years
5.
In terms of urine albumin-to-creatinine ratio, which of these ranges is considered normal urinary albumin excretion?
Which should be a part of the medication regimen for a patient with diabetes and nephropathy?
How often should a patient with diabetes and nephropathy be screened for nephropathy with urinary albumin excretion measurement? a. Twice a year b. Once a year c. Every other year d. Every 5 years
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Which may result from diabetic autonomic neuropathy? a. Silent MI b. Foot amputation c. Carpal tunnel syndrome d. Infection
10. What is the typical clinical presentation of diabetic peripheral neuropathy? a. Constripation b. Pain, tingling, and/or numbness in feet and ankles c. Erectile dysfuntion d. Bladder dysfunction 11. In terms of A1C, which should be the general goal of glycemic control in patients with diabetes according to the ADA?
12. Which 1 of these 4 antihypertensive medications is a preferred agent in patients with diabetes and hypertension? a. Valsartan b. Hydrochlorothiazide c. Amlodipine d. Clonidine
a. Thiazide diuretic b. Angiotensin-converting enzyme inhibitor c. Calcium channel blocker d. Beta blocker 7.
9.
a. <6% b. <6.5% c. <7% d. <8%
a. <30 mg/g b. 30-299 mg/g c. 300-499 mg/g d. >500 mg/g 6.
Which 3 drugs are FDA approved for diabetic peripheral neuropathic pain?
13. Which is NOT a component of metabolic syndrome? a. Central obesity b. Elevated blood pressure c. Elevated low-density lipoprotein (LDL) cholesterol d. Elevated blood glucose 14. According to the 2015 ADA Standards of Medical Care in Diabetes, what is the goal blood pressure for patients with diabetes?
15. What is the goal LDL cholesterol level in patients with diabetes and without overt cardiovascular disease (CVD)? a. <70 mg/dL b. <80 mg/dL c. <100 mg/dL d. No LDL cholesterol goal, treat based on CVD risk factors 16. According to the ADA, aspirin therapy is NOT indicated for which individuals with diabetes? a. 65-year-old male with microalbuminuria b. 55-year-old male with hypertension c. 57-year-old female with osteoporosis d. 62-year old female with dyslipidemia 17. Which anti-lipid agent has been shown to reduce CVD mortality in a patient with diabetes? a. Fenofibrate b. Niacin c. Fish oil d. Atorvastatin 18. Which anti-lipid agent also has an FDAapproved indication for the treatment of type 2 diabetes? a. Colesevelam b. Fenofibrate c. Niacin d. Omega-3 fatty acid 19. Blood pressure control is beneficial for which two microvascular complications of diabetes? a. Retinopathy and nephropathy b. Retinopathy and neuropathy c. Neuropathy and nephropathy d. Neuropathy and myopathy 20. Which is NOT a major risk factor in aspirin therapy criteria for a patient with diabetes who meets the age cut off? a. Smoking b. Dyslipidemia c. Carpal tunnel syndrome d. Albuminuria
a. <120/80 mm Hg b. <130/80 mm Hg c. <140/80 mm Hg d. <140/90 mm Hg
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References 1. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2014. http://www.cdc. gov/diabetes/pubs/statsreport14/national-diabetesreport-web.pdf. Accessed February 24, 2015. 2. Funk SD, Yurdagul A Jr, Orr AW. Hyperglycemia and endothelial dysfunction in atherosclerosis: Lessons from type 1 diabetes. Int J Vasc Med. 2012;2012:569654. 3. Calcutt NA, Cooper ME, Kern TS, Schmidt AM. Therapies for hyperglycaemia-induced diabetic complications: From animal models to clinical trials. Nat Rev Drug Discov. 2009;8:417-429. 4. Fong DS, Aiello LP, Ferris FL 3rd, Klein R. Diabetic retinopathy. Diabetes Care. 2004;27:2540-2553. 5. Watkins PJ. Retinopathy. BMJ. 2003;326:924-926. 6. Harris MI, Klein R, Welborn TA, Knuiman MW. Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis. Diabetes Care. 1992;15:815-819. 7. The Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;1-11. 8. American Diabetes Association. Standards of medical care in diabetes-2015. Diabetes Care. 2015;38(Suppl 1):S1-S94. 9. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352:837-853. 10. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986. 11. Cefalu W.T., Ratner R.E. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study at 30 years: the “gift” that keeps on giving! Diabetes Care. 2014;37:5-7. 12. Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): Prospective observational study. BMJ. 2000;321:405-412. 13. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703-713. 14. Klein R, Klein BE. Blood pressure control and diabetic retinopathy. Br J Ophthalmol. 2002;86:365-367. 15. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria, retinopathy and strokes. Kidney Int. 2002;61:1086-1097. 16. Adler AI, Stevens RJ, Manley SE, et al; UKPDS Group. Development and progression of nephropathy in type 2 diabetes: The United Kingdom Prospective Diabetes Study (UKPDS 64). Kidney Int. 2003;63:225-232. 17. Chaturvedi N, Bandinelli S, Mangili R, et al. Microalbuminuria in type 1 diabetes: Rates, risk factors and glycemic threshold. Kidney Int. 2001;60:219-227. 18. Valmadrid CT, Klein R, Moss SE, Klein BE. The risk of cardiovascular disease mortality associated with microalbuminuria and gross proteinuria in persons with older-onset diabetes mellitus. Arch Intern Med. 2000;160:1093-1100. 19. Gross JL, de Azevedo MJ, Silveiro SP, et al. Diabetic nephropathy: Diagnosis, prevention, and treatment. Diabetes Care. 2005;28:164-176. 20. Ismail-Beigi F, Craven T, Banerji MA, et al.; ACCORD trial group. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes:
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an analysis of the ACCORD randomized trial. Lancet. 2010;376:419-430. 21. Reichard P, Nilsson BY, Rosenqvist U. The effect of longterm intensified insulin treatment on the development of microvascular complications of diabetes mellitus. N Engl J Med. 1993;329:304-309. 22. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: Results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355:253-259. 23. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869. 24. Parving HH, Lehnert H, Brőchner-Mortensen J, et al; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870-878. 25. National Kidney Foundation. KDOQI clinical practice guidelines for diabetes and CKD: 2012 update. Am J Kidney Dis. 2012 Nov;60(5):850-886. 26. Maser RE, Steenkiste AR, Dorman JS, et al. Epidemiological correlates of diabetic neuropathy. Report from Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes. 1989;38:1456-1461. 27. Franklin GM, Shetterly SM, Cohen JA, Baxter J, Hamman RF. Risk factors for distal symmetric neuropathy in NIDDM: The San Luis Valley Diabetes Study. Diabetes Care. 1994;17:1172-1177. 28. Boulton AJ, Gries FA, Jervell JA. Guidelines for the diagnosis and outpatient management of diabetic peripheral neuropathy. Diabet Med. 1998;15:508-514. 29. Boulton AJ, Vinik AI, Arezzo JC, et al; American Diabetes Association. Diabetic neuropathies: A statement by the American Diabetes Association. Diabetes Care. 2005;28:956-962. 30. Boulton AJ, Malik RA, Arezzo JC, Sosenko JM. Diabetic somatic neuropathies. Diabetes Care. 2004;27:14581486. 31. de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: Randomised placebo controlled trial. BMJ. 2010;340:c2181. 32. Abbott CA, Carrington AL, Ashe H, et al; North-West Diabetes Foot Care Study. The North-West Diabetes Foot Care Study: Incidence of, and risk factors for, new diabetic foot ulceration in a community-based patient cohort. Diabet Med. 2002;19:377-384. 33. Lipsky BA, Berendt AR, Cornia PB, et al.; Infectious Diseases Society of America. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012;54:e132-e173. 34. Kim RP, Edelman SV, Kim DD. Musculoskeletal complications of diabetes mellitus. Clin Diab. 2001;19(3):132-135. 35. Spallone V. Management of painful diabetic neuropathy: guideline guidance or jungle? Curr Diab Rep. 2012;12:403-413. 36. Skyler JS, Bergenstal R, Bonow RO, et al; American Diabetes Association; American College of Cardiology Foundation; American Heart Association. Intensive glycemic control and the prevention of cardiovascular events: Implications of the ACCORD, ADVANCE, and VA diabetes trials: A position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care. 2009;32:187-192.
37. Nathan DM, Cleary PA, Backlund JY, et al; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643-2653. 38. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577-1589. 39. UK Prospective Diabetes Study Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;352:854-865. 40. Bloomgarden ZT. Glycemic control in diabetes: A tale of three studies. Diabetes Care. 2008;31:1913-1919. 41. Gerstein HC, Miller ME, Byington RP, et al. Action to Control Cardiovascular Risk in Diabetes Study Group. N Engl J Med. 2008;358:2545-2559. 42. ADVANCE Collaborative Group. Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560–2572. 43. Duckworth W, Abraira C, Moritz TE, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360:129-139. 44. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: A meta-analysis of randomised controlled trials. Lancet. 2009;373:1765-1772. 45. Alberti KG, Eckel RH, Grundy SM, et al; International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640-1645. 46. ACCORD Study Group, Cushman WC, Evans GW, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362:1575-1585. 47. Patel A, ADVANCE Collaborative Group, MacMahon S, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomized controlled trial. Lancet. 2007;370:829-840. 48. James PA, Oparil S, Carter BL, et al. 2014 evidencebased guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eight Joint National Committee (JNC 8). JAMA. 2014;311:507-520. 49. Stone NJ, Robinson JG, Lichtenstein AH, et al; American College of Cardiology/American Heart Association Take Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1-45. 50. Welchol (colesevelam) [package insert]. Daiichi Sankyo, Inc. Parsippany, NJ; 5/2013. 51. American Diabetes Association. Standards of medical care in diabetes-2010. Diabetes Care. 2010;33(Suppl 1):S11-S61. 52. Know your diabetes ABCs. (A1C, blood pressure, and cholesterol). Available at: http://ndep.nih.gov/i-havediabetes/KnowYourABCs.aspx. Accessed 11/28/12.
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