Pathophysiology of Diabetes

The student should be able to:

Incorporate appropriate psychosocial, cultural, health literacy, and family data into the management plan of a patient with type 2 diabetes. Apply evidence-based standards of care to the diagnosis, monitoring, and management of a patient with type 2 diabetes mellitus. Describe the barriers to coordination of diabetes care and systemwide improvements that could improve coordination of diabetes care. Describe the importance of an interprofessional team approach to the care of patients with diabetes. Describe the utility of the electronic medical record in the care of your practice population and in the reporting of quality measures. Educate a patient about type 2 diabetes with attention to and respect for the patient’s own disease model. Pathophysiology of Diabetes

Knowledge

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Comprehensive Annual Diabetes Visit

The American Diabetes Association (ADA) provides standards of care for diabetes management that are updated annually and can be downloaded to a smartphone. Clinician tasks for diabetes care:

Confirm the diagnosis and classify diabetes. Evaluate for diabetes complications and potential comorbid conditions. Review previous treatment and risk factor control in patients with established diabetes. Begin patient engagement in the formulation of a care-management plan. Develop a plan for continuing care.

See the American Diabetes Association’s “Components of the Comprehensive diabetes medical evaluation at initial, follow-up, and annual visits”: Part 1 (.jpg) | Part 2 (.jpg)

Electronic Medical Record

An electronic medical record system:

Offers templates that increase the likelihood that patients will receive the recommended care. May improve the quality of care in primary care settings. Provides tools to evaluate patient care across an entire population. Allows documentation of improved physician performance, which may increase reimbursements by some insurers. Has been shown to interrupt the clinician-patient relationship—particularly via “screen gaze.”

Pathophysiology of Diabetes

Type 1 diabetes mellitus

The pancreas is damaged through autoimmune inflammation leading to destruction of the beta cells. The loss of beta cells leads to the complete inability to produce insulin, (immunologic etiology). Type 2 diabetes mellitus

The body is unable to recognize the insulin produced by the pancreas and use it properly (insulin resistance). Increased beta cell insulin secretion may initially compensate, but over time beta cells fail. Chronic complications

Both types of diabetes can cause the same end-organ damage. High blood glucose eventually affects blood vessels and therefore organs throughout the entire body. The heart, brain, kidneys, eyes, and the nerves that control sensation and autonomic function are affected. Remember: High blood pressure, which many patients with diabetes have, makes the vascular disease much worse.

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Cardiovascular disease, including coronary heart disease, cerebrovascular disease, and peripheral arterial disease

People with diabetes are two to four times more likely to have heart disease or stroke than people without diabetes. Patients with diabetes who have a myocardial infarction have worse outcomes than patients without diabetes, and a diagnosis of diabetes is considered equivalent in risk to having had a previous myocardial infarction. Management of cardiovascular risk factors so commonly found in diabetes is therefore essential in preventing morbidity and mortality in these patients. The American College of Cardiology/American Heart Association ASCVD risk calculator (Risk Estimator Plus) is generally a useful tool to estimate 10-year ASCVD risk. These calculators include diabetes as a risk factor, since diabetes itself confers increased risk for ASCVD, although it should be acknowledged that these risk calculators do not account for the duration of diabetes or the presence of diabetes complications, such as albuminuria. Retinopathy

Diabetes is the most common cause of new cases of blindness among adults aged 18-64 years. Five years after diagnosis of type 2 diabetes, patients with more severe or uncontrolled disease that requires insulin have a 40% prevalence of retinopathy while those on oral hypoglycemic agents have a 24% prevalence. After 15 years of diabetes, almost all patients with type 1 diabetes and two-thirds of patients with type 2 diabetes have background retinopathy. By the time the patient’s vision is affected, substantial retinal damage may have already occurred. Proliferative retinopathy is prevalent in 25% of patients with 25 or more years of diabetes. In addition to optimizing glycemic control, optimizing blood pressure and serum lipid control can also slow the progression of diabetic retinopathy. Neuropathy Pathophysiology of Diabetes

Neuropathy is a heterogeneous condition that is associated with nerve pathology. The condition is classified according to the nerves affected. The classification of neuropathy includes focal, diffuse, sensory, motor, and autonomic neuropathy. The prevalence of neuropathy defined by loss of ankle jerk reflexes is 7% at 1 year, increasing to 50% at 25 years, for both type 1 and type 2 diabetes. Nephropathy

Nephropathy is common in diabetes: 20-40% of people with diabetes develop diabetic nephropathy. Diabetes was listed as the primary cause of kidney failure in 44% of all new cases in 2014.

Acute Diabetic Decompensations (DKA and HHS)

Type 1 diabetes

In patients with type 1 diabetes, without sufficient insulin, blood sugar runs high, and diabetic ketoacidosis (DKA) can develop. Type 2 diabetes

Patients with type 2 diabetes with hyperglycemia more often develop hyperosmolar hyperglycemic state (HHS). Typically it is the patient with type 1 diabetes who is most at risk for developing DKA; however, patients with type 2 diabetes can also develop DKA. This happens because, over time, type 2 diabetes starts to resemble type 1 diabetes as pancreatic function dwindles and patients with type 2 diabetes may begin to require insulin. If insulin deficiency is severe enough, a patient with type 2 diabetes may produce ketones and develop hyperglycemia. For example, an older adult patient with longstanding type 2 diabetes who becomes acutely ill with pneumonia could easily develop DKA.

Screening Recommendations for Type 2 Diabetes

American Diabetes Association recommendations

1. Testing should be considered in overweight or obese (BMI ≥ 25 kg/m2 or ≥ 23 kg/m2 in Asian Americans*) adults who have one or more of the following risk factors:

First-degree relative with diabetes High-risk race/ethnicity** (e.g., African American, Latino, Native American, Asian American, Pacific Islander) History of CVD Hypertension (≥ 140/90 mmHg or on therapy for hypertension) HDL cholesterol level < 35 mg/dL (0.90 mmol/L) and/or a triglyceride level > 250 mg/dL (2.82 mmol/L) Women with polycystic ovary syndrome Physical inactivity Other clinical conditions associated with insulin resistance (e.g., severe obesity, acanthosis nigricans)

2. Patients with prediabetes (A1C ≥ 5.7%, impaired glucose tolerance (two-hour plasma glucose > 140 mg/dL following a 75 gram glucose load) should be tested yearly. 3. Women who were diagnosed with GDM should have lifelong testing at least every three years. 4. For all other patients, testing should begin at age 45. 5. If results are normal, testing should be repeated at a minimum of three-year intervals, with consideration of more frequent testing depending on initial results and risk status. * This lower BMI cut off is due to the difference in distribution of fat. Asian Americans tend to exhibit more visceral than peripheral fat, which is more closely associated with insulin resistance and type 2 diabetes. Pathophysiology of Diabetes

**^ The American Diabetes Association recommends screening in these groups because they are disproportionately affected by type 2 diabetes. It is important to keep in mind that race/ethnicity alone does not cause diabetes, and clinicians should address the modifiable social and structural factors that contribute to these disparities. United States Preventive Services Task Force (USPSTF) Recommendations

For adults aged 40 to 70 years who are overweight or obese, screen for abnormal blood glucose as part of cardiovascular risk assessment. Clinicians should offer or refer patients with abnormal blood glucose to intensive behavioral counseling interventions to promote a healthful diet and physical activity. Rating: grade B recommendation. For obese or overweight adults under age 40 who have additional risk factors (e.g., family history of diabetes, history of gestational diabetes), it may be reasonable to start screening before age 40.

Diagnostic Criteria for Diabetes Mellitus

1. A random glucose of 200 mg/dL or above, plus symptoms of hyperglycemia, such as polyuria or unexplained weight loss, or hyperglycemic crisis.

2. A fasting plasma glucose of greater than or equal to 126 mg/dL. Fasting is defined as no caloric intake for at least eight hours.

3. A hemoglobin A1C greater than or equal to 6.5%. 4. Two-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT).

The diagnosis requires two abnormal test results from the same sample or in two separate test samples unless there is a clear clinical diagnosis (e.g., patient in a hyperglycemic crisis or with classic symptoms of hyperglycemia and a random plasma glucose ≥ 200 mg/dL).

Who Gets Diabetes?

Prevalence of diagnosed and undiagnosed diabetes in the United States, all ages, 2018:

Total: 34.2 million people (10.5% of the population) have diabetes Diagnosed: 26.9 million people Undiagnosed: 7.3 million people (21.4% of the total number of Americans with diabetes)

Prevalence of diabetes (diagnosed and undiagnosed) among people aged 18 years or older, United States, 2018:

Age 18 years or older: 34.1 million, 13% of all people in this age group have diabetes. Age 65 years or older: 14.3 million, 26.8% of all people in this age group have diabetes.

After adjusting for population age differences, 2017-2018 national survey data for U.S. adults aged 18 years or older indicate that the following percentages have diagnosed diabetes:

7.5% of non-Hispanic Whites 9.2% of Asian Americans 12.5% of Hispanics 11.7% of non-Hispanic Blacks 14.7% of American Indians/Alaska natives

Prediabetes

In 2018 prediabetes affected roughly 88 million adults in the U.S. Prediabetes is defined as the presence of either impaired fasting glucose-IFG (fasting glucose 100—125 mg/dl) or impaired glucose tolerance-IGT (2 hr values of oral glucose tolerance testing 140 —199 mg/dl). New evidence shows that damage to end-organs is already occurring during prediabetes and that progression to diabetes can be delayed or prevented with lifestyle modification and to a lesser degree with medication. The Diabetes Prevention Program (DPP) was a randomized, five-year study to evaluate intensive lifestyle modification (education, coaching in diet and exercise, etc.) versus diet/exercise information along with 850 mg of metformin twice a day. The study population included 3,200 participants with impaired glucose tolerance. Intensive lifestyle modification produced a 58% reduction in risk for type 2 diabetes or a delay of about 11 years. The metformin group showed a less impressive 31% risk reduction.

Diabetic Retinopathy

The most frequent cause of new blindness among adults (aged 20—74 years). Laser photocoagulation treatment can slow the progression of retinopathy and reduce vision loss, but it doesn’t restore lost vision. Since the treatment is aimed at preventing vision loss, and retinopathy is asymptomatic for its initial course, it’s important to identify and treat patients early in the course of the disease. In severe, non-proliferative retinopathy, look for the following findings on a fundoscopic exam:

Retinal hemorrhages are dark blots with indistinct borders that indicate partial obstruction and infarction. Cotton wool spots are white spots with fuzzy borders and they indicate areas of previous infarction. They accompany hemorrhages. Microaneurysms are more punctate dark lesions that indicate vascular dilatation.

Neovascularization is the hallmark of proliferative retinopathy. The growth of new blood vessels is prompted by retinal vessel occlusion and hypoxia.

Optimal range for blood glucose:

Fasting blood glucose should be 80—120 mg/dl Postprandial blood glucose between one to two hours after a meal should be < 180 mg/dl

Conditions that contribute to hyperglycemia:

Overeating, missing doses of medication, dehydration, infection and illness, and stress.

Clinical Skills

Understanding the Patient’s Experience of His or Her Illness

Often in practice, clinicians use one-way communication to describe the biomedical explanation for the disease and the recommended treatment. The LEARN model, developed by Berlin and Fowkes, is a simple way to remember the importance of two-way dialogue with your patient about their understanding of their own disease.

Listen with empathy and understanding to the patient’s perception of the problem. Explain your perceptions of the problem and your strategy for treatment. Acknowledge and discuss the differences and similarities between these perceptions. Recommended treatment while remembering the patient’s cultural parameters. Negotiate an agreement. It is important to understand the patient’s explanatory model so that medical treatment fits in their cultural framework.

Think Cultural Health offers a Guide to Providing Effective Communication and Language Assistance Services. This is a tool from the Office of Minority Health of the U.S. Department of Health and Human Services designed to help facilitate communication with patients from various cultural and linguistic backgrounds.

Annual Foot Exam for Patients with Diabetes

The American Diabetes Association recommends that all patients with diabetes have an annual foot exam and provides standard of care guidelines for this exam, including testing for neuropathy. Foot ulceration is the result of impaired sensation (distal symmetric polyneuropathy) and impaired perfusion (diabetes vasculopathy and peripheral vascular disease), both of which are independent, strong risk factors for foot ulceration and amputation. The early recognition and appropriate management of neuropathy in the patient with diabetes is important because:

1. Up to 50% of diabetic peripheral neuropathy (DPN) may be asymptomatic but leave patients at risk of foot ulceration. 2. Nondiabetic neuropathies may be present in patients with diabetes and may be treatable. 3. While specific treatment for the underlying nerve damage is currently not available—other than improved glycemic control,

which may slow progression but not reverse neuronal loss—effective symptomatic treatments are available for some manifestations of DPN.

The foot exam should include:

Testing for loss of protective sensation

Sensory testing, according to the ADA, should be conducted with a 10-gram monofilament PLUS any one of the following: 1. Vibration using a 128-Hz tuning fork 2. Pinprick sensation 3. Ankle reflexes (Achilles necessary but patellar not needed)

Assessment of pedal pulses (dorsalis pedis and posterior tibial arteries). Assessing the arterial supply to the lower limbs and feet is essential in evaluation for peripheral vascular disease, the strongest risk factor for delayed ulcer healing and amputation in diabetes patients. Inspection: Skin changes such as hair loss and temperature changes may signal vascular insufficiency. Since foot ulceration is usually caused by breaks in the skin due to accidental trauma or poorly fitted footwear, at each visit the patient’s feet should be inspected for breaks in the skin, pressure calluses that precede ulceration, existing ulceration, and infection, and bony abnormalities that lead to abnormal pressure distribution and ulceration. The patient’s footwear should also be inspected for abnormal patterns of wear and appropriate sizing.

Monofilament Testing for Patients with Diabetes

Video on Monofilament Sensory Testing

How to Request a Referral

Include pertinent patient information and a clear request or question to be addressed by the consultant. Sending a patient summary that includes the past medical history, medication list, allergies, and insurance information is very helpful. If there are relevant laboratory or imaging results, these should be included or summarized.

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Diabetes Education: Conversation Map

Health Interactions Conversation Maps are ADA-approved tools for facilitating diabetes education. Based on adult learning principles, the maps are designed to engage the group participants in discussion of various aspects of diabetes care (nutrition, glucose monitoring, exercise, complications, etc). The U.S. Conversation Map tools meet the ADA Recognition criteria from a complete DSME curriculum.

Management

Management of Specific ASCVD Risk Factors

Atherosclerotic cardiovascular disease or ASCVD (i.e., coronary heart disease and stroke) is the leading cause of death in patients with diabetes. Patients with diabetes are two to four times more likely to have heart disease or stroke than people without diabetes. Diabetes patients with myocardial infarction have worse outcomes than patients without diabetes, and a diagnosis of diabetes is considered equivalent in risk to having had a previous myocardial infarction. Management of cardiovascular risk factors so commonly found in patients with diabetes is therefore essential in preventing morbidity and mortality in patients with diabetes. Management of specific ASCVD risk factors:

Smoking cessation:

Advise all patients not to use cigarettes and other tobacco products (level of evidence A) or e-cigarettes (level of evidence A).

Include smoking cessation counseling and other forms of treatment as a routine component of diabetes care (level of evidence A).

Advising all patients to simply cut back on their smoking has not been shown to improve cardiovascular outcomes. Strong and convincing evidence exists for a causal link between cigarette smoking and health risk, making smoking the most important modifiable cause of premature death. Patients with diabetes who smoke have a higher risk of premature development of microvascular complications, CVD, and premature death. A number of large randomized clinical trials have demonstrated the efficacy and cost-effectiveness of smoking cessation counseling in changing smoking behavior. Also, there is no evidence that e- cigarettes are a healthier alternative to smoking or that e-cigarettes can facilitate smoking cessation. Hypertension:

Lower blood pressure in diabetic patients with stage 1 hypertension > 130/80 mmHg. Clear observational evidence indicates that lower blood pressures are associated with improved cardiovascular and renal outcomes for patients with diabetes, and this relationship extends as low as systolic pressures of 115 mmHg. In the meta-analysis produced for the 2017 ACC/AHA blood pressure guideline, researchers found evidence that treating patients to a blood pressure < 130/80 mmHg helped prevent such outcomes, AND they found similar outcomes for patients with and without diabetes. Thus the 2017 guideline recommends using both behavioral interventions and medications to lower blood pressures in adults with diabetes to below a goal of 130/80 mmHg. They specifically mention that physicians may choose any of the four classes of medications for patients with diabetes: thiazides, ACE inhibitors, angiotensin receptor blockers (ARBs), or calcium channel blockers. For more required information about hypertension management in patients with diabetes, read the Aquifer Hypertension Guidelines Module . Dyslipidemia:

Dyslipidemia is a known risk factor for CVD in diabetic and non-diabetic populations. Abundant evidence supports the use of statins in the prevention of cardiovascular morbidity and mortality in patients with diabetes. Measurement of fasting lipids is recommended at the time of diagnosis of diabetes and annually for patients on statins. The American College of Cardiology and American Heart Association (ACC/AHA) recommends the following blood cholesterol treatment for patients with diabetes and LDL-c 70—189 mg/dL:

Moderate-intensity statin therapy should be initiated or continued for adults 40 to 75 years of age with diabetes mellitus (level of evidence A). High-intensity statin therapy is reasonable for adults 40 to 75 years of age with diabetes mellitus with a ≥ 7.5% estimated 10-year ASCVD risk unless contraindicated (level of evidence B). In adults with diabetes mellitus who are younger than 40 or older than 75 years of age, it is reasonable to evaluate the potential for ASCVD benefits and for adverse effects, for drug-drug interactions, and to consider patient preferences when deciding to initiate, continue, or intensify statin therapy (level of evidence C). Note, the ACC/AHA recommends all patients older than 21 (with or without diabetes) who have an LDL-c > 190 should be started on statin therapy (level of evidence B).

For more required information about cholesterol management in patients with diabetes, read the Aquifer Cholesterol Guidelines Module.

Lifestyle modification—weight loss, increase exercise, decrease fat intake (level of evidence A).

Aspirin:

Aspirin is effective in reducing cardiovascular morbidity and mortality in patients with previous MI or stroke (secondary prevention). For patients with no previous cardiovascular events (primary prevention), the net benefit is not as evident. Aspirin therapy for primary prevention can be discussed with a patient through a process of shared decision-making, weighing the potential cardiovascular benefits with the risk of bleeding. Recommendations for using aspirin as primary prevention include men and women aged ≥ 50 years with diabetes and at least one additional major risk factor: family history of premature ASCVD,

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Aspirin therapy (75 to 162 mg/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 (level of evidence A). Use aspirin therapy (75 to 162 mg/day) as a secondary prevention strategy in those with diabetes and a history of atherosclerotic cardiovascular disease (level of evidence A). For patients with atherosclerotic cardiovascular disease and documented aspirin allergy, clopidogrel (75 mg/day) should be used (level of evidence B). Dual antiplatelet therapy (with low-dose aspirin and a P2Y12 inhibitor) is reasonable for a year after an acute coronary syndrome (level of evidence A) and may have benefits beyond this period (level of evidence B).

The U.S. Preventive Services Task Force (USPSTF) recommends: Adults aged 50 to 59 years with a ≥ 10% 10-year CVD risk:

The USPSTF recommends initiating low-dose aspirin use for the primary prevention of cardiovascular disease (CVD) and colorectal cancer (CRC) in adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk, are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years (level of evidence B).

Adults aged 60 to 69 years with a ≥ 10% 10-year CVD risk: The decision to initiate low-dose aspirin use for the primary prevention of CVD and CRC in adults aged 60 to 69 years who have a 10% or greater 10-year CVD risk should be an individual one. Persons who are not at increased risk for bleeding, have a life expectancy of at least 10 years, and are willing to take low-dose aspirin daily for at least 10 years are more likely to benefit. Persons who place a higher value on the potential benefits than the potential harms may choose to initiate low-dose aspirin (level of evidence C).

The commonly prescribed dose in the U.S. is 81 mg daily. Glycemic control:

Lowering patients’ A1Cs to < 7% has been shown conclusively to prevent microvascular disease (retinopathy and nephropathy). Whether this glycemic control prevents macrovascular disease has been less clear. A recent meta-analysis of 5 randomized controlled trials of intensive (A1C of 6–6.5) versus standard (A1C of 7%) glycemic control showed a significant reduction in CVD outcomes (fatal and non-fatal myocardial infarction) but very importantly failed to show a decrease in stroke or all-cause mortality. A recent randomized trial of intensive glycemic control found no benefit for preventing CVD over five years, but disturbingly found an increase in all-cause mortality. This isolated finding warrants further study, but the current ADA guidelines recommend that the A1C goal is still close to or less than 7% and that treatment should be tailored to the patient to avoid hypoglycemia and weight gain. More or less stringent targets may be appropriate for individual patients if achieved without significant hypoglycemia or adverse events. Additionally, other organizations may interpret the evidence differently, and recommend higher or lower A1C goals. For example, the American College of Physicians (ACP) recommends aiming to achieve an A1C between 7% and 8%.

​Using the Pooled Cohort Equations risk calculator, you estimate Ms. Sanchez’s ten-year ASCVD risk at 15.2%. Aspirin therapy should be considered for primary prevention in patients with diabetes with a 10-year risk > 10%, which includes females with diabetes 50 years of age or older who have at least one additional major risk factor. Her additional risk factor would be elevated blood pressure (hypertension). You would need to discuss a risk of bleeding, and have a discussion of the benefits and risks with the patient.

ADA Standards of Medical Care in Diabetes

The American Diabetes Association recommends a patient-centered approach to choosing appropriate pharmacologic treatment of blood glucose. This includes consideration of key factors: 1) Important comorbidities such as atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), and heart failure (HF) 2) Hypoglycemia risk 3) Effects on body weight 4) Side effects 5) Cost 6) Patient preferences Lifestyle modifications that improve health should be emphasized along with any pharmacologic therapy. Due to recent evidence in support of some of the newer agents for diabetes, the ADA recently changed its algorithm for medication management for this important disease. While metformin remains the first-line therapy in addition to lifestyle changes, this new algorithm highlights the importance of recognizing patient comorbidities, such as ASCVD or CKD. For patients with established ASCVD or major ASCVD risk factors, a GLP-1 receptor agonist or a SGLT2 inhibitor is preferred based on cardiovascular risk reduction. For patients with heart failure (particularly LVEF <45%) or CKD, SGLT2 inhibitors are recommended with evidence of reducing HF and CKD progression. For patients without established ASCVD or CKD, the choice of a second agent to add to metformin is not as evidence-based. Rather, it is based on avoidance of side effects, particularly hypoglycemia and weight gain, cost, and patient preferences. Pathophysiology of Diabetes

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Recent evidence supports the use of GLP-1 Receptor Agonists in patients with type 2 diabetes who need greater glucose lowering than can be obtained with oral agents. Most GLP-1 RA products are injectable, but there is an oral formulation of semaglutide now available. Trials comparing the addition of an injectable GLP-1 RA or insulin in patients needing further glucose lowering show a similar efficacy between the two treatments. But, GLP-1 RAs in these trials had a decreased risk of hypoglycemia and greater benefit on body weight compared with insulin, although they did have more gastrointestinal side effects. Therefore, in patients with type 2 diabetes who need greater glucose lowering than can be obtained with oral agents, GLP-1 RAs are preferred to insulin when possible (level of evidence B). Still, one must consider the high costs and side effect profile as potential barriers to the use of GLP-1 RAs. Table: available agents for type 2 diabetes management. Pathophysiology of Diabetes