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I have a patient who is concerned that she has diabetes. How do I confirm the diagnosis and treat patients with diabetes🚧 施工中
I have a patient who is concerned that she has diabetes. How do I confirm the diagnosis and treat patients with diabetes?
Diane Altkorn, MD
CHIEF COMPLAINT
PATIENT
Mrs. D is a 50-year-old African American woman who is worried she has diabetes.
What is the differential diagnosis of diabetes? How would you frame the differential?
CONSTRUCTING A DIFFERENTIAL DIAGNOSIS
The differential diagnosis of diabetes mellitus (DM) is actually a classification of the different types of diabetes:
A. Type 1 DM
1. Of the persons with DM in Canada, the United States, and Europe, 5–10% have type 1.
2. Caused by cellular-mediated autoimmune destruction of the pancreatic beta cells in genetically susceptible individuals, triggered by an undefined environmental agent
a. Some combination of antibodies against islet cells, insulin, glutamic acid decarboxylase (GAD65), or tyrosine phosphatases IA-2 and IA-2beta are found in 85–90% of patients.
b. Strong HLA association
c. Risk is 0.4% in patients without family history, 5–6% in siblings and children, and 30% in monozygotic twins.
d. Patients are also prone to autoimmune thyroid disease, Addison disease, vitiligo, celiac disease, autoimmune hepatitis, myasthenia gravis, and pernicious anemia.
3. Insulin therapy is always necessary.
4. Because of the complete lack of insulin production, patients are at high risk for diabetic ketoacidosis (DKA).
B. Type 2 DM
1. Caused by a progressive loss of beta cell insulin secretion frequently with underlying insulin resistance
2. A heterogeneous disorder related to inflammation, metabolic stress, and genetic factors
C. Other, less common causes of diabetes
1. Monogenic diabetes syndromes
2. Exocrine pancreatic diseases that lead to the destruction of beta cells (pancreatitis, trauma, cystic fibrosis, pancreatectomy, pancreatic carcinoma)
3. Endocrinopathies (acromegaly, Cushing syndrome, glucagonoma, pheochromocytoma)
4. Drug or chemical-induced (corticosteroids, HIV/AIDS medications, after organ transplantation)
D. Gestational diabetes
Type 1 DM generally occurs in children, although approximately 7.5–10% of adults assumed to have type 2 DM actually have type 1, as defined by the presence of circulating antibodies. Type 2 DM is becoming more prevalent in teenagers and young adults, presumably related to the increased prevalence of obesity.
In most patients, the distinction between type 1 and type 2 DM is clear. Thus, the primary tasks of the clinician are to determine who should be tested for diabetes, who has diabetes, which complications to monitor, and how to treat the patient.
Mrs. D has worried about having diabetes since her father died of complications from the disease. Over the last couple of weeks, she has been urinating more often and notes larger volumes than usual. She is aware that excess urination can be a symptom of diabetes, so she scheduled an appointment.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?
RANKING THE DIFFERENTIAL DIAGNOSIS
Mrs. D’s pretest probability of diabetes is high because of 2 pivotal points in her history, the polyuria and the positive family history. Excess fluid intake and diseases that cause true polyuria, defined as urinary output of > 3 L/day, should also be considered. Bladder dysfunction and urinary tract infection generally cause frequent, small volume urination. Since patients sometimes have trouble quantifying the amount of urine produced, causes of small volume urinary frequency should be kept in the differential. Table 12-1 lists the differential diagnosis.
Table 12-1. Diagnostic hypotheses for Mrs. D.
Mrs. D has no dysuria or hematuria. She takes no medications, drinks 1 cup of coffee per day, and uses alcohol rarely. She has been trying to lose weight and has been drinking more water in an attempt to reduce her appetite.
On physical exam, she looks a bit tired. Vital signs are temperature, 37.0°C; BP, 138/82 mm Hg; pulse, 96 bpm; RR, 16 breaths per minute. The remainder of the physical exam is normal. A random plasma glucose is 152 mg/dL.
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
Leading Hypothesis: Type 2 DM
Textbook Presentation
Patients with type 2 DM can have the classic symptoms of polyuria, polydipsia, and weight loss. The presentation can also be more subtle, with patients complaining that they feel tired or “just not right.” Many patients are asymptomatic; the diagnosis is made after plasma glucose testing. The complications of diabetes may already be present by the time patients seek medical attention.
Disease Highlights
A. Caused by a combination of impaired insulin secretion and insulin resistance with no evidence of autoimmunity
B. Accounts for 90–95% of cases of DM, with prevalence in the United States of about 9.4%, with considerable variation by ethnic group
1. The prevalence in American Indian/Alaska Native persons is 15.1%.
2. The prevalence in black and Hispanic persons is 12–14%.
3. The prevalence in Asian, non-Hispanic persons is 8%, with Asian Indians having the highest prevalence (11.2%).
4. The prevalence in white, non-Hispanic persons is 7.4%.
C. Diabetes is undiagnosed in 24% of people.
D. Strong genetic component
1. 39% of patients have at least 1 parent with diabetes
2. 60–90% concordance in monozygotic twins
3. The lifetime risk of a first-degree relative of a patient with type 2 DM is 5–10 times higher than that of age- and weight-matched individuals without a family history.
E. The most important risk factor is obesity, which induces insulin resistance.
1. The relative risk of diabetes developing in a woman who has a body mass index (BMI) > 35 kg/m2 is 93, compared with a woman who has a BMI < 22 kg/m2.
2. The relative risk of diabetes developing in a man who has a BMI > 35 kg/m2 is 42, compared with a man who has a BMI < 23 kg/m2.
F. DKA develops less often in patients with type 2 DM than those with type 1; however, DKA can occur in persons with type 2 DM. Recent data show that two-thirds of patients with DKA have type 1 DM, and one-third have type 2 DM.
Do not assume all patients with DKA have type 1 DM; DKA can develop in persons with type 2 DM.
G. Risk factors for type 2 DM include
1. Age ≥ 45
2. BMI ≥ 25 kg/m2
3. A first-degree relative with diabetes
4. Physical inactivity
5. Being a member of a high-risk ethnic group (African American, Latino, Native American, Asian American, Pacific Islander)
6. Having delivered a baby weighing > 9 pounds or having had gestational DM
7. Hypertension
8. High-density lipoprotein (HDL) cholesterol < 35 mg/dL or triglycerides > 250 mg/dL
9. Polycystic ovary syndrome
10. Vascular disease
11. Prediabetes (impaired glucose tolerance [IGT], impaired fasting glucose [IFG], or mildly elevated HbA1c; see Evidence-Based Diagnosis section for definitions)
a. Patients with either IGT or IFG have a 5–10% annual risk of developing diabetes; those with both have a 10–15% annual risk.
b. Patients with an HbA1c in the prediabetes range have an annual risk of 10–50% with the risk increasing as the HbA1c increases.
c. These annual risks are 10–20 times higher than in people without prediabetes.
H. Screening for diabetes
1. American Diabetes Association (ADA) recommends screening patients beginning at age 45.
a. Screening should be done at any age in patients with a BMI ≥ 25 (≥ 23 in Asian Americans) and 1 of the additional risk factors listed above.
b. Screening should be done every 3 years in patients with normal results, and every year in patients with prediabetes.
2. In 2015, the US Preventive Services Task Force recommended screening adults aged 40–70 years who are overweight or obese (B recommendation).
Evidence-Based Diagnosis
A. Table 12-2 lists the ADA diagnostic criteria for diabetes and prediabetes.
Table 12-2. American Diabetes Association diagnostic criteria for prediabetes and diabetes.
B. The ADA recommends that all abnormal results be confirmed with repeat testing.
C. Most physicians screen with either the fasting plasma glucose (FPG), HbA1c, or both; the oral glucose tolerance test is used primarily to screen for gestational diabetes.
1. FPG is widely available and inexpensive; the primary disadvantage is the need for fasting at least 8 hours.
2. The HbA1c is now globally standardized and does not require fasting.
a. Falsely low values can occur in patients with rapid red cell turnover, such as in hemoglobinopathies, active hemolysis, erythropoietin treatment, and stage 4 or 5 chronic kidney disease.
b. Falsely high values can be seen when red cell turnover is low, such as in iron, vitamin B12, or folate deficiency.
c. African American patients tend to have slightly higher HbA1c levels (0.2–0.4%) than white patients at the same glucose levels.
D. Patients may have abnormal results on 1 or both tests; in 1 study, one-third of new diabetes cases were detected by FPG testing only, one-third by HbA1c testing only, and one-third by both tests.
Patients with normal HbA1c levels may still have diabetes by fasting glucose criteria.
Treatment of Prediabetes
A. The goals are to prevent or delay the onset of diabetes and to optimize other cardiac risk factors.
B. Large randomized trials have shown that lifestyle modification or medication can prevent or delay diabetes.
1. Finnish patients with IGT were randomized to brief diet/exercise counseling or intensive individualized instruction.
a. There was a 58% relative reduction in the development of diabetes in the intensive group, (NNT = 22 to prevent 1 case of DM over 1 year; NNT = 5 to prevent 1 case of DM over 5 years).
b. The study cohort has been monitored for 7 years post-intervention; the group of patients initially assigned to the intensive lifestyle intervention maintained a 43% relative risk reduction in the development of diabetes.
2. Patients in the United States (45% African American or Hispanic) were randomized to intensive diet/exercise program, metformin, or placebo.
a. There was a 58% relative reduction in the development of DM in the intensive diet/exercise group and a 31% relative reduction in the metformin group.
b. NNT = 7 over 3 years to prevent 1 case of diabetes for the intensive diet/exercise group, and NNT = 14 for the metformin group.
c. The patients initially assigned to the intensive diet/exercise program maintained a 34% relative risk reduction in the development of diabetes over 10 years.
3. Acarbose, orlistat, liraglutide, and pioglitazone have also been studied, but the ADA does not recommend their use in diabetes prevention.
Lifestyle modification is the best way to prevent or delay the onset of diabetes.
C. Optimal lifestyle modification goals are 150 minutes of aerobic exercise weekly, such as brisk walking, and losing 7% of the baseline body weight.
D. None of the drugs studied is FDA approved for diabetes prevention; the ADA recommends considering metformin in patients under 60 with a BMI > 35 and/or with progressive hyperglycemia, or those with a history of gestational diabetes.
E. The goal of hypertension therapy in patients with prediabetes is the same as that for patients without diabetes (see Chapter 23, Hypertension).
F. Hyperlipidemia should be treated according to current guidelines for nondiabetic patients (see Chapter 23, Hypertension).
MAKING A DIAGNOSIS
Mrs. D’s random glucose is elevated but is not diagnostic of diabetes. She reports that when she reduces her fluid intake, she urinates less. You ask her to return for more testing:
FPG, 120 mg/dL
HbA1c, 6.0%
Urinalysis: negative for protein, glucose, and blood; no WBCs or bacteria; specific gravity, 1.015.
Have you crossed a diagnostic threshold for the leading hypothesis, type 2 DM? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?
Mrs. D does not meet the diagnostic criteria for diabetes, but she does have prediabetes. This does not cause glycosuria of a degree sufficient to cause urinary frequency. A urinary tract infection is ruled out by the normal urinalysis. She has increased her water consumption, so excess fluid intake is a likely cause of her symptoms. Bladder dysfunction should be considered if her symptoms do not resolve with the reduction in fluid intake. Diabetes insipidus and primary polydipsia are rare diseases that do not need to be considered unless she has a documented urinary output of more than 3 L/day. The next diagnostic test should be reducing her fluid intake.
CASE RESOLUTION
Mrs. D stops forcing herself to drink extra water, and her urination pattern returns to normal. She is very concerned about her elevated FPG and wants to know how to prevent progression to diabetes. Her BMI is 30 kg/m2, and her fasting lipid panel shows total cholesterol of 220 mg/dL; HDL, 38 mg/dL; triglycerides, 250 mg/dL; and low-density lipoprotein (LDL), 132 mg/dL. You refer her to a dietician for dietary counseling and recommend that she walk 30 minutes per day 5 days a week. When she returns to see you 4 months later, she has lost 8 pounds. Her FPG is 112 mg/dL; total cholesterol 197 mg/dL, HDL, 42 mg/dL; triglycerides, 150 mg/dL; and LDL, 125 mg/dL.
FOLLOW-UP OF MRS. D
Mrs. D returns 5 years later, having lived in another city in the meantime. She reports that she did quite well with her diet and exercise program for several years, maintaining a 10% weight loss. However, over the last couple of years, she has not been able to continue her exercise program or be as careful about her diet because of the stresses of caring for her chronically ill mother as well as working and caring for her own family. Her mother died recently, so Mrs. D has moved back. She knows that she has gained weight and is especially worried about her blood sugar level because she did not have time to see a doctor herself during her mother’s illness.
On physical exam, her BMI is now 34 kg/m2 (up 4 kg/m2 from her initial visit), and her BP is 155/88 mm Hg. Her lungs are clear, and on cardiac exam, you hear an S4 but no S3 or murmurs. Abdominal exam is normal, and there is no peripheral edema. Her peripheral pulses are normal, and there are no ulcerations on her feet. She does have tinea pedis. Her point-of-care glucose measurement is 335 mg/dL.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?
RANKING THE DIFFERENTIAL DIAGNOSIS
Clearly, Mrs. D now has type 2 DM. At this point, in addition to starting treatment, the clinician should focus on identifying and managing diabetic complications and associated cardiovascular risk factors rather than ruling out other diagnoses (Table 12-3).
Table 12-3. Diagnostic hypotheses for Mrs. D’s follow-up.
Mrs. D does not report any vision loss, numbness, edema, dyspnea, or chest pain.
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
Leading Hypothesis: Diabetic Complications
1. Retinopathy
Textbook Presentation
Most patients with retinopathy are asymptomatic. Other patients experience either gradual or sudden vision loss.
Disease Highlights
A. Most common cause of new cases of blindness in adults aged 20–74 years.
B. Incidence and risk of progression have declined over the past 30 years, with a 77% decrease in the annual incidence of retinopathy in patients with type 1 DM.
C. Stages of diabetic retinopathy (DR)
1. Nonproliferative (NPDR)
a. Earlier stage of DR
b. Earliest signs are microaneurysms and retinal hemorrhages
c. Progressive capillary nonperfusion leads to ischemia, manifested by increasing cotton wool spots, venous beading, and intraretinal vascular abnormalities.
2. Proliferative diabetic retinopathy (PDR)
a. Most advanced form of DR
b. Progressive retinal ischemia causes the formation of new blood vessels on the retina or optic disk.
c. The new vessels bleed, leading to vision loss because of vitreous hemorrhage, fibrosis, or retinal detachment.
3. Diabetic macular edema
a. Can develop at any stage of retinopathy
b. Now the leading cause of vision loss in persons with diabetes
c. Increased vascular permeability causes plasma leaks from the macular vessels, leading to swelling and formation of hard exudates at the central retina.
D. Risk factors include duration of DM, elevated HbA1C level, hypertension, dyslipidemia, pregnancy, and nephropathy.
Evidence-Based Diagnosis
A. Evaluation should include dilated indirect ophthalmoscopy or fundus photography, or both, by an ophthalmologist.
B. Patients with type 1 DM should have an exam within 5 years of disease onset, followed by at least annual exams.
C. Patients with type 2 DM should have an exam at the time of diagnosis, followed by at least annual exams; patients with well-controlled DM and no retinopathy may be able to have exams every 2 years.
Most patients with type 2 DM need eye exams by an ophthalmologist at least annually.
D. Screening fundus photography using smartphones is being studied in low resource areas.
Treatment
A. Glycemic control
1. In persons with type 1 DM without retinopathy, the risk of developing DR is reduced 76% by tight control (HbA1C 7.2% vs 9.1% in the Diabetes Control and Complications Trial).
2. In persons with type 1 DM with retinopathy, the risk of progression is reduced by 54% by tight control.
3. In persons with type 2 DM, better control reduces the risk of microvascular complications (retinopathy and nephropathy) by 16–25%. (HbA1C 7% vs 7.9% in the United Kingdom Prospective Diabetes Study [UKPDS] [1998]; HbA1C 6.5% vs 7.2% in the ADVANCE trial [2008].)
4. In persons with type 2 DM, there is a 35% reduction in the risk of microvascular complications for every percentage point decrease in HbA1C.
B. Better BP control reduces the incidence and progression of retinopathy.
C. Aspirin neither improves nor worsens retinopathy; the presence of DR is not a contraindication to aspirin therapy.
D. Laser photocoagulation is indicated for PDR and selected cases of severe NPDR.
E. Anti-vascular endothelial growth factor, given by intraocular injection, improves vision in patients with diabetic macular edema.
F. There is some evidence that fenofibrate slows the progression of DR; it is recommended for secondary prevention in Australia and Canada.
2. Neuropathy
Textbook Presentation
Diabetic peripheral neuropathy (DPN) can be focal but classically presents as paresthesias or burning pain in a “stocking-glove,” symmetric distribution. Diabetic autonomic neuropathy can manifest in a variety of ways, including orthostatic dizziness, diarrhea, urinary incontinence, and gastroparesis.
Disease Highlights
A. Focal mononeuropathies
1. Cranial (0.05% of mononeuropathies)
a. Usually cranial nerve III or VI
b. Usually acute and transient
c. Caused by ischemia
2. Thoracolumbar
3. Limb
a. Median nerve most common site (5.8% of mononeuropathies)
b. Ulnar (2.1%), femoral, and peroneal also affected
B. Diabetic lumbosacral radiculoplexus neuropathy (also called diabetic amyotrophy): pain, severe asymmetric muscle weakness, and wasting of the iliopsoas and quadriceps muscles
C. Distal symmetric polyneuropathy (most common manifestation of DPN)
D. Epidemiology of distal symmetric polyneuropathy
1. Found in at least 20% of patients with type 1 DM after 20 years of the disease
2. Found in 10–15% of people in whom type 2 DM is newly diagnosed, with up to 50% of patients affected after 10 years
3. May be present in 10–30% of people with prediabetes
4. Patients with distal symmetric polyneuropathy have a 15–25% lifetime risk of a foot ulcer or gangrene and a 15% lifetime risk of amputation.
5. Severity is related to duration of disease, degree of glycemic control, presence of hypertension, obesity, smoking, and hyperlipidemia.
E. Clinical manifestations of distal symmetric polyneuropathy
1. History and physical exam
a. Up to 50% of patients are asymptomatic
b. Classified as small fiber neuropathy, large fiber neuropathy, or mixed
(1) Small fiber dysfunction causes stabbing pains, electric shocks, allodynia, hyperalgesia and hyperesthesia
(2) Small fiber physical findings include abnormal temperature and pinprick sensation and abnormal autonomic function (dry skin, poor blood flow, cold feet, and impaired sweating) with normal strength, reflexes, and nerve conduction
(3) Large fiber neuropathy causes deep-seated, gnawing or aching pain, numbness and tingling, weakness, ataxia, and poor balance
(4) Physical findings in large fiber disease include impaired reflexes, loss of proprioception and vibration sense, weakness in feet, wasting of small muscles of hands and feet
c. Symptoms often worse at night
d. When symptoms ascend to the knees, upper extremity symptoms start
2. Charcot joints develop, usually in the tarsometatarsal region, in 10% of patients.
F. Differential diagnosis of distal symmetric polyneuropathy
1. Cervical myelopathy, lumbar stenosis, tarsal tunnel syndrome, and digital neuropathies can all mimic DPN, and must be looked for on physical exam.
2. Consider other causes of neuropathy if
a. There is greater impairment of motor than sensory function
b. There is rapid progression of symptoms
c. It is asymmetric
d. Proximal or upper extremity involvement is disproportionate to distal lower extremity involvement
3. Be sure to check for other causes of peripheral neuropathy (eg, hypothyroidism, vitamin B12 deficiency, monoclonal gammopathy), even in patients with long-standing diabetes.
Think about other causes of neuropathy in diabetic patients.
G. Diabetic autonomic neuropathy can affect any organ innervated by the autonomic nervous system.
1. Cardiovascular autonomic neuropathy has many possible manifestations.
a. Reduced heart rate variability; associated with increased risk of silent ischemia and cardiac death
b. Fixed heart rate
c. Resting sinus tachycardia
d. Inadequate increase in heart rate/BP with exercise
e. Postural hypotension with systolic BP drop of > 20 mm Hg or >10 mm Hg drop in diastolic BP
f. Intraoperative cardiac instability
2. Gustatory sweating
a. Facial sweating, often accompanied by flushing, that occurs after eating
b. Generally occurs in patients with nephropathy or peripheral neuropathy
c. Cause unknown
3. GI dysfunction
a. Reduced esophageal motility
b. Gastroparesis
(1) Abnormality of gastric motility leading to delayed gastric emptying
(2) Symptoms include nausea, vomiting, anorexia, postprandial fullness, early satiety.
(3) Poor correlation between demonstrated motility abnormalities and symptoms
c. Diabetic diarrhea
(1) Characterized by intermittent, brown, watery, voluminous stools, occasionally accompanied by tenesmus
(2) Can be episodic, separated by periods of normal bowel movements or constipation
(3) Rare in the absence of other manifestations of neuropathy, either peripheral or autonomic
d. Constipation
(1) Constipation specifically resulting from autonomic neuropathy occurs in 20% of patients with type 2 DM.
(2) Caused by abnormality in autonomic neural control of colonic motility
e. Anorectal dysfunction
(1) Results in fecal incontinence, even in the absence of diarrhea
(2) Patients can generally sense the presence of stool, but cannot prevent passage
4. Genitourinary dysfunction
a. Bladder dysfunction
(1) Initially motor function normal, but sensation of bladder distention impaired
(2) Then, detrusor muscle hypocontractility occurs, leading to urinary retention and overflow incontinence.
b. Erectile dysfunction
(1) Present in 28–45% of diabetic men
(2) Most common organic cause of erectile dysfunction
(3) Risk factors include duration of DM, glycemic control, smoking, other diabetic complications.
Evidence-Based Diagnosis
A. Distal symmetric polyneuropathy
1. Nerve conduction studies are the gold standard for large fiber neuropathies but are normal in small fiber disease.
2. A randomized trial showed that patients screened for DPN with a physical exam had lower amputation rates than those not screened.
3. The ADA recommends annual comprehensive foot exams including inspection, assessment of pedal pulses, testing for small fiber function with assessment of either pinprick or temperature sensation, assessing large fiber function by testing vibration sense with a 128-Hz tuning fork, and identifying feet at risk for ulceration and amputation with an annual 10-g monofilament test. (Patients with abnormal monofilament testing have a 2- to 10-fold risk of developing a foot ulcer.)
4. Although studies use variable physical exam techniques, the standards follow (Table 12-4):
Table 12-4. Physical exam findings in diabetic peripheral neuropathy.
a. Semmes-Weinstein monofilament examination
(1) Apply a 5.07/10-g monofilament to a non-callused site on the dorsum of the first toe just proximal to the nail bed.
(2) Repeat 4 times on both feet in an arrhythmic manner.
(3) Add up the total number of times the monofilament is perceived by the patient (score range = 0–8).
(4) Some studies test different sites with the monofilament: plantar surfaces of the first, third, and fifth toes; the first, third, and fifth plantar metatarsal heads, medial foot, lateral foot. One study showed that testing the third and fifth toes plus the first and third metatarsal heads identified 95% of the patients with abnormal results on 8-point testing.
b. On-off vibration testing
(1) Apply a vibrating 128-Hz tuning fork to the bony prominence at the dorsum of the first toe just proximal to the nail bed.
(2) Repeat twice on each foot.
(3) Add up the total number of times the patient perceives the application of the vibrating tuning fork and the cessation of the vibration (score range = 0–8).
c. Timed vibration testing
(1) Apply a vibrating 128-Hz tuning fork to the same location used for the on-off vibration test.
(2) Ask the patient to report the time at which vibration diminished beyond perception and compare with the number of seconds perceived by the examiner when the tuning fork is applied to the examiner’s thumb.
(3) Record number of times patient’s perception time is less than examiner’s (score range = 0–8).
d. Superficial pain sensation
(1) Apply a sterile sharp to the same sites used for the monofilament.
(2) Repeat 4 times on each foot.
(3) Add up the total number of times the patient did not perceive the painful stimulus (score range = 0–8).
5. Monofilament testing is more reproducible than timed vibration testing.
6. Table 12-4 lists the test characteristics.
Patients with any abnormal neurologic exam findings in the foot are likely to have DPN and are at high risk for developing ulcerations; those with normal exams may have early DPN but have a lower risk of developing ulcerations.
B. Diabetic autonomic neuropathy
1. Cardiovascular autonomic neuropathy
a. Cardiology consultation is necessary to evaluate heart rate variability.
b. Postural change in systolic BP is used to diagnose orthostatic hypotension caused by diabetic autonomic neuropathy; the systolic BP is measured with the patient supine and again after 2 minutes of standing.
2. Gustatory sweating is diagnosed by history.
3. Gastrointestinal (GI) dysfunction
a. Esophageal dysmotility: Esophagogastroduodenoscopy and manometry
b. Gastroparesis: Diagnosed clinically or by a “gastric emptying” study, consisting of double-isotope scintigraphy of either solids or liquids.
c. Diabetic diarrhea: Rule out other causes of chronic diarrhea.
d. Anorectal dysfunction: Anorectal manometry and defecography can be done to document abnormalities.
4. Genitourinary dysfunction
a. Urinary bladder dysfunction: Ultrasound and urodynamic testing
b. Erectile dysfunction: History
Treatment
A. Tight glycemic control
1. Definitely prevents and improves neuropathy in persons with type 1 DM (relative risk reduction of 60%, NNT of 15 to prevent 1 case of neuropathy in tightly controlled patients)
2. Possibly prevents and improves neuropathy in persons with type 2 DM
B. Otherwise, treatment is symptomatic.
1. Peripheral neuropathy
a. Pregabalin and duloxetine are FDA approved for the treatment of neuropathic pain in diabetes.
b. Gabapentin, tricyclic antidepressants (such as amitriptyline or nortriptyline), and venlafaxine can also be used.
c. Tramadol has been shown to be effective in two multicenter trials and can be considered in patients refractory to other agents; other opioids should be considered only in consultation with a pain specialist.
d. Nonsteroidal anti-inflammatory drugs generally are not effective; capsaicin is possibly effective.
All patients with DM should receive foot care education. Those with DPN or structural foot abnormalities should be referred to a podiatrist, and screening for peripheral arterial disease with an ankle-brachial index is recommended by some guidelines.
2. Autonomic neuropathy
a. Cardiovascular
(1) Orthostatic hypotension is usually the most disabling symptom.
(a) Patients should raise head of bed and rise slowly.
(b) Patients can try an elasticized garment that extends from the feet to the costal margins.
(c) Midrodrine is FDA approved for the treatment of orthostatic hypotension.
(2) Cardioselective beta-blockers are sometimes helpful.
b. Sweating: no specific treatment available; clonidine may be effective.
c. Esophageal dysmotility: can try prokinetic agents such as metoclopramide but not for longer than 12 weeks due to risk of tardive dyskinesia.
d. Gastroparesis
(1) Severe gastroparesis is very difficult to manage.
(2) Small meals sometimes help.
(3) Prokinetic agents, such as metoclopramide or erythromycin, sometimes are effective.
(4) Gastric electrical stimulation is being studied for refractory cases.
e. Constipation
(1) Increase fiber.
(2) Drug choices include lactulose, polyethylene glycol, stool softeners.
(3) Avoid senna, cascara due to stimulant activity.
f. Urinary bladder dysfunction
(1) Bethanecol
(2) Intermittent self-catheterization
g. Erectile dysfunction: sildenafil and other similar agents
3. Nephropathy
Textbook Presentation
Diabetic nephropathy is asymptomatic until it is advanced enough to cause symptoms of chronic kidney disease.
Disease Highlights
A. Occurs in 20–40% of patients with diabetes
B. The most common cause of end-stage renal disease (ESRD) in the United States
C. Definitions (based on spot collection and calculation of the albumin/creatinine ratio in mcg/mg)
1. Normal < 30 mcg/mg
2. Microalbuminuria = 30–299 mcg/mg
3. Macroalbuminuria (overt nephropathy) ≥ 300 mcg/mg
D. Natural history: much better defined for type 1 than for type 2 DM
1. Type 1 DM
a. Renal enlargement and hyperfunction at onset of diabetes; continues for 5–15 years
b. Microalbuminuria appears 10–15 years after onset of DM; glomerular filtration rate (GFR) and BP initially normal.
c. Over the ensuing 10–15 years, 80% of patients progress to macroalbuminuria; GFR declines and hypertension develops.
d. ESRD develops in 50% of patients with macroalbuminuria within 10 years and in 75% by 20 years.
2. Type 2 DM
a. Natural history is less well defined because the onset of type 2 DM is usually not well defined, and other causes of kidney disease (such as hypertension and vascular disease) are common comorbidities.
b. 20–40% of patients with microalbuminuria progress to macroalbuminuria.
c. 20% have ESRD within 20 years of the onset of macroalbuminuria.
E. Risk factors for development of nephropathy
1. Poor glycemic control
2. Hypertension
3. Long duration of DM
4. Male sex
5. Ethnic predisposition (Native American, African American, Hispanic [especially Mexican American])
F. Patients with any amount of albuminuria have an increased risk of cardiovascular events.
Evidence-Based Diagnosis
A. ADA recommends annual screening for microalbuminuria beginning at the time of diagnosis for patients with type 2 DM and starting at year 5 for patients with type 1 DM.
B. The recommended screening is a spot urinary albumin/creatinine ratio.
1. There is diurnal variation, so first-void or early-morning specimens are best; otherwise, try to obtain confirmatory specimen at same time of day as initial specimen.
2. Short-term hyperglycemia, exercise, urinary tract infection, marked hypertension, heart failure, and acute febrile illness can cause transient elevations in albumin excretion.
3. Because of variability, 2 of 3 specimens in a 3- to 6-month period should be abnormal before diagnosing new or progressive diabetic nephropathy.
4. For morning specimens, sensitivity ranges from 70% to 100% and specificity ranges from 91% to 98%.
5. For random specimens, sensitivity ranges from 56% to 97% and specificity ranges from 81% to 92%.
C. It is not clear whether it is necessary to measure the albumin/creatinine ratio annually in patients being treated with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB); the ADA states it is “reasonable” to do so to monitor response to treatment and progression of diabetic kidney disease.
D. All patients should have a serum creatinine checked at least annually.
Treatment
A. Tight glycemic control reduces nephropathy.
1. Type 1 DM: incidence of microalbuminuria is reduced by up to 43% and that of macroalbuminuria by 56%.
2. Type 2 DM
a. Better control reduces the risk of microvascular complications (retinopathy and nephropathy) by 16–25%.
b. NNT = 36 over 10 years in the UKPDS; NNT = 66 over 5 years in the ADVANCE trial.
c. The microvascular complication rate was 58% for patients with an HbA1C ≥ 10% and 6.1% for patients with an HbA1C < 6.0% (UKPDS).
d. Microvascular complication rate decreases by 37% for every 1% reduction in HbA1C.
B. BP control and choice of agents
1. BP should be < 140/90 mm Hg; aiming for a BP < 130/80 mm Hg is appropriate if it can be achieved without adverse medication effects. Diastolic BPs < 60–70 mm Hg should be avoided.
2. Either ACE inhibitors or ARBs should be used.
a. ACE inhibitors have been shown to reduce
(1) Progression to overt nephropathy in persons with type 1 and type 2 DM who have hypertension and microalbuminuria
(2) Progression to microalbuminuria in persons with type 2 DM who have hypertension and normoalbuminuria
(3) Cardiovascular events in patients with type 2 DM
b. ARBs have been shown to reduce progression to overt nephropathy in persons with type 2 DM who have hypertension and albuminuria.
c. ACE inhibitors should be used first because of the reduction in cardiovascular events, with ARBs used in patients who cannot tolerate ACE inhibitors.
ACE inhibitors and ARBs should not be used together; doing so increases the incidence of acute kidney injury and hyperkalemia without leading to benefits beyond using either agent alone.
3. There is some evidence that adding mineralocorticoid receptor antagonists, such as spironolactone, to an ACE inhibitor or ARB further reduces albuminuria although does not change the risk of progressive kidney disease; hyperkalemia is more frequent.
C. There are conflicting data regarding the efficacy of dietary protein restriction.
D. There is emerging evidence that SGLT-2 inhibitors, such as empagliflozin, may reduce progression of nephropathy.
E. When to refer to a nephrologist
1. Uncertainty regarding the etiology of the kidney disease
2. Advanced chronic kidney disease (estimated GFR < 30 mL/min/1.73 m2)
3. Complications of chronic kidney disease
a. Anemia
b. Secondary hyperparathyroidism
c. Metabolic bone disease
d. Electrolyte abnormalities
F. ACE inhibitors and ARBs are not recommended for primary prevention of diabetic kidney disease in patients with normal BP, normal albumin/creatinine ratio and normal estimated GFR.
4. Diabetic Foot Ulcers
Textbook Presentation
A patient with peripheral neuropathy is unaware of minor trauma and the beginning of plantar ulceration. By the time the ulcer is discovered incidentally, it is usually advanced, often with associated osteomyelitis.
Disease Highlights
A. Lifetime risk of developing an ulcer may be as high as 19–34%.
B. Nearly all patients with ulcers have neuropathy, and over 50% have peripheral arterial disease, a strong predictor of nonhealing ulcers.
C. Tend to occur at pressure points, so plantar surface and sites of calluses are common locations.
1. Venous ulcers generally occur above the medial or lateral malleolus.
2. Arterial ulcers generally occur on the toes, metatarsal heads, or shins.
D. Risk factors
1. Previous amputation or foot ulcer
2. Peripheral neuropathy
3. Foot deformity
4. Peripheral arterial disease
5. Visual impairment
6. Diabetic nephropathy (especially patients on dialysis)
7. Poor glycemic control
8. Smoking
9. Preulcerative callus or corn
E. Pathophysiology
1. Biomechanical abnormalities: foot deformities and sometimes motor neuropathy leading to excess stress on pressure points
2. Loss of protective sensation: sensory neuropathy with impaired or absent pain sensation leading to lack of awareness of incipient ulceration
3. Skin changes: autonomic neuropathy with decreased sweating and dry skin leading to easily injured skin that heals poorly
4. Repetitive external or minor trauma
5. Peripheral artery disease: ischemia leading to poor healing and ulcer progression
F. Classification of diabetic foot infections
1. Mild
a. At least 2 of the following: local swelling or induration, erythema > 0.5 cm around the ulcer, local tenderness or pain, local warmth, purulent discharge
b. Involves skin and subcutaneous tissue, with no involvement of deeper tissues and no systemic signs
c. Erythema extends ≤ 2 cm from the ulcer
2. Moderate: signs of local infection, plus
a. Erythema extends more than 2 cm from the ulcer, or deep structure involved (abscess, osteomyelitis, septic arthritis, fasciitis)
b. No systemic inflammatory response signs (SIRS)
3. Severe: local infection plus at least 2 SIRS criteria
a. Temperature > 38°C or < 36°C
b. Pulse > 90 bpm
c. RR > 20 breaths/min or PaCO2 < 32 mm Hg
d. WBC > 12,000 or < 4000 cells/mcL or ≥ 10% band forms
G. Microbiology (see Table 12-5 for microbiology and empiric treatment based on severity)
Table 12-5. Microbiology and treatment of diabetic foot infections.
1. Acute infections in patients who have not taken antibiotics recently are usually monomicrobial.
2. Gram-negative bacteria are found in patients with chronic, previously treated wounds.
3. Deep and chronic infections are generally polymicrobial, especially if patients have received antibiotics; cultures grow 3–5 isolates, including anaerobes.
H. Osteomyelitis develops in up to 20% of patients with mild foot infections and in 50–60% of those with moderate to severe infections.
Osteomyelitis can still develop in patients with mild foot infections.
Evidence-Based Diagnosis
A. Patients with neuropathy should have a foot exam at every visit.
You cannot examine the feet of your diabetic patients too often, and you cannot examine them with their shoes on!
B. All patients with ulcers should have an ankle-brachial index to look for peripheral arterial disease.
C. Culturing ulcers
1. Do not culture clinically uninfected ulcers.
2. Do not obtain a specimen by swabbing the wound or wound drainage.
3. Cleanse and debride the wound before obtaining a specimen.
a. If purulent secretions are present, aspirate using a sterile needle or syringe.
b. Obtain a tissue specimen by scraping the base of a debrided ulcer with a sterile scalpel or dermal curette.
D. Diagnosing complications
1. Cellulitis: clinical diagnosis (see Chapter 17, Edema)
2. Osteomyelitis (Table 12-6)
Table 12-6. Test characteristics for the diagnosis of osteomyelitis in patients with diabetic foot ulcers.
a. Open bone biopsy with culture is the gold standard.
b. Needle bone biopsy for the diagnosis of osteomyelitis is subject to sampling error (sensitivity, 87%; specificity, 93%; LR+, 12.4; LR–, 0.14).
c. Being able to see bone or to probe the ulcer down to bone substantially increases the probability the patient has osteomyelitis.
d. C-reactive protein, erythrocyte sedimentation rate, CBC, blood cultures are not sufficiently sensitive or specific to diagnose osteomyelitis.
e. MRI is the imaging procedure with the best test characteristics; bone scan and WBC scans are less specific but are sometimes done in patients who cannot undergo MRI.
MRI scan is the best imaging procedure to diagnose osteomyelitis in a patient with a diabetic foot ulcer.
A normal CBC, C-reactive protein, or erythrocyte sedimentation rate does not rule out osteomyelitis.
Treatment
A. Preventive foot care
1. Improve glycemic control to reduce risk of neuropathy.
2. Reduce vascular risk factors (smoking cessation, BP control, lipid management, glycemic control).
3. Examine the feet of high-risk patients at every visit.
4. Examine the feet of low-risk patients at least annually.
5. Ensure patients wear well-fitted shoes.
6. Educate patients regarding need for daily visual inspection of feet.
7. Refer to podiatrist for débridement of calluses, assessment of bony deformities.
B. Treatment of ulcers
1. Treat any infection (see Table 12-5).
2. Determine need for revascularization, and revascularize as early as possible in patients with treatable peripheral vascular disease.
3. Heal the ulcer.
a. Offloading: use orthotics or fiberglass casts to remove pressure from the wound while allowing the patient to remain active.
b. Débride ulcers (surgically or with débriding agents such as hydrogels).
c. Control edema.
d. Growth factors are being studied.
4. Institute preventive measures once the ulcer has healed.
A multidisciplinary approach, including internal medicine, vascular surgery, and podiatry is necessary for the optimal treatment of diabetic foot ulcers.
MAKING A DIAGNOSIS
The ophthalmologist reports that Mrs. D has no retinopathy. Her neurologic exam, including monofilament testing, is normal. She does not complain of orthostatic dizziness or any GI or genitourinary symptoms. She has bilateral bunions but no calluses or ulcers. Her albumin–creatinine ratio is 50 mcg/mg, confirmed on repeat testing. Her HbA1C is 9.1%.
Have you crossed a diagnostic threshold for the leading hypothesis, diabetic complications? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?
The evaluation of diabetic complications is complete. Mrs. D has no evidence of retinopathy, neuropathy, or diabetic foot disease. She does have microalbuminuria. However, before formulating a treatment plan for Mrs. D, it is necessary to assess for the presence or absence of other cardiovascular risk factors and cardiovascular disease:
1. Dyslipidemia
2. Hypertension
3. Obesity
4. Smoking
5. Coronary artery disease (CAD)
6. Cerebrovascular disease
7. Peripheral vascular disease
Table 12-7 outlines the tests recommended by the ADA for all patients with diabetes.
Table 12-7. Summary of testing and monitoring recommended by the ADA for patients with diabetes.
CASE RESOLUTION
Mrs. D has no symptoms of vascular disease on careful questioning, and her exercise tolerance is more than 1 mile. Her fasting lipid panel shows total cholesterol of 230 mg/dL, HDL of 45 mg/dL, triglycerides of 200 mg/dL, and LDL of 145 mg/dL. You refer Mrs. D to a diabetes educator and a dietician for instruction about diet and exercise. You also prescribe metformin for diabetes and atorvastatin for hyperlipidemia. Because she has hypertension and microalbuminuria, you elect to start an ACE inhibitor, lisinopril, to treat her hypertension. You also recommend that she start taking aspirin, 81 mg daily, for primary prevention because she has a high-risk of atherosclerotic cardiovascular disease (ASCVD). Over the next 12–18 months, Mrs. D loses 5 pounds. You increase the dose of metformin and add glipizide, and her HbA1C decreases to 6.7%. After increasing the dose of lisinopril and adding hydrochlorothiazide, her BP is 128/80 mm Hg. Her LDL is now 85 mg/dL.
Treatment of Type 2 DM
The treatment of type 2 DM involves not only the treatment of the hyperglycemia but the management of associated complications and cardiovascular risk factors as well. According to survey data, only 51% of participants reach HbA1C goals, 51% reach BP goals, and 57% reach cholesterol goals; only 14.3% reach all 3 goals.
It is common for patients to require 6–7 medications to meet accepted treatment goals.
Treatment of Hyperglycemia
A. Treatment goals for patients with type 2 DM
1. The ADA recommends treating to a HbA1C < 7.0% in many patients.
a. HbA1C levels < 7% have been clearly shown to reduce microvascular events in patients with type 2 DM (see data above).
b. Intensive control has not been consistently shown to reduce macrovascular events; intensive control may be harmful in older diabetics with cardiovascular disease and may be beneficial in younger persons in whom diabetes was recently diagnosed; specific agents, as discussed below, may reduce cardiovascular events.
2. Goals should be modified for frail elderly, in whom avoidance of hypoglycemia and optimization of functional status may be more important than tight glycemic control.
a. Little evidence that intensive control decreases cardiovascular events in older adults, especially those with estimated life expectancy less than 15 years.
b. Harms, such as hypoglycemia and polypharmacy, are more likely in patients over 80 years of age, those with cognitive impairment, and those treated with insulin or complex regimens.
3. Goals should be individualized based on the overall health and age of the patient (Figures 12-1).
Figure 12-1. Framework for determining HbA1c targets. (Reproduced with permission from Ismail-Beigi F, Moghissi E, Tiktin M, et al: Individualizing glycemic targets in type 2 diabetes mellitus: implications of recent clinical trials, Ann Intern Med. 2011 Apr 19;154(8):554–559.)
B. Monitoring
1. Measure HbA1c levels every 6 months in stable patients meeting goals, and every 3 months in patients not meeting goals or undergoing changes in therapy.
a. Table 12-8 shows the correlation between plasma glucose and HbA1C.
Table 12-8. Correlation between plasma glucose and HgbA1c.
b. 50% of HbA1c is determined by glycemia during the month before the measurement, 25% from the 30–60 days before, and 25% from 60–90 days before.
2. Home glucose monitoring
a. Patients taking multiple doses of daily insulin should test blood levels several times a day (fasting, before lunch, before dinner, and before bed); those taking bedtime long-acting insulin should test in the morning.
b. Optimal frequency for patients taking oral agents is unclear; data regarding effects on control are mixed but show only slight improvement at best.
C. Lifestyle modification
1. Weight loss (goal of at least 10% of body weight), diet modification, and exercise (goal of at least 150 minutes/week) are the foundations of all treatment for patients with type 2 DM.
2. Best instituted in conjunction with a certified diabetes educator or dietician
D. Oral hypoglycemics
1. Metformin (drug class: biguanides)
a. Reduces hepatic glucose production.
b. Average decrease in HbA1c is about 1–2%.
c. Associated with weight loss (or at least no weight gain); hypoglycemia is rare.
d. Most common side effects are abdominal pain, nausea, diarrhea.
e. Associated with an increased risk of vitamin B12 deficiency
f. Relatively contraindicated in patients with estimated GFR < 30 mL/min because of risk of lactic acidosis
Metformin should be withheld in patients with acute illness and those undergoing surgery or imaging using radiocontrast.
g. Has been shown to decrease microvascular and macrovascular outcomes as well as total mortality in obese patients with type 2 DM (UKPDS, 1998)
h. Can be used as monotherapy or in combination with all other agents
2. Glipizide, glimepiride, glyburide (drug class: sulfonylureas)
a. Increase insulin secretion.
b. Average decrease in HbA1c is about 1–1.5%.
c. Side effects include weight gain (2–5 kg) and hypoglycemia, especially in the elderly, patients with reduced kidney function, and those with erratic eating habits; glyburide causes the most severe hypoglycemia and should not be used.
d. Shown to reduce microvascular outcomes; no change in cardiovascular events.
e. May become less effective with time, as beta cell function decreases.
3. Pioglitazone (drug class: thiazolidinediones)
a. Increases insulin-stimulated glucose uptake by skeletal muscle cells and decreases hepatic glucose production
b. Hypoglycemia is rare.
c. Average decrease in HbA1c is about 0.5–1.4%.
d. Tends to increase HDL and decrease triglycerides.
e. Can take weeks or months to obtain maximum effect
f. Side effects include weight gain up to 6 kg and edema.
g. Increases risk of heart failure (relative risk ~3) and fracture
h. Some evidence that pioglitazone decreases cardiovascular events.
Do not use thiazolidinediones in patients with heart failure or edema.
4. Sitagliptin, linagliptin, vildagliptin (drug class: dipeptidyl peptidase 4 (DPP4) inhibitors)
a. Incretins (glucose-dependent insulinotropic polypeptide [GIP] and glucagon-like peptide 1 [GLP-1]) are intestinal peptides that augment insulin secretion in the presence of glucose or nutrients in the gut; they are inactivated by the enzyme DPP4.
b. DPP4 inhibitors potentiate physiologic GLP-1.
c. Decrease HbA1c by ~0.75%.
d. No GI side effects; average weight gain < 1 kg.
e. No data on macrovascular or microvascular outcomes
5. Empagliflozin, dapagliflozin, canagliflozin (drug class: SGLT-2 inhibitors)
a. Increase urinary glucose excretion by inhibiting SGLT-2 in the renal proximal tubule
b. Hypoglycemia is rare, but rate of genitourinary infections is increased.
c. Weight loss of up to 3 kg
d. Must reduce dose in patients with estimated GFR of 30–60 mL/min; should not be used if estimated GFR is < 30 mL/min or in the setting of volume depletion or hypotension.
e. Empagliflozin is shown to decrease cardiovascular events and mortality in patients with established cardiovascular disease and is recommended as second-line therapy in patients with DM and established cardiovascular disease not controlled with metformin.
E. Liraglutide, exenatide (drug class: GLP-1 receptor agonists)
1. Increase insulin secretion, reduce glucagon secretion, slow gastric emptying and increase satiety
2. Given subcutaneously
3. Decrease HbA1c by 1%
4. Most common side effects are nausea and vomiting, which can be reduced by dose titration.
5. Weight loss of up to 4 kg
6. Contraindicated in patients with a history of chronic pancreatitis or pancreatic cancer
7. Liraglutide is shown to decrease cardiovascular events and mortality in patients with established cardiovascular disease and is recommended as second-line therapy in patients with DM and established cardiovascular disease not controlled with metformin.
F. Insulin
1. Types of insulin (Table 12-9)
Table 12-9. Types of insulin.
2. Reduces HbA1c by 1–2.5%
3. Adverse effects of insulin
a. Hypoglycemia, especially with short-acting forms
b. Weight gain of 2–4 kg
G. Choosing a medication to treat type 2 DM (Table 12-10)
Table 12-10. Pharmacologic treatment options for type 2 diabetes mellitus.
Metformin is the preferred initial therapy in most patients with type 2 DM.
1. Most studies compare an agent to placebo, so direct comparison data are limited.
2. 75% of patients require more than 1 drug by 9 years; there is no evidence that any specific combination is better than another, although agents that reduce cardiovascular events are the recommended second agents in patients with established vascular disease.
3. Consider starting metformin plus a second agent in patients who have an HbA1c > 9%.
4. Patients with DKA, hyperosmolar hyperglycemic state (HHS), or an HbA1c > 10% should be given insulin as the initial therapy, although some patients may eventually be able to stop insulin and reach goal with oral agents.
5. Using insulin to manage type 2 DM
a. Beta cell function declines over time in type 2 DM, so many patients will eventually need insulin.
b. The first step is to add long-acting basal insulin to oral agents, titrating the insulin dose to the fasting blood sugar.
c. If the HbA1c target is not achieved, options include adding a rapid-acting insulin, such as lispro, with meals, switching to twice daily biphasic insulin, or adding a GLP-1 receptor agonist.
d. Sulfonylureas should be stopped when short-acting insulins are used because of increased hypoglycemia.
Treatment of Hypertension
Most patients should be treated to a goal of < 140/90 mm Hg. A goal of < 130/80 mm Hg can be considered in patients with a high risk of cardiovascular disease if it can be achieved without excessive side effects. See Nephropathy section and Chapter 23, Hypertension for details.
Treatment of Hypercholesterolemia (see Chapter 23, Hypertension for additional detail)
A. All patients with DM should be counseled regarding lifestyle therapy for hypercholesterolemia (exercise, weight loss, reducing saturated and trans fat intake, increasing intake of plant sterols and viscous fiber).
B. Patients younger than 40 years with no ASCVD risk factors (LDL cholesterol ≥ 100 mg/dL, hypertension, smoking, chronic kidney disease, albuminuria, or family history of premature ASCVD) do not need treatment beyond lifestyle therapy.
C. Patients younger than 40 years with risk factors or ASCVD should take high-dose statins.
D. Patients aged 40–75 years without risk factors should take moderate-dose statins; those with risk factors or ASCVD should take high-dose statins.
E. Patients over 75 years should take moderate- to high-dose statins, if tolerated.
F. The ADA recommends that high-risk patients with a history of ASCVD who cannot tolerate high-dose statins should take moderate-dose statins plus ezetimibe.
G. In patients with ASCVD whose LDL cholesterol is ≥ 70 mg/dL while taking maximally tolerated statin therapy, adding ezetimibe or a PCSK9 inhibitor should be considered.
Antiplatelet Therapy
A. Low-dose aspirin (75–162 mg/day) is indicated for secondary prevention in all patients with cardiovascular disease.
B. Low-dose aspirin is indicated for primary prevention in patients with diabetes and increased cardiovascular risk (ASCVD 10-year risk > 10%; see Chapter 2, Screening and Health Maintenance for information on calculating risk).
1. Patients with low cardiovascular risk (10-year risk < 5%) should not take aspirin for primary prevention; the risk of bleeding is higher than the potential benefit.
2. Aspirin should be considered in patients with intermediate risk (10-year risk of 5–10%).
C. Clopidogrel, 75 mg/day, should be used in patients with aspirin allergies.
CHIEF COMPLAINT
PATIENT
Mr. G is a 56-year-old African American man with diabetes, chronic hepatitis B, CAD status post MI 2 months ago, hypertension, and a history of stroke 1 year ago. He is taking many medications, including Humulin 70/30 20 units twice daily, metoprolol, aspirin, atorvastatin, lisinopril, furosemide, and ribavirin. Despite all of these problems, he has been slowly improving and reported at his last visit 3 weeks ago that he had recently given up his walker for a cane. Today you are paged by his sister, who reports that Mr. G is very weak and cannot get up; his home glucose monitor reading is “critical high.” Mr. G’s voice is barely recognizable over the phone, and he is unable to respond to your questions. You advise his sister to call 911.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?
RANKING THE DIFFERENTIAL DIAGNOSIS
The differential diagnosis at this point is very broad and difficult to organize. It is helpful to recognize that Mr. G appears to be suffering from the syndrome of delirium and to use the framework for delirium to organize your thinking (see Chapter 11, Delirium and Dementia). It is also reasonable to consider Mr. G’s underlying chronic medical problems as important clinical clues and initially focus on the serious complications of these conditions; in other words, initially focus on diseases for which he has a high pretest probability:
1. Diabetes: DKA, HHS, infection with or without sepsis.
2. CAD: recurrent MI, possibly with heart failure or cardiogenic shock
3. Cerebrovascular disease: recurrent stroke
4. Chronic hepatitis B: hepatic encephalopathy
Table 12-11 lists the differential diagnosis.
Table 12-11. Diagnostic hypotheses for Mr. G.
Mr. G could have any, or a combination, of these conditions. His critical high blood sugar makes a complication of diabetes the leading hypothesis; all of the other diagnoses are “must not miss” hypotheses.
When Mr. G arrives in the emergency department, he is barely responsive but able to move all 4 extremities. His BP is 85/50 mm Hg; pulse, 120 bpm; RR, 24 breaths per minute; temperature, 37.2°C. His lungs are clear, and cardiac exam shows an S4 with no S3 or murmurs. His abdomen is nontender, and there is no peripheral edema. He has no foot ulcers. Initial laboratory tests include the following:
Sodium, 140 mEq/L; K, 4.9 mEq/L; Cl, 110 mEq/L; HCO3, 20 mEq/L; BUN, 99 mg/dL; creatinine, 4.3 mg/dL; glucose, 1246 mg/dL.
Arterial blood gases: pH 7.40; PO2, 88 mm Hg; PCO2, 35 mm Hg.
WBC is 8400/mcL, with 75% polymorphonuclear neutrophils, 3% bands, 18% lymphocytes, and 4% monocytes. Albumin, 4.0 g/dL; total bilirubin, 0.3 mg/dL; alkaline phosphatase, 175 units/L; AST, 40 units/L; ALT, 56 units/L; INR, 1.1.
Serum ketones, negative
Urinalysis: 2+ protein, 4+ glucose, no ketones, 3–5 WBC/hpf, occasional bacteria
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
Leading Hypothesis: Hyperosmolar Hyperglycemic State
Textbook Presentation
Patients who have HHS are usually older type 2 diabetics with the gradual onset of polydipsia, polyuria, and lethargy. They become extremely dehydrated, with reduction in urinary output, and have very high serum glucose levels, accompanied by alterations in mental status.
Disease Highlights
A. Epidemiology
1. Risk factors include older age, nursing home residence, inability to recognize thirst, and lack of access to fluids.
2. Mortality rate is 5–6%, compared to < 2% in patients with DKA.
B. Pathogenesis
1. Reduced effective insulin concentrations and a concomitant increase in counterregulatory hormones lead to increased hepatic and renal glucose production and impaired glucose utilization in peripheral tissues.
2. Glycosuria leads to an osmotic diuresis with loss of free water in excess of electrolytes, leading to hyperosmolality.
3. As volume depletion occurs, urinary output drops, and hyperglycemia worsens.
4. Insulin levels are higher than in DKA and are adequate to prevent lipolysis and ketogenesis.
C. Precipitating factors
1. The 3 most common precipitants are infection, lack of compliance with insulin, and first presentation of diabetes.
2. Other precipitants include postoperative state, cerebrovascular accident, MI, pancreatitis, alcohol abuse, trauma, thyrotoxicosis, and medications (eg, corticosteroids, atypical antipsychotic drugs [especially olanzapine and risperidone], total parenteral nutrition).
D. Clinical manifestations
1. History
a. Symptoms and signs usually evolve over several days or even weeks.
b. Common findings include polyuria followed by decreased urinary output, polydipsia, fatigue, and weight loss.
c. Abdominal pain generally does not occur in HHS, as it does in DKA.
d. Neurologic manifestations
(1) Lethargy and disorientation common
(2) Focal neurologic findings, including seizures, can occur with hyperglycemia and resolve with normalization of serum glucose.
(3) Changes in mental status correlate with the degree of hyperosmolarity.
(a) 20–25% present with coma.
(b) Coma is present in half of the patients with effective serum osmolality of ≥ 320 mOsm/L.
(c) Must search for another cause of altered mental status if osmolality < 320 mOsm/L
2. Physical exam
a. Hypothermia often seen resulting from peripheral vasodilation
b. Signs of dehydration often seen (see Chapter 28, Acute Kidney Injury)
c. Tachycardia and hypotension suggest severe dehydration or underlying sepsis.
Evidence-Based Diagnosis
A. Typical total body water deficit is 20–25% (about 9 L).
B. See Table 12-12 for laboratory findings in HHS compared with DKA.
Table 12-12. Laboratory findings in HHS and DKA.
Treatment
A. Patients with HHS generally need more fluid and less insulin than those with DKA.
B. Figure 12-2 outlines the treatment approach.
Figure 12-2. Management of adult patients with HHS. BUN, blood urea nitrogen; Bwt, body weight; DKA, diabetic ketoacidosis; HHS, hyperosmolar hyperglycemic state; IV, intravenous; SC, subcutaneous. (Reproduced with permission, from Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycemic crises in adult patients with diabetes. Diabetes Care. 2009; Jul;32(7):1335–1343.)
MAKING A DIAGNOSIS
Mr. G’s glucose is > 600 mg/dL, ketones are negative, and calculated serum osmolality is 345 mOsm/L (effective serum osmolality = 2 × measured Na + glucose/18 = (2 × 138) + 1246/18 = 345).
Have you crossed a diagnostic threshold for the leading hypothesis, HHS? Have you ruled out the active alternatives? Do other tests need to be done to exclude the alternative diagnoses?
Mr. G fulfills the diagnostic criteria for HHS. It is not necessary to consider other diagnoses, but it is essential to determine the precipitant for this event. Considering Mr. G’s complicated history, he is at risk for many of the precipitants of HHS, especially infection, MI, and cerebrovascular accident.
Always look for the precipitant when patients present with either HHS or DKA.
CASE RESOLUTION
Mr. G’s chest radiograph is clear, his urine and blood cultures are negative, his ECG shows no acute changes, and his cardiac enzymes are normal. He responds well to IV hydration and insulin therapy. When he becomes more alert, he reports that he had become depressed and had stopped taking his insulin.
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