simultaneously. The initiation and rate adjustments are the same as with DKA,
except that the plasma glucose cut-off to reduce the insulin infusion rate is 300
mg/dL (not 200 mg/dL as with DKA; see Case 53-10, Question 3, and Table 53-24
for details). Rehydration and insulin administration corrected J.M’s metabolic
imbalance, allowing his diabetes control to be addressed.
CASE 53-17, QUESTION 3: What are the goals of therapy for J.M.?
It is widely recognized that strict glycemic control is associated with an increased
In the elderly patient with age-related autonomic
dysfunction and CVD, hypoglycemia may present without the usual premonitory
symptoms and can result in severe adverse effects such as angina, seizures, stroke, or
MI. Therefore, the general tendency when treating elderly diabetic patients is to aim
for slightly less aggressive glycemic goals. Thus, an FBG target of between 100 and
140 mg/dL with postprandial glucose values less than 180 mg/dLand an A1C goal of
close to 8%, while avoiding hypoglycemia, is appropriate in this frail patient.
The ADA recommends individualized MNT for all patients with diabetes mellitus.
The Dietary Approaches to Stop Hypertension (DASH) diet and Mediterranean diets
have been shown to be effective for glycemic control and lowering CVD risk.
Because most elderly patients have Type 2 diabetes, nutrition and exercise
programs are the initial steps in therapy. Older people with diabetes, especially
those in a long-term care facility, have a tendency to be underweight rather than
51–53 Therefore, caution should be used when considering a weight-loss
diet because this could cause malnutrition or dehydration. For obese individuals, a
modest weight loss of 5% to 10% may be indicated. However, an involuntary weight
gain or loss of more than 10 lb or 10% of body weight in less than 6 months should
Several factors can adversely affect proper nutrition in the elderly. They include
an impaired ability to shop for and prepare food, limited finances, an age-related
decline in taste perceptions, and coexisting illnesses. Ill-fitting dentures, difficulty in
chewing and swallowing, and lack of companionship during meals also can
contribute to malnutrition as well.
High-fiber diets may lower BG and improve plasma lipids. However, high-fiber
diets in frail, elderly patients, particularly those who are bedridden, should be used
cautiously because they can be constipating and result in fecal impaction. Ambulatory
patients, on the other hand, generally benefit from increased dietary fiber. Because
many elderly patients are malnourished, a daily multivitamin preparation containing
the recommended daily allowance of each vitamin should be prescribed.
Exercise in the elderly provides all the benefits derived by younger individuals. It
increases well-being and glucose stability, and may decrease a propensity to fall.
Exercise also improves BP, the lipid profile, hypercoagulability, and bone density.
Physical activity is necessary to minimize any lean body mass loss that can occur
with caloric restriction. For patients with arthritis, aquatic exercise may be
substituted. Before such an exercise program is initiated, careful evaluation is
mandatory to avoid myocardial ischemia or the acceleration of retinopathy.
SELECTING AN ANTIDIABETIC AGENT IN THE ELDERLY
CASE 53-17, QUESTION 5: Why is it important to institute drug therapy to treat J.M.’s diabetes? What
considerations should be made in selecting an initial treatment regimen?
As in all patients with diabetes mellitus, poor glycemic control increases the risk
of long-term complications. Although it is tempting to minimize the importance of
glycemic control because these complications take so long to develop, patients such
as J.M. may have had unrecognized hyperglycemia for many years before clinical
diagnosis. Thus, many have already begun to develop complications. Furthermore, as
life expectancy increases, one can expect that these individuals will live long enough
to experience morbidity related to diabetes if they are not treated. Therefore,
pharmacologic treatment should be considered in J.M.
The general approach to treating an elderly patient with Type 2 diabetes is
basically the same as described in Case 53-11, Questions 3, 7, and 8. The initial
choice of an antidiabetic agent should be based on the severity of hyperglycemia.
Other considerations include body weight, coexisting diseases, and cost of the agent.
Patients with IFG (FPG >100, but <126 mg/dL) should be treated with diet and
exercise tailored to their individual capabilities. For patients with Type 2 diabetes,
acarbose, a short-acting insulin secretagogue (e.g., nateglinide or repaglinide),
to the multiple daily regimen is problematic, a short-acting sulfonylurea is an
appropriate alternative agent. In J.M.’s case, metformin should probably be used in
caution because he has chronic obstructive pulmonary disease increasing the risk of
hypoxia. Also, he is older than 80 years of age and requires an assessment of his
GFR, which is likely diminished. The favorable effect metformin has on weight is
irrelevant in J.M. Thus, although the efficacy of metformin is comparable to that of
sulfonylureas, it is not the agent of first choice for elderly patients such as J.M.
Patients with an FPG greater than 300 mg/dL and no overt stress should be
considered insulin deficient and started on insulin therapy.
QUESTION 1: L.S. is a 53-year-old, obese man with an 8-year history of Type 2 diabetes. His current
laboratory values are as follows:
Seventy-five percent of adults with diabetes report having a BP of 130/80 mm Hg
or more or use medications for hypertension.
1 Hypertension in Type 1 diabetes is
origin and occurs 1 to 2 years after the onset of nephropathy as indicated by
albuminuria (see Case 53-19, Question 2).
7 The relationship between Type 2
diabetes and hypertension is more complex and not as closely correlated to
nephropathy. In Type 2 diabetes, hypertension is often part of the metabolic syndrome
and may be present for years before diabetes is actually detectable.
Patients with diabetes and hypertension have an increased risk for experiencing
microvascular complications such as retinopathy and nephropathy. They are also at a
twofold increased risk of having CVD.
7 A 5-mm Hg reduction in mean diastolic BP
can produce a 37% reduction in microvascular complications, and a 10-mm Hg
reduction in mean systolic BP had previously been found to reduce the risk of MI by
11% and death related to diabetes by 15%.
7,245,246 However, because lower BP
targets are tested, the benefits are becoming less clear. In the ACCORD blood
pressure study, the intensive control arm (achieved systolic BP of 119 mm Hg) did
not reduce total cardiovascular events (nonfatal MI, nonfatal stroke or death from
cardiovascular causes) compared with standard therapy (achieved systolic BP of
9 However, microvascular benefits were observed, as was a
statistically significant reduction in stroke. Therefore, the existing ADA BP goal of
less than 140/90 mm Hg is reasonable, and lower goals should not be targeted in
practice unless it can be done without adverse effects.
Treatment includes weight management, exercise, sodium restriction (<1,500
mg/day), smoking cessation, and antihypertensive therapy. L.S. should be started on
an angiotensin-converting enzyme inhibitor (ACEI). ACEI have traditionally been
available as less expensive generics, although angiotensin receptor II blockers
(ARB) are also available and appropriate. Many patients require two or three
medications to achieve the target BP goal of less than 140/90 mm Hg.
CASE 53-18, QUESTION 2: What is the significance of the presence of albumin in L.S.’s urine? How
Diabetes is the leading cause of end-stage renal disease and accounted for 44% of
new cases of renal failure in 2005.
1,7 Diabetic nephropathy is characterized by
nephrotic syndrome and azotemia. It is a major cause of death in patients with Type 1
diabetes and is an increasing source of morbidity in Type 2 diabetic individuals.
Thickening of the glomerular capillary basement membranes is the hallmark of
284 Diffuse deposition of basement membrane-like material
expands the mesangium. This process narrows the capillary lumina, impedes blood
flow, and thereby reduces the filtering surface area in the glomerulus. Hyperglycemia
causes intraglomerular hypertension and renal hyperfiltration. Hyperfiltration is
followed by albuminuria with minimal glomerulosclerosis, which still is potentially
reversible. If left untreated, overt proteinuria occurs, and the patient usually
progresses to nephrotic syndrome. Progression of diabetic renal disease can be
accelerated in the presence of hypertension, proteinuria, and diabetic retinopathy.
Lipid abnormalities also may contribute to the progression of glomerulosclerosis.
Management includes early detection through screening for albuminuria, tight glucose
control, use of ACEIs and ARBs for patients with albuminuria (to slow progression),
aggressive management of hypertension that includes an ACEI or ARB as first-line
7 aggressive management of dyslipidemia, and smoking cessation. A thorough
discussion on the management of diabetic nephropathy and end-stage renal disease is
presented in Chapter 28, Chronic Kidney Diseases, and of hypertension in people
with diabetes, in Chapter 9, Essential Hypertension.
Screening for and Confirmation of Albuminuria
sample). Albuminuria is defined as a urinary albumin excretion of 30 mcg or more
per milligram of creatinine (or mg albumin/g creatinine) during a spot collection.
Because of day-to-day variability in albumin excretion, two of three urine samples
collected in a 3- to 6-month period need to be abnormal before a designation is
made. Annual screening should be performed in patients with Type 1 diabetes with a
duration of at least 5 years and in patients with Type 2 diabetes from the time of
diagnosis. More frequent screening is indicated if hypertension, any increase in SCr,
or retinopathy develops. Urine albumin concentrations can be falsely elevated over
true baseline values by exercise within 24 hours, fever, infection, uncontrolled
diabetes, uncontrolled hypertension, and HF.
On the basis of established criteria, L.S. has albuminuria (180 mg albumin/g
creatinine). Management includes tight BG control and an ACEI or ARB should be
started (L.S. should already be receiving one of these agents to treat his hypertension
as noted). After initiation of therapy, continued periodic monitoring of the
albuminuria is recommended to assess the response to therapy and progression of
7 Serum potassium and creatinine levels should be followed as well.
persons without diabetes? What is the pathogenesis of CHD in persons with diabetes?
CHD is the leading cause of premature death in the Type 2 population and
accounts for 50% of the deaths in people with diabetes. Relative to nondiabetic
individuals, those with diabetes are 2 to 3 times more likely to develop CHD, and
their risk of death after an MI also is 2 to 3 times higher than their nondiabetic
counterparts. Women with diabetes, regardless of their age or menopausal status,
have equal risk for CHD to that of nondiabetic men. These sobering figures point to
the importance of minimizing or eliminating all other preventable risk factors for
CVD in patients with diabetes (i.e., tobacco use, hypertension, hypercholesterolemia,
obesity) through the prescription of exercise, diet, and appropriate medications.
The pathogenesis of CVD in people with diabetes is complex. The metabolic
syndrome with its attendant cardiovascular risk factors, dyslipidemia, inflammation,
and hemostatic abnormalities are only some of the mechanisms under study.
The most common lipid abnormality in Type 2 diabetes is hypertriglyceridemia
(>150 mg/dL) with low levels of HDL-C (<40 mg/dL in men or <50 mg/dL in
women), similar to the lipid profile seen in L.S. Poor control of Type 1 diabetes also
is associated with low levels of HDL-C and a smaller, more-dense LDL particle.
These lipid abnormalities, along with a greater prevalence of hypertension,
contribute to the risk for CVD.
In patients with diabetes, clinical trials of lipid-lowering therapy (primarily with
statins) have demonstrated primary and secondary CHD prevention. Although the
evidence for the reduction in “hard” CVD outcomes (e.g., CHD death and nonfatal
MI) is stronger in diabetic patients who have a high baseline CVD risk
(i.e., known CVD or very high LDL-C levels), the overall benefits of statins in
patients with diabetes at moderate or high risk for CVD are convincing. Readers are
referred to the ADA Standards of Medical Care for more detailed information on the
CVD clinical trials in patients with diabetes.
CASE 53-18, QUESTION 4: Should L.S. be treated with drug therapy for his dyslipidemia?
The ACC/AHA made important changes in the management of dyslipidemia
regarding cholesterol management recommendations. Although the previous ATP III
guidelines focused on specific LDL and non-HDL cholesterol target goals, the new
guidelines recommend initiating statin therapy based on cardiovascular risk.
Cardiovascular risk is determined by age, comorbidities, lipid panel, social, and
family history. The ACC/AHA guidelines recommend a moderate-intensity statin for
diabetics between the ages of 40 to 75 with LDL between 70 and 189 mg/dL with
estimated 10-year ASCVD (atherosclerotic cardiovascular disease) risk <7.5%. A
high-intensity statin is recommended for diabetics between the ages of 40 to 75 with
LDL between 70 and 189 mg/dL with estimated 10-year ASCVD risk > 7.5%. All
patients between the ages of 40 to 75 are recommended a high-intensity statin if they
have had a clinical ASCVD, including CHD, MI, unstable/stable angina, stroke, TIA,
or peripheral arterial disease. Patients greater than the age of 75 are generally
recommended to be initiated on a moderate-intensity statin due to risk of myalgias.
Diet and exercise are cornerstones in the management of dyslipidemia in patients
such as L.S. Weight loss is associated with improvements in insulin sensitivity and
glucose control, as well as a reduction in triglycerides, total cholesterol, and LDL-C.
Physical activity enhances weight loss and increases HDL-C levels. Thus, L.S.’s diet
and exercise habits should be reassessed, and instruction in both should be
reinforced as appropriate. Because insulin resistance may be the underlying cause of
elevated lipids in these patients, efforts should be devoted to reversing insulin
resistance as well. Given L.S.’s age and risk factors, a statin is indicated.
For a detailed discussion on statin therapy and other lipid-lowering agents see
Chapter 8 (Dyslipidemias, Atherosclerosis, and Coronary Heart Disease chapter).
Ocular disorders related to diabetes are the leading cause of new cases of legal
blindness in Americans. Patients with diabetes may experience blurred vision
associated with poor glycemic control, but retinopathy, senile-type cataracts, and
glaucoma are the complications that threaten sight. Diabetic retinopathy appears as
early as 3 years after diagnosis and is evident in 90% of Type 1 diabetic individuals
after 15 years. Comparable figures for patients with Type 2 diabetes treated with
insulin and for those treated with diet and oral agents are 80% and 55%,
respectively. Proliferative retinopathy is less prevalent, but nevertheless is present in
30% of people with Type 1 diabetes and in 10% to 15% of insulin-treated patients
with Type 2 diabetes who have had diabetes for 15 years or longer.
Patients with Type 1 diabetes should have a dilated retinal examination within 5
years of diagnosis; evaluation is not necessary before 10 years of age. Patients with
Type 2 diabetes should have a comprehensive eye examination soon after diagnosis.
The ADA recommends annual comprehensive eye examinations.
examinations (every 2–3 years) can be considered in patients with normal
examinations based on the advice of an ophthalmologist.
Current theories addressing the possible causes of this complication have been
287 Microvascular disease characterized by thickening of the
capillary membrane may be the underlying lesion for two forms of retinopathy. The
first and most common presentation is a nonproliferative retinopathy, which is
characterized by microaneurysms that may progress to hard, yellow exudates,
signifying chronic leakage, retinal edema, and punctate hemorrhage. This form of
retinopathy may be associated with loss of central vision, but generally is associated
with excellent visual prognosis. Focal laser photocoagulation of the retina in patients
with nonproliferative diabetic retinopathy and macular edema decreases the
likelihood of visual loss by 50%.
A second, less common presentation is proliferative retinopathy. This form is
characterized by neovascularization (presumably owing to retinal hypoxia).
Neovascularization ultimately leads to fibrosis, vitreous hemorrhage, and retinal
detachment. Photocoagulation therapy may arrest progression and decrease loss of
vision associated with neovascularization.
287 Because hypertension, smoking, uremia,
and hyperglycemia may lead to more rapid progression of the retinopathy, every
effort should be made to eliminate these risk factors for L.S.
The ACCORD study assessed the impact of intensive glycemic, BP, and lipid
control on the progression of retinopathy.
268 After 4 years, the rates of progression of
diabetic retinopathy were reduced with intensive glycemic control (7.3% vs. 10.4%
with standard therapy) and also with fenofibrate (6.5% vs. 10.2% with standard
therapy of just a statin alone). Somewhat surprisingly, intensive BP control did not
have an effect (10.4% vs. 8.8% with standard therapy). However, on closer
interpretation, this finding makes sense as the BP in the standard therapy group
achieved excellent control (133.5 mm Hg), so further lowering the BP (119.3 mm Hg
in the intensive group) did not provide additional benefit in reducing the rate of
retinopathy progression (see Case 53-19, Question 1).
CASE 53-18, QUESTION 6: Should L.S. be started on aspirin therapy?
The issue of aspirin use for primary prevention continues to be debated. The ADA
recommends aspirin therapy as secondary prevention in patients with a history of
CVD (e.g., MI, vascular bypass procedure, peripheral vascular disease, stroke or
transient ischemic attack, claudication, or angina). Primary prevention is indicated in
diabetic individuals who have a significant risk of CVD events (10-year risk >10%).
Although the ADA lists several risk calculators that can be used in patients with
diabetes, the UKPDS calculator can be downloaded and is relatively easy to use
(http://www.dtu.ox.ac.uk/riskengine/).
In patients with a very low risk (10-year
risk <5%), the ADA recommends against aspirin because the risk of significant
bleeding outweighs the benefit for vascular event reduction.
calculation in patients with diabetes can be difficult, the ADA also provided more
general clinical guidance and recommends that men older than the age of 50 and
women older than the age of 60 who have at least one additional major risk factor (a
family history of CVD, smoking, hypertension, albuminuria, dyslipidemia) are good
candidates for aspirin therapy.
In elderly, patients assess the need for aspirin
therapy. Clinicians should weigh risks versus benefits for the primary prevention of
CVD events in patients >80 years of age. Newer studies have shown antiplatelet
therapy renders this patient population to increased incidences of
bleeding without significant reduction in CVD events. L.S. has several
cardiovascular risk factors (albuminuria, dyslipidemia, hypertension, obesity, and
age) and should be started on aspirin therapy as primary prevention. L.S. should take
an enteric-coated aspirin, 81 mg daily. Although some authors have suggested that
higher doses of aspirin should be used because of the increased platelet reactivity
that can be seen in people with diabetes, the clinical literature does not support this
approach and the ADA does not recommend doses greater than 162 mg daily.
AUTONOMIC NEUROPATHY: GASTROPARESIS
control (A1C, 12%) and complains of frequent, severe hypoglycemic reactions that “don’t make sense.”
the cause of diabetic gastroparesis? How should H.D. be treated?
Autonomic neuropathy may present as gastroparesis with feelings of bloating and
nausea, urinary retention, impotence in men (manifested as retrograde ejaculation or
an inability to attain an erection), postural hypotension, tachycardia, and diarrhea
289 The presence of autonomic insufficiency may have
profound effects on the patient’s response to vasodilating drugs and ability to
Poor glycemic control with “unexplained” hypoglycemia may result from the
disrupted delivery of food to the intestine; that is, glucose delivery does not
correspond with prandial insulin action. As a result, the BG levels can fluctuate
greatly. Many patients with diabetic gastroparesis, like H.D., have had diabetes for
many years and also have evidence of peripheral and autonomic neuropathies.
Conventional antiemetic therapy is usually not helpful in the treatment of
gastroparesis. Prokinetic agents, such as metoclopramide, are considered first-line
290 Metoclopramide increases gut motility through indirect cholinergic
stimulation of the gut muscle. However, symptomatic improvement does not always
correlate with improved gastric emptying, which implies that the effectiveness of
metoclopramide also is related to its centrally mediated antiemetic activity. A usual
starting dose of metoclopramide is 10 mg orally 4 times daily (QID), 30 minutes
before meals and at bedtime. Although treatment may not eliminate all symptoms, it
should minimize most of the patient’s complaints. Patients should be monitored for
tardive dyskinesia, a potentially irreversible and disfiguring condition that is
characterized by involuntary movements of the tongue, face, or extremities. In 2009,
the FDA added tardive dyskinesia as a black box warning for metoclopramide.
The risk of tardive dyskinesia increases with the duration of treatment and the total
Other pharmacotherapeutic interventions include domperidone (not available in
the United States), cisapride (withdrawn from the US market), erythromycin, and
290 A key component to treating H.D.’s gastroparesis is
improving his glycemic control. Also, H.D. should be advised to try eating smaller,
more frequent meals and to chew his food well; this of course will require
adjustments to his prandial insulin therapy. Also, eating a low-fiber and low-fat diet
CASE 53-19, QUESTION 2: Six months after institution of metoclopramide 10 mg QID and several insulin
evidenced by elimination of hypoglycemic episodes and a recent A1C of 7.5%. However, H.D. has been
Diabetic neuropathy may be a consequence of metabolic disturbances in the
neurons, microangiopathy affecting the capillary supply to neurons, or an autoimmune
process. It affects 60% to 70% of the diabetic population and has a broad spectrum
of presentation. Clinically, it most commonly presents as a diffuse symmetric
sensorimotor syndrome, as carpal tunnel syndrome, or as autonomic neuropathy (e.g.,
tachycardia or orthostatic hypotension caused by cardiovascular autonomic
neuropathy). Symptomatic diabetic peripheral neuropathy occurs in 25% of patients
with diabetes. It is characterized by paresthesia and pain in the lower extremities that
may be mild or severe and unrelenting, decreased sensation to monofilament testing,
decreased ankle and knee jerks, and decreased nerve conduction velocity. The
decreased sensation associated with peripheral neuropathy contributes to the
progression of foot injuries and infections that may go unnoticed by the patient until
they are severe. The management of diabetic neuropathies has been reviewed.
To view a video of how to perform a complete foot examination, see
http://www.medscape.com/viewarticle/708703.
Pharmacologic management consists of symptomatic therapies. Painful neuropathy
of responsiveness to these agents as well as their duration of action and side effect
profiles. Side effects include GI upset and bleeding, and renal and hepatic toxicity.
Avoid chronic nonsteroidal anti-inflammatory drug use owing to their renal toxicity
and development of GI ulcers. Other pharmacologic options include tricyclic
antidepressants (TCAs), duloxetine (a serotonin and norepinephrine reuptake
inhibitor), gabapentin, pregabalin, and other anticonvulsants (carbamazepine,
lamotrigine, topiramate, and oxcarbazepine). Only pregabalin and duloxetine have
the FDA indication for the treatment of DPN; others are off label. Efficacy, side
effects, drug interactions, renal and hepatic function, and cost should all be
considered when an agent is chosen. Often less expensive options are tried first, off
label such as gabapentin or a TCA.
Topical application of 0.075% capsaicin has been recommended for diabetic
neuropathy but may take several weeks to work. Lidocaine 5% patches have also
been used. These may be helpful in patients intolerant to oral medications. These may
be used in combination with oral medications. Tramadol or opiates may also be used
CASE 53-19, QUESTION 3: Can anything be done for H.D.’s peripheral vascular disease?
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