Diabetes
Up to 4 percent of Americans have diabetes. Vascular disease accounts for over 70 percent
of deaths in adults with diabetes.
Classification and pathophysiology
Type 1 diabetes mellitus primarily occurs in children and adolescents. Patients with type 1
diabetes have an absolute deficiency of endogenous insulin and require exogenous insulin for
survival.
Type 2 diabetes accounts for 90% of individuals with diabetes mellitus, and the incidence
increases in frequency with age, obesity and physical inactivity. The initial problem in type 2
diabetes is resistance to the action of insulin at the cellular level.
Type 1 and type 2 diabetes are associated with serious micro- and macrovascular
complications. Vascular disease is the cause of death in over 70%.
Screening
All adults should be screened for diabetes at regular intervals. Factors that confer an
increased risk for development of diabetes include impaired glucose tolerance, hypertension,
lipid disorders, coronary artery disease, obesity, and physical inactivity.
A fasting plasma glucose test is recommended for screening. A level of 110 to 125 mg/dL is
considered to represent "impaired fasting glucose," and a value of greater than or equal to
126 mg/dL, if confirmed on repeat testing, establishes the diagnosis of diabetes. If a patient is
found to have a random plasma glucose level over 160 mg/dL, more formal testing with a
fasting plasma glucose should be considered.
Criteria for Diagnosis of Diabetes in Nonpregnant Adults
Fasting plasma glucose 126 mg/dL or higher
or
Random plasma glucose 200 mg/dL or higher with symptoms of diabetes (fatigue, weight
loss, polyuria, polyphagia, polydipsia)
or
Abnormal two-hour 75-g oral glucose tolerance test result, with glucose 200 mg/dL or higher
at two hours
Any abnormal test result must be repeated on a subsequent occasion to establish the
diagnosis
Screening for microvascular complications in diabetics
Retinopathy. Diabetic retinopathy and macular degeneration are the leading causes of
blindness in diabetes. These complications affect nearly all patients with type 1 diabetes and
60% of those with type 2 disease of at least 20 years duration. Adults with diabetes should
receive annual dilated retinal examinations beginning at the time of diagnosis.
Nephropathy
Diabetes-related nephropathy affects 40% of patients with type 1 disease and 10-20% of
those with type 2 disease of 20 or more years duration. Microalbuminuria of 30 to 300 mg/24
hours heralds the onset of nephropathy. Microalbuminuria can be detected with annual urine
screening for albumin/creatinine ratio. Abnormal screening test results should be confirmed,
and a 24-hour urine sample should be obtained for total microalbuminuria assay and
evaluation for creatinine clearance.
The clinical progression of nephropathy can be slowed by (1) administering ACE inhibitors,
such as lisinopril (Prinivil) or enalapril (Vasotec), (2) controlling blood pressure to 130-185 mm
Hg or lower, (3) promptly treating urinary tract infections, (4) smoking cessation, and (5)
limiting protein intake to 0.6 g/kg/day.
Peripheral neuropathy affects many patients with diabetes and causes nocturnal or constant
pain, tingling and numbness and confers an increased risk for foot infections, foot ulcers, and
amputation.
The feet should be evaluated regularly for sensation, pulses and sores. Semmes-Weinstein
10-g monofilament testing should be performed to assess sensation.
Autonomic neuropathy is found in many patients with long-standing diabetes. This problem
can result in diarrhea, constipation, gastroparesis, vomiting, orthostatic hypotension, and
erectile or ejaculatory dysfunction.
Pharmacologic treatment of diabetes
Pharmacotherapy of Diabetes
Agent
Starting
dose
Maximum
dose
5 mg daily
20 mg twice
daily
Sulfonylureas
Glipizide (Glucotrol)
Glyburide (DiaBeta,
Micronase)
2.5 mg
daily
10 mg twice
daily
Comments
May cause hypoglycemia, weight gain.
Maximum dose should be used only in
combination with insulin therapy
Glimepiride (Amaryl)
1 mg daily
8 mg daily
Biguanide
Metformin (Glucophage)
500 mg
daily
850 mg three
times daily
Do not use if serum creatinine is greater than
1.4 mg/dL in women or 1.5 mg/dL in men or in
the presence of heart failure, chronic obstructive
pulmonary disease or liver disease; may cause
lactic acidosis
Thiazolidinedione
Pioglitazone (Actos)
15 mg
daily
45 mg per
day
Rosiglitazone (Avandia)
4 mg daily
Alpha-glucosidase
inhibitor
Acarbose (Precose)
25 mg
daily
Miglitol (Glyset)
25 mg
daily
4 mg twice
daily
100 mg three
times daily
100 mg three
times daily
Meglitamide
Repaglinide (Prandin)
0.5 mg
before
meals
Flatulence; start at low dose to minimize side
effects; take at mealtimes
4 mg three to
four times
daily
Mechanism of action similar to that of
sulfonylureas; may cause hypoglycemia; take at
mealtimes
Routine Diabetes Care
History
Review physical activity, diet, self-monitored blood glucose readings, medications
Assess for symptoms of coronary heart disease
Evaluate smoking status, latest eye examination results, foot care
Physical examination
Weight
Blood pressure
Foot examination
Pulse
Sores or callus
Monofilament test for sensation
Insulin injection sites
Refer for dilated retinal examination annually
Laboratory studies
HbA1c every three to six months
Annual fasting lipid panel
Annual urine albumin/creatinine ratio
Annual serum creatinine
Targets for control. The American Diabetes Association recommends a glycosylated
hemoglobin (HbA1c) level of 7 percent or less as the target for glycemic control, with a level
persistently over 8 percent serving as a signal to reassess and revise treatment.
The agents used to manage type 2 diabetes can be divided into two groups: those that
augment the patient's supply of insulin and those that enhance the effectiveness of insulin.
Insulin-augmenting agents
The sulfonylureas and the meglitinides increase the secretion of endogenous insulin, as long
as pancreatic beta-cell function remains. Insulin-augmenting agents act by binding to a
receptor on the beta cell. Insulin-augmenting agents are ineffective in patients with juvenileonset type 1 diabetes.
Two long-acting sulfonylureas are now available: glimepiride (Amaryl) and extended-release
glipizide (Glucotrol XL). The first meglitinide to become available is repaglinide (Prandin).
The various insulin-augmenting agents have equivalent therapeutic power but differ in
duration of action and site of clearance. Repaglinide and tolbutamide (Orinase) are the most
rapid- and short-acting agents, whereas chlorpropamide (Diabinese), extended-release
glipizide and glimepiride are the slowest and longest acting agents.
At present, glyburide (Micronase), extended-release glipizide (Glucotrol XL) and glimepiride
(Amaryl) are the oral antidiabetic agents most widely used. Glyburide is inexpensive;
however, for full effectiveness, it must be taken twice daily, and it has an active metabolite
that accumulates when renal function declines. Extended-release glipizide and glimepiride are
taken once daily, and their clearance depends very little on renal excretion.
Insulin-assisting agents
The insulin-assisting agents include metformin (Glucophage), which is a biguanide; acarbose
(Precose) and miglitol (Glyset), which are alpha-glucosidase inhibitors; and pioglitazone
(Actos), and rosiglitazone (Avandia), which are thiazolidinediones.
Metformin improves the hepatic response to insulin and reduces overnight glucose production
and fasting hyperglycemia. At higher dosages, metformin may reduce food intake and help
with weight control.
Acarbose and miglitol delay the digestion and absorption of complex carbohydrates.
Acarbose and miglitol are quite safe, but they often cause flatulence. Neither agent should be
used in patients with intestinal disorders.
Pioglitazone and rosiglitazone (thiazolidinediones) improve the response of muscle and
adipose tissue to insulin, especially in patients who are extremely obese. Rosiglitazone and
pioglitazone have not been reported to have liver toxicity, and less frequent ALT
measurements (every two months for the first year) are advised.
Metformin is not metabolized and must be excreted by the kidney. Because high blood levels
of metformin can cause fatal lactic acidosis, this oral agent cannot be used when the serum
creatinine concentration exceeds 1.4 mg per dL in women or 1.5 mg per dL in men. When
first taken, metformin often causes nausea or diarrhea.
Comparison of the Clinical Effects of Oral Antihyperglycemic Agents
Class or
generic
name
Brand
name
Acarbose
Precose
Effect
on
glucose
level
Average
reduction
of HbA1c
level (%)
Patients best suited for treatment
0.5 to 1
Patients with high postprandial glucose levels
1 to 2
Obese patients with recently diagnosed type 2 diabetes
Decreases
postprandial
increase
Decreases
Metformin
Glucophage
fasting and
24-hour
mean levels
Decreases
Repaglinide
Prandin
fasting and
postprandial
1 to 2
Patients with recently diagnosed type 2 diabetes who have high
postprandial glucose levels
levels
Decrease
Sulfonylureas
fasting and
24-hour
1 to 2
Patients with recently diagnosed type 2 diabetes
mean levels
Initiation of treatment
Metformin ( Glucophage) can be quite effective in a dosage of 500 mg taken once daily
before a major meal or at bedtime. The dosage can be titrated to 850 mg once daily, 500 mg
twice daily, or higher.
Acarbose ( Precose) or miglitol ( Glyset) is a better initial choice in patients who have renal
impairment and thus cannot use metformin, especially if their fasting glucose level is below
140 mg per dL but their HbA1c concentration is above 7.5 percent (suggesting marked
postprandial hyperglycemia).
Acarbose and miglitol are best started at a dosage of 25 mg taken once daily with a meal for
two weeks. Then the dosage is increased to 25 mg taken twice daily at meals for two more
weeks. Finally, the dosage is increased to 25 mg taken three times daily at meals. If
necessary, the dosage may be increased to 50 mg with each meal. Gradual titration reduces
flatulence.
The sulfonylureas have fast and predictable effects on glucose levels, few side effects, oncedaily dosage and low cost. To minimize the risk of hypoglycemia, the starting dosage of a
sulfonylurea should be low. For example, glyburide ( DiaBeta, Micronase) should be initiated
in a dosage of 1.25 or 2.5 mg once or twice daily, and glimepiride should be started in a
dosage of 1 mg once daily. The lowest available dosage of extended-release glipizide is 5 mg
per day, which is usually the maximal effective dosage. The starting dosage of repaglinide
(Prandin) is 1 mg taken three times daily with meals.
The need for low cost or a quick response favors a sulfonylurea. The need for weight control
supports the use of metformin. Acarbose is useful for patients with mainly postprandial
hyperglycemia. A thiazolidinedione may have a role in patients who are highly insulin
resistant.
Combinations of oral agents
Sulfonylurea and metformin. The combination of a sulfonylurea with metformin has been
most widely used. When a sulfonylurea alone or metformin alone fails, the other agent can be
added in a gradually titrated dosage.
Sulfonylurea and thiazolidinedione. The combination of a sulfonylurea plus a
thiazolidinedione is also widely used. The starting dosages of pioglitazone and rosiglitazone
are 15 mg per day and 4 mg per day, respectively, and both agents can be taken with or
without food.
Insulin should be prescribed for all patients with type 1 diabetes and is beneficial in some
individuals with type 2 diabetes. NPH may be injected once per day at bedtime or twice per
day, with about two-thirds of the daily dose given before breakfast and one-third given before
the evening meal. Insulin therapy may be initiated in patients using oral agents by continuing
the oral medications and adding 10 units of NPH insulin at 10 p.m. or bedtime.