Download DIABETES MELLITUS

TREATMENT REPORT
Diabetes Mellitus
Note: For data on treated rate or diagnosed rate, return to the IPD and run a two-keyword search on this topic with
"treated rate" or "diagnosed rate" as the second keyword. View the Article Reviews or IPD Summary report (the
"Subgroups and Trends" section specifically) in your search results list.
Treatment Regimens
A. Diet
1. American Diabetes Association (ADA) recommendations
2. Dietary fiber
3. Artificial sweeteners
B. Oral Drugs for Treating Hyperglycemia
1. Drugs that stimulate insulin secretion
2. Drugs that alter insulin action
3. Drugs that affect absorption of glucose
4. Drug combinations
5. Safety of the oral hypoglycemic agents
C. Incretins
D. Insulin
1. Characteristics of available insulin preparations
2. Insulin preparations
3. Methods of insulin administration
E. Transplantation
General Considerations in the Treatment of Diabetes
Steps in the Management of the Diabetic Patient
A. Diagnostic Examination
B. Patient Education (Self-Management Training)
C. Initial Therapy
1.
1. Type 2 diabetes
2.
2. Type 1 diabetes
Acceptable Levels of Glycemic Control
Prognosis
Treatment Regimens
A. Diet
A well-balanced, nutritious diet remains a fundamental element of therapy. However, in
more than half of cases, diabetic patients fail to follow their diet. In prescribing a diet, it
is important to relate dietary objectives to the type of diabetes. In obese patients with
mild hyperglycemia, the major goal of diet therapy is weight reduction by caloric
restriction. Thus, there is less need for exchange lists, emphasis on timing of meals, or
periodic snacks, all of which are so essential in the treatment of insulin-requiring
nonobese diabetics. This type of patient represents the most frequent challenge for the
clinician. Weight reduction is an elusive goal that can only be achieved by close
supervision and education of the obese patient.
1. American Diabetes Association (ADA) recommendations
The ADA releases an annual position statement on medical nutrition therapy that replaces
the calculated ADA diet formula of the past with suggestions for an individually tailored
dietary prescription based on metabolic, nutritional, and lifestyle requirements. They
contend that the concept of one diet for "diabetes" and the prescription of an "ADA diet"
no longer can apply to both major types of diabetes. In their recommendations for
persons with type 2 diabetes, the 55-60% carbohydrate content of previous diets has been
reduced considerably because of the tendency of high carbohydrate intake to cause
hyperglycemia, hypertriglyceridemia, and a lowered HDL cholesterol. In obese type 2
patients, glucose and lipid goals join weight loss as the focus of therapy. These patients
are advised to limit their carbohydrate content by substituting noncholesterologenic
monounsaturated oils such as olive oil, rapeseed (canola) oil, or the oils in nuts and
avocados. This maneuver is also indicated in type 1 patients on intensive insulin regimens
in whom near-normoglycemic control is less achievable on higher carbohydrate diets.
They should be taught "carbohydrate counting" so they can administer 1 unit of regular
insulin or insulin lispro for each 10 or 15 g of carbohydrate eaten at a meal. In these
patients, the ratio of carbohydrate to fat will vary among individuals in relation to their
glycemic responses, insulin regimens, and exercise pattern.
The current recommendations for both types of diabetes continue to limit cholesterol to
300 mg daily and advise a daily protein intake of 10-20% of total calories. They suggest
that saturated fat be no higher than 8-9% of total calories with a similar proportion of
polyunsaturated fat and that the remainder of caloric needs be made up of an
individualized ratio of monounsaturated fat and of carbohydrate containing 20-35 g of
dietary fiber. Poultry, veal, and fish continue to be recommended as a substitute for red
meats for keeping saturated fat content low. The present ADA position statement proffers
no evidence that reducing protein intake below 10% of intake (about 0.8 g/kg/d) is of any
benefit in patients with nephropathy and renal impairment, and doing so may be
detrimental.
Exchange lists for meal planning can be obtained from the American Diabetes
Association and its affiliate associations or from the American Dietetic Association, 216
W. Jackson Blvd., Chicago, IL 60606 (312-899-0040). Their Internet address is
http://www.eatright.org.
2. Dietary fiber
Plant components such as cellulose, gum, and pectin are indigestible by humans and are
termed dietary "fiber." Insoluble fibers such as cellulose or hemicellulose, as found in
bran, tend to increase intestinal transit and may have beneficial effects on colonic
function. In contrast, soluble fibers such as gums and pectins, as found in beans, oatmeal,
or apple skin, tend to retard nutrient absorption rates so that glucose absorption is slower
and hyperglycemia may be slightly diminished. Although its recommendations do not
include insoluble fiber supplements such as added bran, the ADA recommends food such
as oatmeal, cereals, and beans with relatively high soluble fiber content as staple
components of the diet in diabetics. High soluble fiber content in the diet may also have a
favorable effect on blood cholesterol levels.
3. Artificial sweeteners
Aspartame (NutraSweet) has proved to be a popular sweetener for diabetic patients. It
consists of two amino acids (aspartic acid and phenylalanine) that combine to produce a
nutritive sweetener 180 times as sweet as sucrose. A major limitation is that it cannot be
used in baking or cooking because of its lability to heat.
The nonnutritive sweetener saccharin continues to be available in certain foods and
beverages despite warnings by the Food and Drug Administration (FDA) about its
potential long-term carcinogenicity to the bladder. The latest position statement of the
ADA concludes that all nonnutritive sweeteners that have been approved by the FDA
(such as aspartame and saccharin) are safe for consumption by all people with diabetes.
Two other nonnutritive sweeteners have been approved by the FDA as safe for general
use: sucralose (Splenda) and acesulfame potassium (Sunett, Sweet One, DiabetiSweet).
These are both highly stable and, in contrast to aspartame, can be used in cooking and
baking.
Nutritive sweeteners such as sorbitol and fructose have increased in popularity. Except
for acute diarrhea induced by ingestion of large amounts of sorbitol-containing foods,
their relative risk has yet to be established. Fructose represents a "natural" sugar
substance that is a highly effective sweetener and induces only slight increases in plasma
glucose levels. However, because of potential adverse effects of large amounts of
fructose (up to 20% of total calories) on raising serum cholesterol and LDL cholesterol,
the ADA feels it may have no overall advantage as a sweetening agent in the diabetic
diet. This does not preclude, however, ingestion of fructose-containing fruits and
vegetables or fructose-sweetened foods in moderation.
B. Oral Drugs for Treating Hyperglycemia
(Tables 27-7, 27-8, and 27-9.) The drugs for treating type 2 diabetes fall into three
categories: (1) Drugs that primarily stimulate insulin secretion: Sulfonylureas remain the
most widely prescribed drugs for treating hyperglycemia. The meglitinide analog
repaglinide and the d-phenylalanine derivative nateglinide also bind the sulfonylurea
receptor and stimulate insulin secretion. (2) Drugs that alter insulin action: Metformin
works primarily in the liver. The thiazolidinediones appear to have their main effect on
skeletal muscle and adipose tissue. (3) Drugs that principally affect absorption of
glucose: The Α-glucosidase inhibitors acarbose and miglitol are such currently available
drugs.
Table 27-7. Oral antidiabetic drugs that stimulate insulin secretion.
Drug
Tablet
Size
Daily Dose
Duration Cost per
of Action Unit
Cost for 30 Days
Treatment
Based on
Maximum
Dosage1
Sulfonylureas
Tolbutamide
(Orinase)
250 and 0.5-2 g in 2 or 3 6-12 hours $0.28/500 $33.60
500 mg divided doses
mg
Tolazamide
(Tolinase)
100,
0.1-1 g as single Up to 24
250, and dose or in 2
hours
500 mg divided doses
$0.77/250 $83.40
mg
Acetohexamide 250 and 0.25-1.5 g as
8-24 hours $1.34/500 $120.60
2
(Dymelor)
500 mg single dose or in
mg
2 divided doses
Chlorpropamide 100 and 0.1-0.5 g as
(Diabinese)2
250 mg single dose
24-72
hours
Glyburide
1.25,
1.25-20 mg as
Up to 24
(Dia&bgr;eta, 2.5, and single dose or in hours
Micronase)
5 mg
2 divided doses
(Glynase)
Glipizide
(Glucotrol)
(Glucotrol
XL)
1.5, 3,
and 6
mg
1.5-18 mg as
Up to 24
single dose or in hours
2 divided doses
$0.67/250 $40.20
mg
$0.78/5
mg
$93.60
$1.07/6
mg
$96.30
5 and 10 2.5-40 mg as
6-12 hours $0.59/10
mg
single dose or in
mg
2 divided doses
on an empty
stomach
$70.80
5 and 10 Up to 20 or 30
mg
mg daily as a
$72.90
Up to 24
hours
$0.81/10
mg
single dose
Gliclazide (not
available in the
US)
80 mg
Glimepiride
(Amaryl)
1, 2, and 1-4 mg as single Up to 24
4 mg
dose
hours
Meglitinide analogs
Repaglinide
0.5, 1,
(Prandin)
and 2
mg
40-80 mg as
12 hours
single dose; 160320 mg as
divided dose
4 mg in two
3 hours
divided doses
given 15 minutes
before breakfast
and dinner
d-Phenylalanine derivative
60 mg 60 or 120 mg 3
Nateglinide
and 120 times a day
(Starlix)
mg
before meals
1.5 hours
-
-
$1.31/4
mg
$39.30
$1.29/2
mg
$77.40
$1.29/120 $116.10
mg
1
Average wholesale price (AWP, for AB-rated generic when available) for quantity listed.
Source: Red Book Update, Vol. 24, No. 4, April 2005. AWP may not accurately represent
the actual pharmacy cost because wide contractual variations exist among institutions.
2
There has been a decline in use of these formulations. In the case of chlorpropamide, the
decline is due to its numerous side effects (see text).
Table 27-8. Oral antidiabetic drugs that are insulin-sparing.
Drug
Tablet
Size
Daily Dose
Duration
of Action
Cost per
Unit
Cost for 30 Days
Treatment Based
on Maximum
Dosage1
Biguanides
Metformin
(Glucophage)
500, 850, 1-2.5 g; one
and 1000 tablet with
mg
meals 2 or 3
times daily
Extended500 mg
release metformin
(Glucophage XR)
7-12 hours $1.46/850 $131.40
mg
500-2000 mg
once a day
Up to 24
hours
$0.88/500 $105.60
mg
Thiazolidinediones
Rosiglitazone
2, 4, and 4-8 mg daily
(Avandia)
8 mg
(can be
divided)
Up to 24
hours
$5.59/8
mg
$167.70
Pioglitazone
(Actos)
15, 30,
and 45
mg
15-45 mg
daily
Up to 24
hours
$6.28/45
mg
75-300 mg in
3 divided
doses with
first bite of
food
4 hours
$0.99/100 $89.10
mg
25, 50, 75-300 mg in
and 100 3 divided
mg
doses with
first bite of
food
4 hours
$0.97/100 $87.30
mg
a-Glucosidase inhibitors
Acarbose
50 and
(Precose)
100 mg
Miglitol
(Glyset)
$188.42
1
Average wholesale price (AWP, for AB-rated generic when available) for quantity listed.
Source: Red Book Update, Vol. 24, No. 4, April 2005. AWP may not accurately represent
the actual pharmacy cost because wide contractual variations exist among institutions.
Table 27-9. Combination oral antidiabetic drugs.
Drug
Tablet Daily Dose
Size
Glyburide/metformin
(Glucovance)
1.25
mg/250
mg
2.5
mg/500
mg
5
mg/500
mg
Rosiglitazone/metformin 1
(Avandamet)
mg/500
mg
2
mg/500
mg
4
mg/500
Maximum daily
dose of 20 mg
glyburide/2000
mg metformin
Duration Cost per
of Action Unit
Cost for
30 Days
Treatment
Based on
Maximum
Dosage1
See
$1.13/5/500 $135.60
individual mg
drugs2
Maximum daily See
$1.75/2/500 $210.00
dose of 8 mg
individual mg
rosiglitazone/2000 drugs2
mg metformin
mg
1
Average wholesale price (AWP, for AB-rated generic when available) for quantity listed.
Source: Red Book Update, Vol. 24, No. 4, April 2005. AWP may not accurately represent
the actual pharmacy cost because wide contractual variations exist among institutions.
2
Glyburide, Table 27-7; metformin, Table 27-8; and rosiglitazone, Table 27-8.
1. Drugs that stimulate insulin secretion
a. Sulfonylureas
The primary mechanism of action of the sulfonylureas is to stimulate insulin release from
pancreatic B cells. Specific receptors on the surface of pancreatic B cells bind
sulfonylureas in the rank order of their insulinotropic potency (glyburide with the greatest
affinity and tolbutamide with the least affinity). It has been shown that activation of these
receptors closes potassium channels, resulting in depolarization of the B cell. This
depolarized state permits calcium to enter the cell and actively promote insulin release.
Sulfonylureas are not indicated for use in type 1 diabetes patients since these drugs
require functioning pancreatic B cells to produce their effect on blood glucose. These
drugs are used in patients with type 2 diabetes, in whom acute administration improves
the early phase of insulin release that is refractory to acute glucose stimulation.
Sulfonylureas are generally contraindicated in patients with hepatic or renal impairment.
Idiosyncratic reactions are rare, with skin rashes or hematologic toxicity (leukopenia,
thrombocytopenia) occurring in less than 0.1% of users.
(1) First-generation sulfonylureas (tolbutamide, tolazamide, acetohexamide,
chlorpropamide)
Tolbutamide is supplied as 500-mg tablets. It is rapidly oxidized in the liver to inactive
metabolites, and its approximate duration of effect is relatively short (6-10 hours).
Tolbutamide is probably best administered in divided doses (eg, 500 mg before each meal
and at bedtime); however, some patients require only one or two tablets daily with a
maximum dose of 3000 mg/d. Because of its short duration of action, which is
independent of renal function, tolbutamide is probably the safest sulfonylurea to use if
liver function is normal. Prolonged hypoglycemia has been reported rarely with
tolbutamide, mostly in patients receiving certain antibacterial sulfonamides
(sulfisoxazole), phenylbutazone for arthralgias, or the oral azole antifungal drugs to treat
candidiasis. These drugs apparently compete with tolbutamide for oxidative enzyme
systems in the liver, resulting in maintenance of high levels of unmetabolized, active
sulfonylurea in the circulation.
Tolazamide is supplied in tablets of 100, 250, and 500 mg. It has a longer duration of
action than tolbutamide, lasting up to 20 hours, with maximal hypoglycemic effect
occurring between the fourth and fourteenth hours. It is often effective, as are other
longer-acting sulfonylureas also, when tolbutamide fails to correct prebreakfast
hyperglycemia. Tolazamide is metabolized to several compounds that retain
hypoglycemic effects. If more than 500 mg/d is required, the dose should be divided and
given twice daily. Doses larger than 1000 mg daily do not improve the degree of
glycemic control.
Acetohexamide and chlorpropamide are now rarely used. Chlorpropamide has a
prolonged biologic effect, and severe hypoglycemia can occur especially in the elderly as
their renal clearance declines with aging. Its other side effects include alcohol-induced
flushing and hyponatremia due to its effect on vasopressin secretion and action.
(2) Second-generation sulfonylureas (glyburide, glipizide, gliclazide, glimepiride)
Glyburide, glipizide, gliclazide, and glimepiride are 100-200 times more potent than
tolbutamide. These drugs should be used with caution in patients with cardiovascular
disease or in elderly patients, in whom prolonged hypoglycemia would be especially
dangerous.
Glyburide is available in 1.25-mg, 2.5-mg, and 5-mg tablets. The usual starting dose is
2.5 mg/d, and the average maintenance dose is 5-10 mg/d given as a single morning dose;
maintenance doses higher than 20 mg/d are not recommended. Some reports suggest that
10 mg is a maximum daily therapeutic dose, with 15-20 mg having no additional benefit
in poor responders and doses over 20 mg actually worsening hyperglycemia. Glyburide is
metabolized in the liver into products with hypoglycemic activity, which probably
explains why assays specific for the unmetabolized compound suggest a plasma half-life
of only 1-2 hours, yet the biologic effects of glyburide are clearly persistent 24 hours
after a single morning dose in diabetic patients. Glyburide is unique among sulfonylureas
in that it not only binds to the pancreatic B cell membrane sulfonylurea receptor but also
becomes sequestered within the B cell. This may also contribute to its prolonged biologic
effect despite its relatively short circulating half-life. A "Press Tab" formulation of
"micronized" glyburide-easy to divide in half with slight pressure if necessary-is
available in tablet sizes of 1.5 mg, 3 mg, and 6 mg.
Glyburide has few adverse effects other than its potential for causing hypoglycemia,
which at times can be prolonged. Flushing has rarely been reported after ethanol
ingestion. It does not cause water retention, as chlorpropamide does, but rather slightly
enhances free water clearance. Glyburide is absolutely contraindicated in the presence of
hepatic impairment and should not be used in patients with renal insufficiency, in elderly
patients, or in those who would be put at serious risk from an episode of hypoglycemia.
Glipizide is available in 5-mg and 10-mg tablets. For maximum effect in reducing
postprandial hyperglycemia, this agent should be ingested 30 minutes before meals, since
rapid absorption is delayed when the drug is taken with food. The recommended starting
dose is 5 mg/d, with up to 15 mg/d given as a single daily dose before breakfast. When
higher daily doses are required, they should be divided and given before meals. The
maximum dose recommended by the manufacturer is 40 mg/d, although doses above 10-
15 mg probably provide little additional benefit in poor responders and may even be less
effective than smaller doses.
At least 90% of glipizide is metabolized in the liver to inactive products, and 10% is
excreted unchanged in the urine. Glipizide therapy is therefore contraindicated in patients
with hepatic or renal impairment, who would be at high risk for hypoglycemia; but
because of its lower potency and shorter duration of action, it is preferable to glyburide in
elderly patients. Glipizide has also been marketed as Glucotrol-XL in 5-mg and 10-mg
tablets. It provides extended release during transit through the gastrointestinal tract with
greater effectiveness in lowering prebreakfast hyperglycemia than the shorter-duration
immediate-release standard glipizide tablets. However, this formulation appears to have
sacrificed its lower propensity for severe hypoglycemia compared with longer-acting
glyburide without showing any demonstrable therapeutic advantages over glyburide.
Gliclazide (not available in the United States) is another intermediate duration
sulfonylurea with a duration of action of about 12 hours. It is available as 80 mg tablets.
The recommended starting dose is 40-80 mg/d with a maximum dose of 320 mg. Doses
of 160 mg and above are given as divided doses before breakfast and dinner. The drug is
metabolized by the liver; the metabolites and conjugates have no hypoglycemic effect.
An extended release preparation is available.
Glimepiride is given once daily as monotherapy or in combination with insulin to lower
blood glucose in diabetes patients who cannot control their glucose level through diet and
exercise. Glimepiride achieves blood glucose lowering with the lowest dose of any
sulfonylurea compound, and this tends to increase its cost-effectiveness. A single daily
dose of 1 mg/d has been shown to be effective, and the maximal recommended dose is 8
mg. It has a long duration of action with a pharmacodynamic half-life of 5 hours,
allowing once-daily administration, which improves compliance. It is completely
metabolized by the liver to relatively inactive metabolic products.
b. Meglitinide analogs
Repaglinide is structurally similar to glyburide but lacks the sulfonic acid-urea moiety. It
acts by binding to the sulfonylurea receptor and closing the ATP-sensitive potassium
channel. It is rapidly absorbed from the intestine and then undergoes complete
metabolism in the liver to inactive biliary products, giving it a plasma half-life of less
than 1 hour. The drug therefore causes a brief but rapid pulse of insulin. The starting dose
is 0.5 mg three times a day 15 minutes before each meal. The dose can be titrated to a
maximal daily dose of 16 mg. Like the sulfonylureas, repaglinide can be used in
combination with metformin. Hypoglycemia is the main side effect. In clinical trials,
when the drug was compared with a long-duration sulfonylurea (glyburide), there was a
trend toward less hypoglycemia. Like the sulfonylureas also, repaglinide causes weight
gain. Metabolism is by cytochrome P450 3A4 isoenzyme, and other drugs that induce or
inhibit this isoenzyme may increase or inhibit (respectively) the metabolism of
repaglinide. The drug may be useful in patients with renal impairment or in the elderly. It
remains to be shown that this drug has significant advantages over short-acting
sulfonylureas.
c. d-Phenylalanine derivative
Nateglinide stimulates insulin secretion by binding to the sulfonylurea receptor and
closing the ATP-sensitive potassium channel. This compound is rapidly absorbed from
the intestine, reaching peak plasma levels within 1 hour. It is metabolized in the liver and
has a plasma half-life of about 1.5 hours. Like repaglinide, it causes a brief rapid pulse of
insulin, and when given before a meal it reduces the postprandial rise in blood glucose.
The drug is available as 60-mg and 120-mg tablets. The 60-mg dose is used in patients
who have mild elevations in HbA1c. For most patients, the recommended starting and
maintenance dose is 120 mg three times a day before meals. Like the other insulin
secretagogues, its main side effects are hypoglycemia and weight gain. This drug has
been approved for use either alone or in combination with metformin.
2. Drugs that alter insulin action
a. Metformin
Metformin (1,1-dimethylbiguanide hydrochloride) is used, either alone or in conjunction
with other oral agents or insulin, in the treatment of patients with type 2 diabetes. The
exact mechanism of action remains unclear. It reduces both the fasting level of blood
glucose and the degree of postprandial hyperglycemia in patients with type 2 diabetes but
has no effect on fasting blood glucose in normal subjects. Metformin is particularly
effective in reducing hepatic gluconeogenesis by interfering with lactate oxidation and
uptake by the liver. Other proposed mechanisms include a slowing down of
gastrointestinal absorption of glucose and increased glucose uptake by skeletal muscle,
which have been reported in some but not all clinical studies. Because of its very high
concentration in intestinal cells after oral administration, metformin increases glucose to
lactate turnover, which may account for a reduction in hyperglycemia.
Metformin has a half-life of 1.5-3 hours, is not bound to plasma proteins, and is not
metabolized in humans, being excreted unchanged by the kidneys.
Metformin may be used as an adjunct to diet for the control of hyperglycemia and its
associated symptoms in patients with type 2 diabetes, particularly those who are obese or
are not responding optimally to maximal doses of sulfonylureas. A side benefit of
metformin therapy is its tendency to improve both fasting and postprandial
hyperglycemia and hypertriglyceridemia in obese diabetics without the weight gain
associated with insulin or sulfonylurea therapy. Metformin is not indicated for patients
with type 1 diabetes and is contraindicated in diabetics with serum creatinine levels of 1.5
mg/dL or higher, hepatic insufficiency, alcoholism, or a propensity to develop tissue
hypoxia.
Metformin is dispensed as 500 mg, 850 mg, and 1000 mg tablets. A 500 mg extendedrelease preparation is also available. Although the maximal dosage is 2.55 g, little benefit
is seen above a total dose of 2000 mg. It is important to begin with a low dose and
increase the dosage very gradually in divided doses-taken with meals-to reduce minor
gastrointestinal upsets. A common schedule would be one 500 mg tablet three times a
day with meals or one 850 mg or 1000 mg tablet twice daily at breakfast and dinner. One
to four tablets of the extended-release preparation can be given once a day.
The most frequent side effects of metformin are gastrointestinal symptoms (anorexia,
nausea, vomiting, abdominal discomfort, diarrhea), which occur in up to 20% of patients.
These effects are dose-related, tend to occur at onset of therapy, and often are transient.
However, in 3-5% of patients, therapy may have to be discontinued because of persistent
diarrheal discomfort.
Hypoglycemia does not occur with therapeutic doses of metformin, which permits its
description as a "euglycemic" or "antihyperglycemic" drug rather than an oral
hypoglycemic agent. Dermatologic or hematologic toxicity is rare.
Lactic acidosis has been reported as a side effect but is uncommon with metformin in
contrast to phenformin. While therapeutic doses of metformin reduce lactate uptake by
the liver, serum lactate levels rise only minimally if at all, since other organs such as the
kidney can remove the slight excess. However, if tissue hypoxia occurs, the metformintreated patient is at higher risk for lactic acidosis due to compromised lactate removal.
Similarly, when renal function deteriorates, affecting not only lactate removal by the
kidney but also metformin excretion, plasma levels of metformin rise far above the
therapeutic range and block hepatic uptake enough to provoke lactic acidosis without
associated increases in lactic acid production. Almost all reported cases have involved
subjects with associated risk factors that should have contraindicated its use (renal,
hepatic, or cardiorespiratory insufficiency, alcoholism, advanced age). Acute renal failure
can occur rarely in certain patients receiving radiocontrast agents. Metformin therapy
should therefore be temporarily halted on the day of the test and for 2 days following
injection of radiocontrast agents to avoid potential lactic acidosis if renal failure occurs.
b. Thiazolidinediones
Drugs of this newer class of antihyperglycemic agents sensitize peripheral tissues to
insulin. They bind a nuclear receptor called peroxisome proliferator-activated receptor
gamma (PPAR-γ) and affect the expression of a number of genes and regulate the release
of the adipokines-resistin and adiponectin-from adipocytes. Adiponectin secretion is
stimulated, which sensitizes tissues to the effects of insulin, and resistin secretion is
inhibited, which reduces insulin resistance. Observed effects of thiazolidinediones
include increased glucose transporter expression (GLUT 1 and GLUT 4), decreased free
fatty acid levels, decreased hepatic glucose output, and increased differentiation of
preadipocytes into adipocytes. Like the biguanides, this class of drugs does not cause
hypoglycemia. Troglitazone, the first drug in this class to go into widespread clinical use,
has been withdrawn from clinical use because of drug-associated fatal liver failure.
Two other drugs in the same class are available for clinical use: rosiglitazone and
pioglitazone. Both are effective as monotherapy and in combination with sulfonylureas or
metformin or insulin. When used as monotherapy, these drugs lower HbA1c by about 1 or
2 percentage points. When used in combination with insulin, they can result in a 30-50%
reduction in insulin dosage, and some patients can come off insulin completely. The
combination of a thiazolidinedione and metformin has the advantage of not causing
hypoglycemia. Patients inadequately managed on sulfonylureas can do well on a
combination of sulfonylurea and rosiglitazone or pioglitazone. About 25% of patients in
clinical trials fail to respond to these drugs, presumably because they are significantly
insulinopenic.
The thiazolidinediones not only lower glucose but also have effects on lipids and other
cardiovascular risk factors. Rosiglitazone therapy is associated with increases in total
cholesterol, low-density lipoprotein (LDL)-cholesterol (15%), and high-density
lipoprotein (HDL)-cholesterol (10%). There is a reduction in free fatty acids of about 815%. The changes in triglycerides were generally not different from placebo. The
increase in the LDL-cholesterol need not necessarily be detrimental-studies with
troglitazone showed that there is a shift from the atherogenic small dense LDL particles
to larger, less dense LDL particles. Pioglitazone in clinical trials lowered triglycerides
(9%) and increased HDL-cholesterol (15%) but did not cause a consistent change in total
cholesterol and LDL-cholesterol levels. A prospective randomized comparison of the
metabolic effects of pioglitazone and rosiglitazone on patients who had previously taken
troglitazone showed similar effects on HbA1c and weight gain. Pioglitazone-treated
subjects, however, had lower total cholesterol, LDL-cholesterol, and triglycerides when
compared with rosiglitazone. The thiazolidinediones have also been demonstrated to
decrease levels of plasminogen activator inhibitor type 1, matrix metalloproteinase 9, Creactive protein, and interleukin 6. These effects make these drugs particularly beneficial
for patients with the metabolic syndrome. The thiazolidinediones also may limit vascular
smooth muscle proliferation after injury, and there are reports that troglitazone and
piogliotazone reduce neointimal proliferation after coronary stent placement. Also, in one
double-blind, placebo-controlled study, rosiglitazone was shown to be associated with a
decrease in the ratio of urinary albumin to creatinine excretion.
Anemia occurs in 4% of patients treated with these drugs, but this effect may be due to a
dilutional effect of increased plasma volume rather than a reduction in red cell mass.
Weight gain occurs especially when the drug is combined with a sulfonylurea or insulin.
Edema occurs in about 3-4% of patients receiving monotherapy with rosiglitazone or
pioglitazone. The edema occurs more frequently (10-15%) in patients receiving
concomitant insulin therapy and may result in congestive heart failure. The drugs are
contraindicated in diabetic individuals with New York Heart Association class III and IV
cardiac status.
The dosage of rosiglitazone is 4-8 mg daily and of pioglitazone 15-45 mg daily, and the
drugs do not have to be taken with food. Rosiglitazone is primarily metabolized by the
CYP 2C8 isoenzyme and pioglitazone is metabolized by CYP 2C8 and CYP 3A4.
These two agents have so far not (unlike troglitazone) caused drug-induced
hepatotoxicity. The FDA has, however, recommended that patients should not initiate
drug therapy if there is clinical evidence of active liver disease or the alanine
aminotransferase (ALT) level is 2.5 times greater than the upper limit of normal.
Obviously, caution should be used in initiation of therapy in patients with even mild ALT
elevations. Liver function tests should be performed prior to initiation of treatment and
periodically thereafter.
3. Drugs that affect absorption of glucose
Α-Glucosidase inhibitors competitively inhibit the Α-glucosidase enzymes in the gut that
digest dietary starch and sucrose. Two of these drugs-acarbose and miglitol-are available
for clinical use. Both are potent inhibitors of glucoamylase, Α-amylase, and sucrase but
have less effect on isomaltase and hardly any on trehalase and lactase. Acarbose binds
1000 times more avidly to the intestinal disaccharidases than do products of carbohydrate
digestion or sucrose. A fundamental difference between acarbose and miglitol is in their
absorption. Acarbose has the molecular mass and structural features of a tetrasaccharide,
and very little (about 2%) crosses the microvillar membrane. Miglitol, however, has a
structural similarity with glucose and is absorbable. Both drugs delay the absorption of
carbohydrate and lower postprandial glycemic excursion.
a. Acarbose
Acarbose is available as 50-mg and 100-mg tablets. The recommended starting dose of
acarbose is 50 mg twice daily, gradually increasing to 100 mg three times daily. For
maximal benefit on postprandial hyperglycemia, acarbose should be given with the first
mouthful of food ingested. In diabetic patients, it reduces postprandial hyperglycemia by
30-50%, and its overall effect is to lower the HbA1c by 0.5-1%.
The principal adverse effect, seen in 20-30% of patients, is flatulence. This is caused by
undigested carbohydrate reaching the lower bowel, where gases are produced by bacterial
flora. In 3% of cases, troublesome diarrhea occurs. This gastrointestinal discomfort tends
to discourage excessive carbohydrate consumption and promotes improved compliance
of type 2 patients with their diet prescriptions. When acarbose is given alone, there is no
risk of hypoglycemia. However, if combined with insulin or sulfonylureas, it might
increase the risk of hypoglycemia from these agents. A slight rise in hepatic
aminotransferases has been noted in clinical trials with acarbose (5% versus 2% in
placebo controls, and particularly with doses > 300 mg/d). The levels generally return to
normal on stopping the drug.
In the UKPDS, approximately 2000 patients on diet, sulfonylurea, metformin, or insulin
therapy were randomized to acarbose or placebo therapy. By 3 years, 60% of the patients
had discontinued the drug, mostly because of gastrointestinal symptoms. If one looked
only at the 40% who remained on the drug, they had an 0.5% lower HbA1c compared
with placebo.
b. Miglitol
Miglitol is similar to acarbose in terms of its clinical effects. It is indicated for use in dietor sulfonylurea-treated patients with type 2 diabetes. Therapy is initiated at the lowest
effective dosage of 25 mg three times a day. The usual maintenance dose is 50 mg three
times a day, although some patients may benefit from increasing the dose to 100 mg three
times a day. Gastrointestinal side effects occur as with acarbose. The drug is not
metabolized and is excreted unchanged by the kidney. Theoretically, absorbable Αglucosidase inhibitors could induce a deficiency of one or more of the Α-glucosidases
involved in cellular glycogen metabolism and biosynthesis of glycoproteins. This does
not occur in practice because, unlike the intestinal mucosa, which sees a high
concentration of the drug, the blood level is 200-fold to 1000-fold lower than the
concentration needed to inhibit intracellular Α-glucosidases. Miglitol should not be used
in renal failure, when its clearance would be impaired.
4. Drug combinations
A glyburide and metformin combination (Glucovance) is available in dose forms of 1.25
mg/250 mg, 2.5 mg/500 mg, and 5 mg/500 mg. A rosiglitazone and metformin
combination (Avandamet) is available in dose forms of 1 mg/500 mg, 2 mg/500 mg, and
4 mg/500 mg. These drug combinations, however, limit the clinician's ability to optimally
adjust dosage of the individual drugs and for that reason are of questionable usefulness.
5. Safety of the oral hypoglycemic agents
The UKPDS has put to rest previous concerns regarding the safety of sulfonylureas. It did
not confirm any cardiovascular hazard among over 1500 patients treated intensively with
sulfonylureas for over 10 years, compared with a comparable number who received either
insulin or diet therapy. Analysis of a subgroup of obese patients receiving metformin also
showed no hazard and even a slight reduction in cardiovascular deaths compared with
conventional therapy.
The currently available thiazolidinediones have not to date exhibited the idiosyncratic
hepatotoxicity seen with troglitazone. However, these drugs can precipitate congestive
heart failure and should not be used in patients with New York Heart Association class
III and IV cardiac status. Lactic acidosis from metformin (see above) is quite rare and
probably not a major problem with its use in the absence of major risk factors such as
impaired renal or hepatic disease or conditions predisposing to hypoxia.
C. Incretins
Oral glucose provokes a threefold to fourfold higher insulin response than an equivalent
dose of glucose given intravenously because the oral glucose causes a release of gut
hormones, principally glucagon-like peptide 1 (GLP-1) and glucose-dependent
insulinotropic polypeptide (GIP1), which amplify the glucose-induced insulin release.
This "incretin effect" has been reported to be impaired in patients with type 2 diabetes.
GLP-1, when infused in patients with type 2 diabetes, stimulates insulin secretion and
lowers glucose levels. GLP-1, however, is rapidly proteolysed by dipeptidyl peptidase-IV
(DPP IV) and is not a practical therapeutic agent. Exenatide is a GLP-1 analog that is
more resistant to DPP IV action, and it lowers blood glucose and HbA1c levels when
given subcutaneously twice a day to patients with type 2 diabetes. Oral DPP IV
inhibitors, which work by prolonging the action of endogenously released GLP-1, are
also in clinical trials for use in type 2 diabetes.
D. Insulin
Insulin is indicated for type 1 diabetes as well as for type 2 diabetic patients with
insulinopenia whose hyperglycemia does not respond to diet therapy either alone or
combined with oral hypoglycemic drugs.
With the development of highly purified human insulin preparations, immunogenicity has
been markedly reduced, thereby decreasing the incidence of therapeutic complications
such as insulin allergy, immune insulin resistance, and localized lipoatrophy at the
injection site. However, the problem of achieving optimal insulin delivery remains
unsolved with the present state of technology. It has not been possible to reproduce the
physiologic patterns of intraportal insulin secretion with subcutaneous injections of
soluble or longer-acting insulin suspensions. Even so, with the help of appropriate
modifications of diet and exercise and careful monitoring of capillary blood glucose
levels at home, it has often been possible to achieve acceptable control of blood glucose
by using various mixtures of short- and longer-acting insulins injected at least twice daily
or portable insulin infusion pumps.
1. Characteristics of available insulin preparations
Commercial insulin preparations differ with respect to the animal species from which
they are obtained, their purity and solubility, and the time of onset and duration of their
biologic action. As many as 17 different formulations of insulin are available in the
United States.
a. Species of insulin
Human insulin is produced by recombinant DNA techniques (biosynthetic human insulin)
as Humulin (Eli Lilly) and as Novolin (Novo Nordisk). It is dispensed as either regular
(R), NPH (N), lente (L), or ultralente (U) formulations (Table 27-10). Four analogs of
human insulin-three rapidly acting (insulin lispro, insulin aspart, insulin glulisine) and
one very long-acting (insulin glargine)-have been approved by the FDA for clinical use
(see below). A limited supply of monospecies pork insulin (Iletin II) remains available
for use in certain patients who may benefit from the slightly more prolonged and
sustained effect of animal insulin compared with human insulin. The cost of human
insulin is slightly less than the cost of purified pork insulin.
b. Purity of insulin
"Purified" insulin is defined by FDA regulations as the degree of purity wherein
proinsulin contamination is less than 10 ppm, whether extracted from animal pancreas or
produced from biosynthetic proinsulin. All human insulin and pork insulin products of
Novo Nordisk and Eli Lilly presently available contain less than 10 ppm of proinsulin
and are labeled as "purified." These purified insulins seem to preserve their potency quite
well, so that refrigeration is recommended but not crucial. During travel, reserve supplies
of insulin can thus be readily transported for weeks without losing potency if protected
from extremes of heat or cold.
c. Concentration of insulin
At present, insulins in the United States are available in a concentration of 100 units/mL
(U100), and all are dispensed in 10-mL vials. With the popularity of "low-dose" (0.5- or
0.3-mL) disposable insulin syringes, U100 can be measured with acceptable accuracy in
doses as low as 1-2 units. For use in rare cases of severe insulin resistance in which large
quantities of insulin are required, U500 regular human insulin (Humulin R) is available
from Eli Lilly.
2. Insulin preparations
Four principal types of insulins are available: (1) rapid-acting insulin analogs with more
rapid onset and a shorter duration of action than regular insulin after subcutaneous
injection; (2) short-acting regular insulin; (3) intermediate-acting; and (4) long-acting,
with slow onset of action.
Table 27-10. Some insulin preparations available in the United States.1
Species Source
Concentration
Cost1
Insulin lispro (Humalog,
Lilly)
Human analog
(recombinant)
U100
$67.58
Insulin aspart (Novolog,
Novo Nordisk)
Human analog
(recombinant)
U100
$74.88
Insulin glulisine (Apidra,
Sanofi Aventis)
Human analog
(recombinant)
U100
Human
U100
Preparation
Rapid-acting insulin analogs
Short-acting regular insulins
"Purified"2
Regular Novolin (Novo
Nordisk)3
$30.50
Regular Humulin (Lilly)
Human
U100, U500 20 mL
$29.28,
$210.68
Regular Iletin II (Lilly)
Pork
U100
$47.98
Lente Humulin (Lilly)
Human
U100
$29.28
Lente Iletin II (Lilly)
Pork
U100
$47.98
Lente Novolin (Novo
Nordisk)3
Human
U100
$30.50
NPH Humulin (Lilly)
Human
U100
$29.28
NPH Iletin II (Lilly)
Pork
U100
$47.98
Human
U100
$30.50
Human
U100
$30.50
Humulin 70/30 and 50/50 Human
(Lilly)
U100
$29.28
Intermediate-acting insulins
"Purified"2
NPH Novolin (Novo
Nordisk)3
Premixed insulins
% NPH/% regular
Novolin 70/30 (Novo
Nordisk)3
Other Mixes
75% insulin lispro
protamine/25% insulin lispro
(Humalog Mix 75/25 [Lilly])
Human analog
(recombinant)
U100 (insulin pen,
Pen
prefilled syringes, 5 × 3- $144.63,
mL cartridges)
Vial $71.88
70% insulin aspart
protamine/30% insulin aspart
(Novolog Mix 70/30 [Novo
Nordisk])
Human analog
(recombinant)
U100 (insulin pen,
Pen
prefilled syringes, 5 × 3- $144.62,
mL cartridges)
Vial $74.88
Long-acting insulins
"Purified"2
Ultralente Humulin (Lilly) Human
Insulin glargine (Lantus,
Aventis)
1
Human analog
(recombinant)
U100
$29.28
U100
$66.85
All of these agents (except insulin lispro and U500) are available without a prescription.
Average wholesale price (AWP, for AB-rated generic when available) for 10-mL vial
unless otherwise specified. Source: Red Book Update, Vol. 24, No. 4, April 2005.
Wholesale prices for all human preparations (except insulin lispro and U500) are
similar. AWP may not accurately represent the actual pharmacy cost because wide
contractual variations exist among institutions.
2
3
Less than 10 ppm proinsulin.
Novo Nordisk human insulins are termed Novolin R, L, and N.
Rapid-acting insulin analogs and regular insulin are dispensed as clear solutions at neutral
pH and contain small amounts of zinc to improve their stability and shelf life. The longacting insulin analog insulin glargine is also dispensed as a clear solution but at acidic
pH. Other intermediate-acting and long-acting insulins are dispensed as turbid
suspensions at neutral pH with either protamine in phosphate buffer (NPH insulin) or
varying concentrations of zinc in acetate buffer (ultralente and lente insulins). The rapidacting insulin analogs, intermediate-acting, and long-acting insulins are designed for
subcutaneous administration only, while regular insulin can also be given intravenously.
a. Rapid-acting insulins
Insulin lispro (Humalog) is an insulin analog produced by recombinant technology,
wherein two amino acids near the carboxyl terminal of the B chain have been reversed in
position: Proline at position B28 has been moved to B29 and lysine has been moved from
B29 to B28. Insulin aspart (Novolog) is a single substitution of proline by aspartic acid at
position B28. Insulin glulisine (Apidra) differs from human insulin in that the amino acid
asparagine at position B3 is replaced by lysine and the lysine in position B29 by glutamic
acid. These changes result in these three analogs having less tendency to form hexamers,
in contrast to human insulin. When injected subcutaneously, the analogs quickly
dissociate into monomers and are absorbed very rapidly, reaching peak serum values in
as soon as 1 hour-in contrast to regular human insulin, whose hexamers require
considerably more time to dissociate and become absorbed. The amino acid changes in
these analogs do not interfere with their binding to the insulin receptor, with the
circulating half-life, or with their immunogenicity, which are all identical with those of
human regular insulin.
Clinical trials have demonstrated that the optimal times of preprandial subcutaneous
injection of comparable doses of the rapid-acting insulin analogs and of regular human
insulin are 20 minutes and 60 minutes, respectively, before the meal. While this more
rapid onset of action has been welcomed as a great convenience by diabetic patients who
object to waiting as long as 60 minutes after injecting regular human insulin before they
can begin their meal, patients must be taught to ingest adequate absorbable carbohydrate
early in the meal to avoid hypoglycemia during the meal. Another desirable feature of
insulin lispro is that its duration of action remains at about 4 hours irrespective of dosage.
This contrasts with regular insulin, whose duration of action is prolonged when larger
doses are used.
Table 27-11. Examples of intensive insulin regimens using rapid-acting insulin
analogs (insulin lispro, aspart, or glulisine) and ultralente, NPH, or insulin glargine
in a 70-kg man with type 1 diabetes.1-3
Pre-Breakfast Pre-Lunch Pre-Dinner At Bedtime
Rapid-acting insulin analog 5 units
4 units
6 units
-
Ultralente insulin
-
8 units
-
8 units
OR
Rapid-acting insulin analog 5 units
4 units
6 units
-
NPH insulin
3 units
2 units
8-9 units
3 units
OR
Rapid-acting insulin analog 5 units
4 units
6 units
-
Insulin glargine
-
-
15-16 units
-
1
Assumes that patient is consuming approximately 75 g carbohydrate at breakfast, 60 g
at lunch, and 90 g at dinner.
2
The dose of insulin lispro or insulin aspart can be raised by 1 or 2 units if extra
carbohydrate (15-30 g) is ingested or if premeal blood glucose is > 170 mg/dL. Insulin
lispro or insulin aspart can be mixed in the same syringe with ultralente or NPH insulin.
3
Insulin glargine cannot be mixed with any of the available insulins and must be given as
a separate injection.
b. Short-acting regular insulin
Regular insulin is a short-acting soluble crystalline zinc insulin whose effect appears
within 30 minutes after subcutaneous injection and lasts 5-7 hours when usual quantities
are administered. Intravenous infusions of regular insulin are particularly useful in the
treatment of diabetic ketoacidosis and during the perioperative management of insulinrequiring diabetics. When intravenous insulin is needed for hyperglycemic emergencies,
the rapid-acting insulin analogs have no advantage over regular human insulin, which is
instantly converted to the monomeric form when given intravenously. Regular insulin is
indicated when the subcutaneous insulin requirement is changing rapidly, such as after
surgery or during acute infections-although the rapid-acting insulin analogs may be
preferable in these situations.
The rapid-acting analogs are also commonly used in pumps. In a double-blind crossover
study comparing insulin lispro with regular insulin in insulin pumps, persons using
insulin lispro had lower HbA1c values and improved postprandial glucose control with the
same frequency of hypoglycemia. The concern remains that in the event of pump failure,
users of the rapid-acting insulin analogs will have more rapid onset of hyperglycemia and
ketosis.
c. Intermediate-acting insulins
Lente insulin is a mixture of 30% semilente (an amorphous precipitate of insulin with
zinc ions) with 70% ultralente insulin (an insoluble crystal of zinc and insulin). Its onset
of action is delayed for up to 2 hours, and because its duration of action often is less than
24 hours (with a range of 18-24 hours), most patients require at least two injections daily
to maintain a sustained insulin effect. Lente insulin has its peak effect in most patients
between 8 and 12 hours, but individual variations in peak response time must be
considered when interpreting unusual or unexpected patterns of glycemic responses in
individual patients. NPH (neutral protamine Hagedorn or isophane) insulin is an
intermediate-acting insulin whose onset of action is delayed by combining 2 parts soluble
crystalline zinc insulin with 1 part protamine zinc insulin. This produces equivalent
amounts of insulin and protamine, so that neither is present in an uncomplexed form
("isophane").
The onset and duration of action of NPH insulin are comparable to those of lente insulin;
it is usually mixed with regular insulin and given at least twice daily for insulin
replacement in type 1 patients. Occasional vials of NPH insulin have tended to show
unusual clumping of their contents or "frosting" of the container, with considerable loss
of bioactivity. This instability is rare and occurs less frequently if NPH human insulin is
refrigerated when not in use and if bottles are discarded after 1 month of use.
d. Long-acting insulins
Humulin ultralente is a crystalline insulin whose duration of action is less than that of the
previously available beef ultralente. It is generally recommended that the daily dose be
split into two equal doses given 12 hours apart. Its peak is less than that of NPH insulin,
and it is often used to provide basal coverage while the short-acting insulins are used to
cover the glucose rise associated with meals.
Insulin glargine is an insulin analog in which the asparagine at position 21 of the A chain
of the human insulin molecule is replaced by glycine and two arginines are added to the
carboxyl terminal of the B chain. The arginines raise the isoelectric point of the molecule
closer to neutral, making it more soluble in an acidic environment. In contrast, human
insulin has an isoelectric point of pH 5.4. Insulin glargine is a clear insulin which, when
injected into the neutral pH environment of the subcutaneous tissue, forms
microprecipitates that slowly release the insulin into the circulation. It lasts for about 24
hours without any pronounced peaks and is given once a day to provide basal coverage.
This insulin cannot be mixed with the other human insulins because of its acidic pH.
When this insulin was given as a single injection at bedtime to type 1 patients, fasting
hyperglycemia was better controlled when compared with bedtime NPH insulin. The
clinical trials also suggest that there may be less nocturnal hypoglycemia with this insulin
when compared with NPH insulin.
In one clinical trial involving type 2 patients, insulin glargine was associated with a
slightly higher progression of retinopathy when compared with NPH insulin. The
frequency was 7.5% with the analog and 2.7% with the NPH. This finding, however, was
not seen in other clinical trials with this analog. Insulin glargine does have a sixfold
greater affinity for IGF-1 receptor compared with the human insulin. There has also been
a report that insulin glargine had increased mitogenicity compared with human insulin in
a human osteosarcoma cell line. The significance of these observations is not yet clear.
Because of lack of safety data, use of insulin glargine during pregnancy is not
recommended.
e. Mixtures of insulin
Since intermediate insulins require several hours to reach adequate therapeutic levels,
their use in type 1 patients requires supplements of regular or lispro insulin preprandially.
It is well established that insulin mixtures containing increased proportions of lente to
regular insulins may retard the rapid action of admixed regular insulin. The excess zinc in
lente insulin binds the soluble insulin and partially blunts its action, particularly when a
relatively small proportion of regular insulin is mixed with lente (e.g., 1 part regular to
1.5 or more parts lente). NPH preparations do not contain excess protamine and so do not
delay absorption of admixed regular insulin. They are therefore preferable to lente when
mixtures of intermediate and regular insulins are prescribed. For convenience, regular
and NPH insulin may be mixed together in the same syringe and injected subcutaneously
in split dosage before breakfast and supper. It is recommended that the regular insulin be
withdrawn first, then the NPH insulin. No attempt should be made to mix the insulins in
the syringe, and the injection is preferably given immediately after loading the syringe.
Stable premixed insulins (70% NPH and 30% regular or 50% of each) are available as a
convenience to patients who have difficulty mixing insulin because of visual problems or
impairment of manual dexterity.
With increasing use of rapid-acting insulin analogs as a popular and convenient
preprandial insulin, it has become evident that combination with a more sustained insulin
is essential to maintain postabsorptive glycemic control. It has been demonstrated that the
rapid-acting insulin analogs can be acutely mixed with NPH without affecting their rapid
absorption. Insulin lispro can also be mixed with ultralente insulin. Premixed
preparations of insulin lispro and NPH insulins are unstable because of exchange of
insulin lispro with the human insulin in the protamine complex. Consequently, the
soluble component becomes over time a mixture of regular and insulin lispro at varying
ratios. In an attempt to remedy this, an intermediate insulin composed of isophane
complexes of protamine with insulin lispro was developed called NPL (neutral protamine
lispro). This insulin has the same duration of action as NPH insulin. Premixed
combinations of NPL and insulin lispro (eg, 75:25, 50:50, and 25:75 of NPL:insulin
lispro) have been tested. The 75% NPL:25% insulin lispro mixture (Humalog Mix 75/25)
is available for clinical use. Similarly, a 70% insulin aspart protamine/30% insulin aspart
(NovoLogMix 70/30) is now available. The main advantages of these new mixtures is
that they can be given within 15 minutes of starting a meal and they are superior in
controlling the postprandial glucose rise after a carbohydrate rich meal. These benefits
have not translated into improvements in HbA1c levels when compared with the usual
70% NPH/30% regular mixture.
3. Methods of insulin administration
a. Insulin syringes and needles
Plastic disposable syringes are available in 1-mL, 0.5-mL, and 0.3-mL sizes. The "lowdose" 0.3-mL syringes have become increasingly popular, because many diabetics do not
take more than 30 units of insulin in a single injection except in rare instances of extreme
insulin resistance. Two lengths of needles are available: short (8 mm) and long (12.7
mm). Long needles are preferable in obese patients to reduce variability of insulin
absorption. Ultrafine needles as small as 31 gauge reduce the pain of injections.
"Disposable" syringes may be reused until blunting of the needle occurs (usually after
three to five injections). Sterility adequate to avoid infection with reuse appears to be
maintained by recapping syringes between uses. Cleansing the needle with alcohol may
not be desirable since it can dissolve the silicone coating and can increase the pain of skin
puncturing.
Any part of the body covered by loose skin can be used, such as the abdomen, thighs,
upper arms, flanks, and upper buttocks. Preparation with alcohol is no longer required
prior to injection as long as the skin is clean. Rotation of sites continues to be
recommended to avoid delayed absorption when fibrosis or lipohypertrophy occurs from
repeated use of a single site. However, considerable variability of absorption rates from
different sites, particularly with exercise, may contribute to the instability of glycemic
control in certain type 1 patients if injection sites are rotated too frequently in different
areas of the body. Consequently, it is best to limit injection sites to a single region of the
body and rotate sites within that region. The abdomen is recommended for subcutaneous
injections, since regular insulin has been shown to absorb more rapidly from there than
from other subcutaneous sites. The effect of anatomic regions appears to be much less
pronounced with the analog insulins.
b. Insulin pen injector devices
Insulin pens eliminate the need for carrying insulin vials and syringes. Cartridges of
insulin lispro, insulin aspart, insulin glargine, regular insulin, NPH insulin, and 70%
NPH/30% regular insulin are available for reusable pens (Novo Nordisk, Becton
Dickinson, and Sanofi Aventis pens). Disposable prefilled pens are also available for
insulin lispro, NPH, 70% NPH/30% regular, 75% NPL/25% insulin lispro, and 70%
insulin aspart protamine/30% insulin aspart. Thirty-one gauge needles (5, 6, and 8 mm
long) for these pens make injections almost painless.
c. Insulin pumps
In the United States, Medtronic Mini-Med, Animas, and Deltec Cozmo insulin infusion
pumps are available for subcutaneous delivery of insulin. These pumps are small (about
the size of a pager) and very easy to program. They offer many features, including the
ability to set a number of different basal rates throughout the 24 hours and to adjust the
time over which bolus doses are given. They also are able to detect pressure build-up if
the catheter is kinked. Improvements have also been made in the infusion sets. The
catheter connecting the insulin reservoir to the subcutaneous cannula can be
disconnected, allowing the patient to remove the pump temporarily (e.g., for bathing).
The great advantage of continuous subcutaneous insulin infusion (CSII) is that it allows
for establishment of a basal profile tailored to the patient. The patient therefore is able to
eat with less regard to timing because the basal insulin infusion should maintain constant
blood glucose between meals. Also the ability to adjust the basal insulin infusion makes it
easier for the patient to manage glycemic excursions that occur with exercise.
CSII therapy is appropriate for patients who are motivated, mechanically inclined,
educated about diabetes (diet, insulin action, treatment of hypoglycemia and
hyperglycemia), and willing to monitor their blood glucose four to six times a day.
Known complications of CSII include ketoacidosis, which can occur when insulin
delivery is interrupted, and skin infections. Another disadvantage is its cost and the time
demanded of physicians and staff in initiating therapy.
d. Inhaled insulin
A novel method for delivering preprandial insulin by inhalation has been reported. A 12week study in type 1 patients showed that inhaled insulin is as efficacious as
subcutaneously delivered insulin without additional side effects. Patients required 300400 units of insulin a day, since only 10% of the inhaled insulin is bioavailable. Safety
studies are in progress to determine whether long-term use affects pulmonary tissues.
E. Transplantation
Pancreas transplantation at the time of renal transplantation is becoming more widely
accepted. Patients undergoing simultaneous pancreas and kidney transplantation have an
85% chance of pancreatic graft survival and a 92% chance of renal graft survival after 1
year. Solitary pancreatic transplantation in the absence of a need for renal transplantation
should be considered only in those rare patients who fail all other insulin therapeutic
approaches and who have frequent severe hypoglycemia or who have life-threatening
complications related to their lack of metabolic control.
Islet cell transplantation is a minimally invasive procedure, and investigators in
Edmonton, Canada, have reported initial insulin independence in a small number of
patients with type 1 diabetes who underwent this procedure. Using islets from multiple
donors and corticosteroid-free immunosuppression, percutaneous transhepatic portal vein
transplantation of islets was achieved in over 20 subjects. Although all of the initial
cohort was able to achieve insulin independence posttransplantation (some for more than
2 years of follow-up), a decline in insulin secretion has occurred over time and the
subjects have again required supplemental insulin. All patients had complete correction
of severe hypoglycemic reactions, leading to a marked improvement in overall quality of
life. Even if long-term insulin independence is demonstrated, wide application of this
procedure for the treatment of type 1 diabetes is limited by the dependence on multiple
donors and the requirement for potent long-term immunotherapy.
General Considerations in Treatment of Diabetes
Insulin-treated patients with diabetes can have a full and satisfying life. However, "free"
diets and unrestricted activity are still not advised. Until new methods of insulin
replacement are developed that provide more normal patterns of insulin delivery in
response to metabolic demands, multiple feedings with carbohydrate counting will
continue to be recommended, and certain occupations potentially hazardous to the patient
or others will continue to be prohibited because of risks due to hypoglycemia. The
American Diabetic Association can act as a patient advocate in case of employment
questions.
Exercise increases the effectiveness of insulin, and moderate exercise is an excellent
means of improving utilization of fat and carbohydrate in diabetic patients. A judicious
balance of the size and frequency of meals with moderate regular exercise can often
stabilize the insulin dosage in diabetics who tend to slip out of control easily. Strenuous
exercise can precipitate hypoglycemia in an unprepared patient, and diabetics must
therefore be taught to reduce their insulin dosage in anticipation of strenuous activity or
to take supplemental carbohydrate. Injection of insulin into a site farthest away from the
muscles most involved in exercise may help ameliorate exercise-induced hypoglycemia,
since insulin injected in the proximity of exercising muscle may be more rapidly
mobilized.
All diabetic patients must receive adequate instruction on personal hygiene, especially
with regard to care of the feet, skin, and teeth. All infections (especially pyogenic ones)
provoke the release of high levels of insulin antagonists such as catecholamines or
glucagon and thus bring about a marked increase in insulin requirements. Supplemental
regular insulin is often required to correct hyperglycemia during infection.
Steps in the Management of the Diabetic Patient
A. Diagnostic Examination
Any features of the clinical picture that suggest end-organ insensitivity to insulin, such as
visceral obesity, must be identified. The family history should document not only the
incidence of diabetes in other members of the family but also the age at onset, whether it
was associated with obesity, and whether insulin was required. Other factors that increase
cardiac risk, such as smoking history, presence of hypertension or hyperlipidemia, or oral
contraceptive pill use, should be recorded.
Laboratory diagnosis should document fasting plasma glucose levels above 126 mg/dL or
postprandial values consistently above 200 mg/dL and whether ketonuria accompanies
the glycosuria. A glycohemoglobin measurement is useful for assessing the effectiveness
of future therapy. Some flexibility of clinical judgment is appropriate when diagnosing
diabetes mellitus in the elderly patient with borderline hyperglycemia.
Baseline values include fasting plasma triglycerides, total cholesterol and HDLcholesterol, electrocardiography, renal function studies, peripheral pulses, and
neurologic, podiatric, and ophthalmologic examinations to help guide future assessments.
B. Patient Education (Self-Management Training)
Since diabetes is a lifelong disorder, education of the patient and the family is probably
the most important obligation of the clinician who provides initial care. The best persons
to manage a disease that is affected so markedly by daily fluctuations in environmental
stress, exercise, diet, and infections are the patients themselves and their families. The
"teaching curriculum" should include explanations by the physician or nurse of the nature
of diabetes and its potential acute and chronic hazards and how they can be recognized
early and prevented or treated. Self-monitoring of blood glucose should be emphasized,
especially in insulin-requiring diabetic patients, and instructions must be given on proper
testing and recording of data. Patients should be provided with algorithms they can use to
adjust the timing and quantity of their insulin dose, food, and exercise in response to
measured blood glucose values. The targets for blood glucose control should be elevated
appropriately in elderly patients since they have the greatest risk if subjected to
hypoglycemia and the least long-term benefit from more rigid glycemic control. Advice
on personal hygiene, including detailed instructions on foot care as well as individual
instruction on diet and specific hypoglycemic therapy, should be provided. Patients
should be told about community agencies, such as Diabetes Association chapters, that can
serve as a continuing source of instruction. Finally, vigorous efforts should be made to
persuade new diabetics who smoke to give up the habit, since large vessel peripheral
vascular disease and debilitating retinopathy are less common in nonsmoking diabetic
patients.
C. Initial Therapy
Treatment must be individualized on the basis of the type of diabetes and specific needs
of each patient. However, certain general principles of management can be outlined for
hyperglycemic states of different types.
1. Type 2 diabetes
a. The obese type 2 patient
The most common type of diabetic patient is obese, is non-insulin-dependent, and has
hyperglycemia because of insensitivity to normal or elevated circulating levels of insulin.
(1) Weight reduction
Treatment is directed toward achieving weight reduction, and prescribing a diet is only
one means to this end. Behavior modification to achieve adherence to the diet-as well as
increased physical activity to expend energy-is also required. Cure can be achieved by
reducing adipose stores, with consequent restoration of tissue sensitivity to insulin, but
weight reduction is hard to achieve and even more difficult to maintain with our current
therapies. The presence of diabetes with its added risk factors may motivate the obese
diabetic to greater efforts to lose weight.
(2) Hypoglycemic agents
Monotherapy with metformin (or Α-glucosidase inhibitors) is the first-line therapy in the
obese patient with mild diabetes if pharmacotherapy is required since they are not
associated with weight gain or drug-induced hypoglycemia. If metformin therapy
(combined with a weight reduction regimen) is inadequate to control blood glucose
levels, then a thiazolidinedione or a sulfonylurea should be added. Some individuals may
require metformin, a thiazolidinedione, and a sulfonylurea to achieve adequate glycemic
control.
Insulin therapy should be instituted if the combination of these three drugs fails to restore
euglycemia. Weight-reducing interventions should continue and may allow for
simplification of this regimen in the future.
b. The nonobese type 2 patient
In the nonobese diabetic, mild to severe hyperglycemia is usually due to refractoriness of
B cells to glucose stimulation. Treatment depends on whether insulinopenia is mild (type
2 or mild type 1 in partial remission) or severe, with ketoacidosis.
(1) Diet therapyIf hyperglycemia is mild, normal metabolic control can occasionally be restored by
means of multiple feedings of a diet limited in simple sugars and with a caloric content
sufficient to maintain ideal weight. Restriction of saturated fats and cholesterol is also
strongly advised.
(2) Oral hypoglycemic agents
When diet therapy in nonketotic type 2 patients is not sufficient to correct hyperglycemia,
a trial of sulfonylureas is often successful in reducing the glycohemoglobin concentration
below 9.5%. Once the dosage of one of the more potent sulfonylureas reaches the upper
recommended limit in a compliant patient without maintaining fasting blood glucose
below 140 mg/dL during the day, combination therapy with metformin (up to 1000 mg
twice daily) or a thiazolidinedione-or both-should be tried. When the patient fails the
combination of these three drugs, insulin therapy is indicated.
c. Treatment of type 2 diabetes with insulin
When the combination of metformin, sulfonylurea, and a thiazolidinedione fails and
patients with type 2 diabetes require insulin, various insulin regimens may be effective. A
single nighttime injection of NPH or insulin glargine can be added and titrated to achieve
target fasting blood glucose values while continuing the oral antidiabetic medications. If
the patient does not achieve target glucose levels during the day, daytime insulin
treatment can be initiated. A convenient insulin regimen under these circumstances is a
split dose of 70/30 NPH/regular mixture (or Humalog Mix 75/25 or NovoLogMix 70/30)
before breakfast and before dinner. If this regimen fails to achieve satisfactory glycemic
goals or is associated with unacceptable frequency of hypoglycemic episodes, then a
more intensive regimen of multiple insulin injections can be instituted. Metformin
principally reduces hepatic glucose output and the thiazolidinediones improve peripheral
resistance, and it is a reasonable option to continue these drugs when insulin therapy is
instituted. The sulfonylureas also have been shown to be of continued benefit. Thus, the
continued use of the oral drugs may permit the use of lower doses of insulin and simpler
regimens.
2. Type 1 diabetes
Traditional once- or twice-daily insulin regimens are usually ineffective in type 1 patients
without residual endogenous insulin. In these patients, information and counseling based
on the findings of the DCCT should be provided about the advantages of taking multiple
injections of insulin in conjunction with self-blood glucose monitoring. If nearnormalization of blood glucose is attempted, at least three or four measurements of
capillary blood glucose and three or four insulin injections are necessary.
A combination of rapid-acting insulin analogs and long-acting insulins (ultralente or
insulin glargine) allows for more physiologic insulin replacement. The rapid-acting
insulin analogs have been advocated as a safer and much more convenient alternative to
regular human insulin for preprandial use. In a study comparing regular insulin with
insulin lispro, daily insulin doses and hemoglobin A1c levels were similar, but insulin
lispro improved postprandial control, reduced hypoglycemic episodes, and improved
patient convenience compared with regular insulin. However, because of their relatively
short duration (no more than 3-4 hours), the rapid-acting insulin analogs need to be
combined with longer-acting insulins to provide basal coverage and avoid hyperglycemia
prior to the next meal. In addition to carbohydrate content of the meal, the effect of
simultaneous fat ingestion must also be considered a factor in determining the ultra-fastacting insulin dosage required to control the glycemic increment during and just after the
meal. With low-carbohydrate content and high-fat intake, there is an increased risk of
hypoglycemia from insulin lispro within 2 hours after the meal. Table 27-11 illustrates
some regimens that might be appropriate for a 70-kg person with type 1 diabetes eating
meals providing standard carbohydrate intake and moderate to low fat content.
Table 27-12. Prebreakfast hyperglycemia: Classification by blood glucose and
insulin levels.
Blood Glucose
Free Immunoreactive
(mg/dL)
Insulin
(microunit/mL)
10:00 3:00 7:00 10:00
PM
AM AM PM
3:00
AM
7:00 AM
Somogyi effect
90
40
200
High
Slightly Normal
high
Dawn phenomenon
110
110
150
Normal Normal Normal
Waning of insulin dose 110
plus dawn phenomenon
190
220
Normal Low
Waning of insulin dose 110
plus dawn phenomenon
plus Somogyi effect
40
380
High
Low
Normal Low
Multiple injections of NPH insulin (or twice-daily ultralente insulin) can be mixed in the
same syringe as the insulin lispro, insulin aspart, and insulin glulisine. Insulin glargine is
usually given once in the evening to provide 24-hour coverage. This insulin cannot be
mixed with any of the other insulins and must be given as a separate injection. There are
occasional patients in whom insulin glargine does not seem to last for 24 hours, and in
such cases it needs to be given twice a day.
Continuous subcutaneous insulin infusion (CSII) by portable battery-operated "open
loop" devices currently provides the most flexible approach, allowing the setting of
different basal rates throughout the 24 hours and permitting patients to delay or skip
meals and vary meal size and composition. The dosage is usually based on providing
50% of the estimated insulin dose as basal and the remainder as intermittent boluses prior
to meals. For example, a 70-kg man requiring 35 units of insulin per day may require a
basal rate of 0.7 units per hour throughout the 24 hours with the exception of 3 am to 8
am, when 0.8 units per hour might be appropriate (for the dawn phenomenon). The meal
bolus would depend on the carbohydrate content of the meal and the premeal blood
glucose value. One unit per 15 g of carbohydrate plus 1 unit for 50 mg/dL of blood
glucose above a target value (eg, 120 mg/dL) is a common starting point. Further
adjustments to basal and bolus dosages would depend on the results of blood glucose
monitoring. The majority of patients use the rapid-acting insulin analogs in the pumps.
One of the more difficult therapeutic problems in managing patients with type 1 diabetes
is determining the proper adjustment of insulin dose when the prebreakfast blood glucose
level is high. Occasionally, the prebreakfast hyperglycemia is due to the Somogyi effect,
in which nocturnal hypoglycemia leads to a surge of counterregulatory hormones to
produce high blood glucose levels by 7 am. However, a more common cause for
prebreakfast hyperglycemia is the waning of circulating insulin levels by the morning.
Also, the "dawn phenomenon"-reduced tissue sensitivity to insulin between 5 am and 8
am-is present in as many as 75% of type 1 patients and can aggravate the hyperglycemia.
Table 27-12 shows that diagnosis of the cause of prebreakfast hyperglycemia can be
facilitated by self-monitoring of blood glucose at 3 am in addition to the usual bedtime
and 7 am measurements. This is required for only a few nights, and when a particular
pattern emerges from monitoring blood glucose levels overnight, appropriate therapeutic
measures can be taken. The Somogyi effect can be treated by eliminating the dose of
intermediate insulin at dinnertime and giving it at a lower dosage at bedtime or by
supplying more food at bedtime. When a waning insulin level is the cause, then either
increasing the evening dose or shifting it from dinnertime to bedtime (or both) can be
effective. A bedtime dose either of insulin glargine or of NPH insulin made from pork
insulin provides more sustained overnight insulin levels than human NPH or human
ultralente insulin and may be effective in managing refractory prebreakfast
hyperglycemia. If this fails, insulin pump therapy may be required. When the dawn
phenomenon alone is present, the dosage of intermediate insulin can be divided between
dinnertime and bedtime; when insulin pumps are used, the basal infusion rate can be
increased (e.g., from 0.8 unit/h to 0.9 unit/h from 6 am until breakfast).
Acceptable Levels of Glycemic Control
See above for a discussion of the DCCT and the UKPDS and their implications for
diabetes therapy. A reasonable aim of therapy is to approach normal glycemic excursions
without provoking severe or frequent hypoglycemia. What has been considered
"acceptable" control includes blood glucose levels of 90-130 mg/dL before meals and
after an overnight fast, and levels no higher than 180 mg/dL 1 hour after meals and 150
mg/dL 2 hours after meals. Glycohemoglobin levels should be no higher than 1% above
the upper limit of the normal range for any particular laboratory. It should be emphasized
that the value of blood pressure control was as great as or greater than glycemic control in
type 2 patients as regards microvascular as well as macrovascular complications.
Prognosis
The DCCT showed that the previously poor prognosis for as many as 40% of patients
with type 1 diabetes is markedly improved by optimal care. DCCT participants were
generally young and highly motivated and were cared for in academic centers by skilled
diabetes educators and endocrinologists who were able to provide more attention and
services than are usually available. Improved training of primary care providers may be
beneficial.
For type 2 diabetes, the UKPDS documented a reduction in microvascular disease with
glycemic control, although this was not apparent in the obese subgroup. Cardiovascular
outcomes were not improved by glycemic control, although antihypertensive therapy
showed benefit in reducing the number of adverse cardiovascular complications as well
as in reducing the occurrence of microvascular disease among hypertensive patients. In
patients with visceral obesity, successful management of type 2 diabetes remains a major
challenge in the attempt to achieve appropriate control of hyperglycemia, hypertension,
and dyslipidemia. Once safe and effective methods are devised to prevent or manage
obesity, the prognosis of type 2 diabetes with its high cardiovascular risks should
improve considerably.
In addition to poorly understood genetic factors relating to differences in individual
susceptibility to development of long-term complications of hyperglycemia, it is clear
that in both types of diabetes, the diabetic patient's intelligence, motivation, and
awareness of the potential complications of the disease contribute significantly to the
ultimate outcome.
Bibliography
American Association of Diabetes Educators http://www.aadenet.org/
American Diabetes Association http://www.diabetes.org/home
American Dietetic Association http://www.eatright.org
Juvenile Diabetes Foundation http://www.jdf.org/index.html
Abraira C et al: Intensive insulin therapy in patients with type 2 diabetes: implications of
the Veterans Affairs (VA CSDM) feasibility trial. Am Heart J 1999;138:S360.
American Diabetes Association Position Statement: Diabetes nephropathy. Diabetes Care
2004;27(Suppl 1):S79.
American Diabetes Association Position Statement: Preventive foot care in people with
diabetes. Diabetes Care 2004;27 (Suppl 1):S63.
American Diabetes Association: Standards of Medical Care in Diabetes. Diabetes Care
2005;28(Suppl 1):S4.
Atkinson MA et al: Type 1 diabetes: new perspectives on disease pathogenesis and
treatment. Lancet 2001;358:221.
Diabetes Prevention Trial - Type 1 Diabetes Study Group. Effects of insulin in relatives
of patients with type 1 diabetes mellitus. N Engl J Med 2002;346:1685.
Effect of intensive blood-glucose control with metformin on complications in overweight
patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS)
Group. Lancet 1998;352:854.
Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular
complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group.
BMJ 1998;317:713.
Frank RN: Diabetic retinopathy. N Engl J Med 2004;350:48.
Gaede P et al: Multifactorial intervention and cardiovascular disease in patients with type
2 diabetes. N Engl J Med 2003;348:383.
Genuth S et al: Expert Committee on the Diagnosis and Classification of Diabetes
Mellitus: Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care
2003;26:3160.
Harris R et al: Screening adults for type 2 diabetes: a review of the evidence for the U.S.
Preventive Services Task Force. Ann Intern Med 2003;138:215.
Hebel G et al: Hypoglycemia: pathophysiology and treatment. Endocrinol Metab Clin
North Am 2000;29:725.
Holst JJ et al: Role of incretin hormones in the regulation of insulin secretion in diabetic
and nondiabetic humans. Am J Physiol Endocrinol Metab 2004;287:E199.
Intensive blood-glucose control with sulphonylureas or insulin compared with
conventional treatment and risk of complications in patients with type 2 diabetes
(UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352: 837.
Knowler WC et al: Reduction in the incidence of type 2 diabetes with lifestyle
intervention or metformin. N Engl J Med 2002;346:393.
Lipshultz LI et al: Treatment of erectile dysfunction in men with diabetes. JAMA
1999;281:465.
Ohkubo Y et al: Intensive insulin therapy prevents the progression of diabetic
microvascular complications in Japanese patients with non-insulin-dependent diabetes
mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995;28:103.
Owens DR et al: Insulins today and beyond. Lancet 2001;358:739.
Poncelet AN: Diabetic polyneuropathy. Risk factors, patterns of presentation, diagnosis,
and treatment. Geriatrics 2003;58: 16.
Screening for type 2 diabetes mellitus in adults: recommendations and rationale. Ann
Intern Med 2003;138:212:
Setter SM et al: Metformin hydrochloride in the treatment of type 2 diabetes mellitus: a
clinical review with a focus on dual therapy. Clin Ther 2003;25:2991.
Snow V et al: The evidence base for tight blood pressure control in the management of
type 2 diabetes mellitus. Ann Intern Med 2003;138:587.
Shichiri M et al: Long-term results of the Kumamoto Study on optimal diabetes control in
type 2 diabetic patients. Diabetes Care 2000;23(Suppl 2):B21.
Stumvoll M et al: Clinical features of insulin resistance and beta cell dysfunction and the
relationship to type 2 diabetes. Clin Lab Med 2001;21:31.
Tight blood pressure control and risk of macrovascular and microvascular complications
in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998;317:
703.
Van der Berghe G et al: Intensive insulin therapy in the critically ill patient. N Engl J
Med 2001;345:1359.
Vijan S et al: Treatment of hypertension in type 2 diabetes mellitus: blood pressure goals,
choice of agents, and setting priorities in diabetes care. Ann Intern Med 2003;138:593.
Yki-Jarvinen H: Thiazolidinediones. N Engl J Med 2004;351: 1106.
Yusuf S et al: Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on
cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation
Study Investigators. N Engl J Med 2000;342:145. Erratum in: 2000;342:1376. N Engl J
Med 2000;342:748.
Wajchenberg BL: Subcutaneous and visceral adipose tissue: their relation to the
metabolic syndrome. Endocr Rev 2000;21: 697.
Weissberg-Benchell J et al: Insulin pump therapy: a meta-analysis. Diabetes Care
2003;26:1079.
Zinman B et al: American Diabetes Association: Physical activity/exercise and diabetes.
Diabetes Care 2004;27(Suppl 1):S58.
Source: Current Medical Diagnosis and Treatment 2006