In a small randomized, prospective study, bicarbonate did not affect
recovery in patients with severe DKA (arterial pH, 6.9–7.14).
J.L.’s acidosis seemed severe on admission (pH, 7.05; bicarbonate, 10 mEq/L;
Kussmaul respirations [deep, frequent respirations resulting in blowing off of CO2
bicarbonate was not administered. It is apparent that with fluid and insulin therapy
alone, her acidosis is beginning to improve.
CASE 53-10, QUESTION 5: What is the expected course of DKA in J.L.?
After 3 L of fluid and a constant insulin infusion of 6 units/hour for 3 hours, J.L.’s
glucose concentration had dropped to 400 mg/dL and she had no orthostatic BP
changes, reflecting recovery from her volume-depleted status. Potassium (40 mEq/L)
was added to her fluids, which were administered at a reduced rate of 300 mL/hour.
Three hours later, the glucose concentration had dropped to 350 mg/dL and her pH
had increased to 7.21 with an anion gap of 24 mEq/L. The serum potassium remained
low-normal at 3.4 mEq/L, and serum sodium increased to 151 mEq/L. In view of
these changes, the IV infusion fluid was changed to half-normal saline with 5%
dextrose to which 40 mEq/L of potassium was added. The rate was slowed to 250
mL/hour, and the insulin infusion was continued at 6 units/hour.
Four hours later (10 hours after admission), the BG was 205 mg/dL and the serum
potassium was 3.5 mEq/dL. The IV fluids were changed to 5% dextrose with 40
mEq/L of potassium chloride, administered at a rate of 250 mL/hour, and the regular
insulin infusion was decreased from 6 to 3 units/hour. J.L. continued to improve
during the next 12 hours, and she began taking full oral liquids by the second hospital
day. At that time, her IV infusion rate was decreased to 200 mL/hour, but her insulin
Approximately 24 hours after admission, J.L.’s BG concentration was 175 mg/dL,
potassium was 4.6 mEq/L, sodium was 144 mEq/L, and the anion gap had closed
down to 16 mEq/L. There were no ketones in the plasma. The urine contained 1%
discontinued. J.L. continued to receive rapid-acting insulin SC every 4 hours
according to a sliding scale (see Case 53-2, Question 12). Thirty-six hours after
admission, J.L. was given her usual dose of insulin glargine and insulin lispro and
was sent home for follow-up in the clinic.
Type 2 diabetes must be managed in the context of the metabolic syndrome. At the
time of diagnosis, many people with Type 2 diabetes already have evidence of
macrovascular and microvascular
disease. Every effort to lower glucose concentrations toward normal values and to
control BP and lipids is important to delay the onset or slow the progression of these
complications, improve the overall quality of the patient’s life, and save the
healthcare system millions of dollars in hospitalization costs to treat these
complications. MNT, physical activity, and SMBG are cornerstones in the treatment
of people with Type 2 diabetes. Unfortunately, these measures alone are usually not
successful in achieving control for the majority of patients, and drug therapy is
eventually required. Because these patients also often require a number of
medications to treat related conditions (e.g., hypertension, dyslipidemia, CVD, and
depression) and may also be medicating themselves with over-the-counter drugs,
herbal products, and nutritional supplements, the aim of therapy for Type 2 diabetes
should be the simplest and safest regimen that provides the best glycemic control
Tables 53-25 and 53-26 summarize the comparative pharmacology,
pharmacokinetics, and dosing of the noninsulin antidiabetic drugs. The clinical use of
these agents in specific situations is illustrated in cases presented later in this
Metformin belongs to the biguanide class of oral antidiabetic agents. It has been
available in the United States since 1995 and became generically available in 2002.
Currently, both the immediate-release and the extended-release formulations are
available generically. The clinical pharmacology of metformin has been extensively
The biguanides are described more accurately as antihyperglycemic agents. Although
they lower BG concentrations in people with Type 2 diabetes, they do not cause
hypoglycemia in nondiabetic individuals or individuals with diabetes when used as
monotherapy. Partly because of this lack of hypoglycemia, metformin is
recommended by the ADA to reduce the risk for developing diabetes in patients at
high risk (IGT and IFG) because of its strong evidence base and long-term safety.
Metformin is considered first-line therapy for diabetes because it is the only agent
with outcome data showing a reduction in all-cause mortality and vascular
complications independent of glycemic control.
7,160 Metformin primarily lowers FPG
intestinal absorption of glucose.
Metformin has been shown to activate 5′ adenosine monophosphate-activated
protein kinase (AMPK), a major regulator of glucose and lipid metabolism.
primary cellular site of metformin is thought to be complex I in the mitochondria,
whose inhibition by metformin leads to the activation of AMPK.
activation, acetyl-CoA carboxylase is inactivated, resulting in decreased lipid
synthesis and increased fatty acid oxidation. Sterol regulatory element-binding
protein-1, a key lipogenic transcription factor, is also suppressed, leading to a
reduction in hepatic lipid production. AMPK activation is also thought to play a role
in metformin’s inhibition of hepatocyte glucose production and induction of muscle
Metformin modestly lowers total cholesterol and triglycerides and may maintain or
164 The observed effects on lipid metabolism as well as
others on clotting factors, platelet function, and vascular function may impart some of
metformin’s favorable effects on CVD and outcomes (see Case 53-11, Question 3). A
key advantage with metformin is that weight loss rather than weight gain is more
likely to occur with its use (mean weight loss of 0.5 to 3.8 kg can occur in adults
receiving metformin immediate-release tablets as monotherapy and negligible weight
loss occurs with extended-release tablets).
Approximately 50% to 60% of metformin is absorbed from the small intestine, and
peak plasma concentrations are achieved at approximately 2.5 hours.
Approximately 10% of an oral dose is excreted in the feces and about 90% of a dose
is excreted through an active tubular process in the kidneys. The rate and extent of
absorption are both decreased by food. Metformin has a plasma half-life of 6.2 hours
in patients with normal renal function and a whole-blood half-life of 17.6 hours.
is not bound to plasma proteins.
Transient side effects include diarrhea and other GI disturbances such as nausea,
abdominal discomfort, metallic taste, flatulence and anorexia.
diarrhea is the most common GI complaint with immediate-release tablets (53.2%
metformin vs. 11.7% placebo-treated patients) and occurs in roughly 9.6% of
patients taking extended-release tablets. Symptoms can be minimized by taking
metformin with food and slowly titrating the dose. To enhance adherence to therapy,
patients should be informed of the possibility of GI side effects that will likely
subside with continued use, and instructed to discuss any suspected side effects with
their provider before discontinuing therapy (see Case 53-11, Question 4).
Much of the perceived risk of lactic acidosis secondary to metformin use is based on
historical data for phenformin, a biguanide that was withdrawn from the market in
165 The risk of lactic acidosis secondary to metformin is 10 to 20 times lower
than with phenformin. Unlike phenformin, metformin is not metabolized, does not
inhibit peripheral glucose oxidation, and does not enhance peripheral lactate
166 However, it may decrease conversion of lactate to glucose (decreased
gluconeogenesis) and increase lactate production in the gut and liver.
has rarely been associated with lactic acidosis. The few patients in whom this event
has been reported had renal, liver, or cardiorespiratory contraindications to the use
of biguanides. A Cochrane review including 347 studies compared the risk of lactic
acidosis among patients taking metformin, placebo, or other nonbiguanide therapies.
The review found no difference between groups in either lactate levels or in the
development of lactic acidosis.
157 Despite the rarity of lactic acidosis with metformin
therapy, patients should be warned to bring the following symptoms of lactic acidosis
to the attention of their physician: weakness, malaise, myalgias, abdominal distress,
and heavy, labored breathing (see Case 53-16, Question 2).
CONTRAINDICATIONS AND PRECAUTIONS
Patients with renal impairment, liver disease, or other states predisposing them to
hypoxia, acute or chronic metabolic acidosis, DKA, or a history of lactic acidosis
should be excluded from therapy.
164 Metformin can accumulate in patients whose
renal function is impaired, thereby increasing their risk for lactic acidosis. For this
reason, metformin caries a black box warning. Its use is not recommended in patients
with a decreased GFR (see Dosage and Clinical Use; see Case 53-16, Question 2,
for detailed discussion) or elevated creatinine levels (≥1.4 mg/dLfor women or ≥1.5
). Because even a temporary reduction in renal function could cause
lactic acidosis in patients taking metformin, the manufacturer recommends
withholding it after some radiologic procedures (see Drug Interactions section).
Other predisposing factors for lactic acidosis include the following: excessive
alcohol ingestion, dehydration, surgery, decompensated congestive HF, hepatic
failure, shock, or sepsis. Because aging is associated with reduced renal function,
metformin should be titrated to the minimal effective dose and renal function should
be monitored regularly. An estimated GFR (eGFR) or creatinine clearance (ClCr)
should be measured in patients older than 80 years of age to ensure adequate renal
function prior to metformin use, because these patients are more susceptible to
Alcohol potentiates the effect of metformin on lactate metabolism. Patients should
be warned against excessive alcohol intake while taking metformin. Metformin
should be avoided in patients who are alcoholics.
Vitamin B12 absorption may be decreased in patients taking metformin. Each 1 g/day
increment dose of metformin significantly increases the odds of vitamin B12
deficiency, as well as taking metformin therapy for more than 3 years.
Dofetilide should not be administered in patients taking metformin due to the
competition for common renal tubular transport systems, which may result in an
increase in the plasma concentrations of either drug.
Topiramate should be avoided in patients on metformin because topiramate may
increase the risk of developing lactic acidosis.
Parenteral contrast studies (e.g., pyelography or angiography) that use iodinated
withheld at the time of or before and for 48 hours after the procedure. Metformin
should be reinstituted only after renal function has been re-evaluated and
As monotherapy, metformin can be expected to reduce the A1C by 1.3% to 2.0% and
160 Research suggests that certain genetic variations may
impact patient response to metformin therapy. Patients exhibiting reduced function
polymorphisms of organic cation transporter 1, which is involved in the hepatic
uptake of metformin, may be less responsive to metformin therapy.
Metformin is the first line of therapy for Type 2 diabetes.
its initiation as monotherapy in combination with lifestyle interventions (e.g., MNT,
physical activity, weight-loss education, lifestyle education) on diagnosis. To
minimize GI side effects, metformin should be initiated at 500 mg twice a day or 850
mg once a day, to be taken with food, followed by weekly increases in 500 mg
increments or 850mg increases every 2 weeks (see Case 53-11, Question 4).
Metformin is dosed 2 to 3 times daily (500–1,000 mg/dose; maximal dose 2,550
mg/day or 850 mg PO 3 times a day [TID]), unless an extended-release preparation
is prescribed. Using the ER formulation as initial therapy may decrease GI side
effects. It should still be initiated at 500 mg daily and titrated similarly. It can,
however, be dosed once a day, usually with the evening meal. Clinicians should
obtain a SCr/eGFR (using the Modification of Diet in Renal Disease equation) and
hepatic function tests at baseline and then annually. A recent review 169
that metformin dose reduction should be considered in patients with an eGFR <45
mL/minute/1.73 m2 and the TDD should not exceed 1,000 mg/day. Renal function
should be closely monitored in these patients every 3 months. Metformin should be
discontinued in patients with an eGFR <30 mL/minute/1.73 m2 or in patients with
additional risk factors such as hypotension, hypoxia, sepsis, or an increased risk for
acute kidney injury (e.g., use of radiocontrast dye in patients with an eGFR <60
). Metformin should not be used in patients older than 80 years
unless a ClCr/eGFR demonstrates normal renal function.
candidates for treatment if the ClCr is more than 60 mL/minute (or eGFR >60
). For patients unable to achieve goals of therapy with metformin
alone within 3 months of initiating therapy, addition of insulin or another agent should
be considered (also see Case 53-13).
Nonsulfonylurea Insulin Secretagogues (Glinides)
Repaglinide (Prandin) and nateglinide (Starlix) are nonsulfonylurea insulin
secretagogues (i.e., they stimulate insulin secretion). They belong to a class of agents
referred to as meglitinides and are often called “glinides.” Repaglinide was
approved by the FDA in December 1997, and nateglinide was approved in
These agents close the adenosine triphosphate (ATP)-sensitive potassium channels in
the β-cell, which leads to cell membrane depolarization, an influx of calcium, and
secretion of insulin. The release of insulin depends on the glucose level and
decreases at low concentrations of glucose.
170,171 Unlike the sulfonylureas, they have
a rapid onset and shorter duration of action, so they are given with meals to enhance
postprandial glucose utilization.
Repaglinide has a bioavailability of 56% and is rapidly absorbed and excreted.
maximal serum concentration (Cmax
) occurs at approximately 1 hour, and its half-life
is 1 hour. Repaglinide is highly (>98%) protein bound (volume of distribution, 31 L).
It is completely metabolized (via cytochrome P-450 [CYP] 3A4 and 2C8) by the
liver to inactive products, with 90% excreted in the feces and 8% excreted in urine.
Nateglinide has a bioavailability of 73%.
It is rapidly absorbed, with a Cmax
occurring within 1 hour after dosing and a half-life of 1.5 hours. Nateglinide is
metabolized (CYP 2C9, 70%; CYP 3A4, 30%) to less-potent compounds, which are
75% excreted in the urine and 10% in the feces. Sixteen percent is excreted
unchanged in the urine. It is highly (98%) protein bound, primarily to albumin, and, to
Mild hypoglycemia may occur, particularly if patients delay or forget to eat after the
dose. A weight gain of 0.9 to 3 kg compared with baseline has been observed.
Rare side effects include elevated hepatic enzymes and hypersensitivity reactions.
There has been at least one case report of repaglinide-induced hepatic toxicity.
CONTRAINDICATIONS AND PRECAUTIONS
Because a functioning pancreas is required, these agents should not be used in people
with Type 1 diabetes. They should be used with caution in patients with liver
dysfunction. They are contraindicated for use in patients with DKA. Repaglinide
clearance is reduced in patients with severe renal insufficiency, but may still be used
170 The clearance of nateglinide is not affected in patients
with moderate-to-severe renal insufficiency.
Comparative Pharmacology of Antidiabetic Agents
Name)/Mechanism FDA Indications A1C Efficacy
Glucose Reabsorption Inhibitors
Delayers of Carbohydrate Absorption
Enhancers of Dopaminergic Tone
aComparative effectiveness data provided for SFUs, glinides, TZDs, and α-glucosidase inhibitors.
Theoretically, unlimited glucose lowering with insulin therapy.
Clinically relevant drug interactions include those that occur when these drugs are
taken in combination with other glucose-lowering agents or drugs known to induce or
173 Therefore, BG levels should be closely monitored when
either drug is taken in combination with other agents known to lower BG or affect
their metabolism. Repaglinide is metabolized by CYP 2C8 and 3A4.
shown that repaglinide has no pharmacokinetic effects on digoxin or warfarin.
Gemfibrozil should be avoided in combination with repaglinide owing to the risk of
hypoglycemia. The combination of gemfibrozil and itraconazole synergistically
inhibits repaglinide metabolism and should be avoided. Concomitant use of
clopidogrel may result in increased serum concentrations of repaglinide; therefore,
dose reduction of repaglinide may be required. Cyclosporine inhibits the metabolism
of repaglinide causing increased serum concentrations of repaglinide; therefore, a
dose reduction may be required. Nateglinide is metabolized largely by CYP 2C9
(70%) and to a lesser extent by 3A4 (30%).
171 When evaluated in clinical studies,
there were no clinically relevant interactions with nateglinide and glyburide,
metformin, digoxin, diclofenac, or warfarin. Concomitant use of oral systemic azole
antifungals should be used cautiously due to potential for increased hypoglycemic
effects. Fibric acid derivatives including fenofibrate, clofibrate, and gemfibrozil may
increase the effects of nateglinide. Concomitant use of either repaglinide or
nateglinide with rifampin may lower their efficacy.
The efficacy of repaglinide is comparable to metformin and the sulfonylureas.
When used as monotherapy, the mean decrease in FPG, postprandial glucose, and the
A1C values were 61 mg/dL, 104 mg/dL, and 1.7%, respectively, compared with
mg/dL, −47.6 mg/dL, and −0.6% compared with baseline).
monotherapy results in a mean decrease in FPG and A1C of 13.6 mg/dL and 0.7%,
respectively, compared with placebo (−4.5 mg/dL and −0.5% compared with
In comparison with metformin monotherapy, both drugs produce a
similar or slightly smaller reduction in A1C.
Repaglinide and nateglinide are approved to treat people with Type 2 diabetes as
monotherapy or in combination with metformin or a TZD.
same mechanism of action as the sulfonylureas, combining these agents does not
produce any additional benefit. The agents are usually added to therapy for patients
with postprandial hyperglycemia, particularly nateglinide. When repaglinide is used
as the initial treatment in patients who are naïve to oral antidiabetic therapy or in
patients with A1C values less than 8%, the recommended starting dose is 0.5 mg 15
to 30 minutes prior to eating up to 4 times a day. When used in patients who have
failed sulfonylureas or in those with A1C values greater than 8%, the initial dose is 1
to 2 mg with each meal up to 4 times a day. Doses can be titrated weekly at a rate of
1 mg/meal to a maximum of 4 mg/dose or 16 mg/day. Repaglinide should be initiated
at a 0.5-mg dose in patients with severe renal dysfunction and should be titrated
cautiously in patients with liver dysfunction. The recommended starting dose of
nateglinide is 120 mg TID 0 to 30 minutes before meals. For patients close to their
A1C goal, a dose of 60 mg TID may be used. Doses should be omitted if a meal is
skipped and added if an extra meal is ingested (repaglinide only). There are no
dosage adjustments required for nateglinide in patients with renal or hepatic
Until metformin and other antidiabetic agents became available in the United States,
sulfonylureas were the first-line pharmacologic treatment for people with Type 2
diabetes who had failed diet and exercise therapy. Six sulfonylureas are available in
the United States. The three first-generation sulfonylureas (chlorpropamide,
tolazamide, and tolbutamide) are considered equally effective despite differences in
their pharmacokinetic properties and adverse effect profiles (see the following
discussion and Tables 53-25 and 53-26).
Glipizide and glyburide, two second-generation sulfonylureas, were first
introduced into the United States in May 1984. Glimepiride was approved for use in
1995. Despite being approximately 100 times more potent than the first-generation
sulfonylureas on a milligram-for-milligram basis, these agents are not more clinically
effective. Their duration of activity allows for once- or twice-daily dosing.
Antidiabetic Pharmacokinetic Data
Nonsulfonylurea Insulin Secretagogues (Glinides)
First-Generation Sulfonylureas
≥35 hours 24–72 hours Inactive and
7 hours 6–12 hours Metabolized to
Second-Generation Sulfonylureas
1–8 mg daily 9 hours 24 hours F = 100%
2–4 hours 12–24 hours Metabolized
5–20 mg daily 4–13 hours 24 hours Same as
4–13 hours 12–24 hours Metabolized
GLP-1 Receptor Agonists/Incretin Mimetics
100 mg daily 12.4 hours 24 hours F = 87%;
5 mg daily 5 mg daily 12 hours 24 hours F = 30%;
25 mg daily 21 hours 24 hours F=100%, 76%
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