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In a small randomized, prospective study, bicarbonate did not affect

recovery in patients with severe DKA (arterial pH, 6.9–7.14).

159 Thus, even though

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

infusion was continued.

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%

glucose and moderate amounts of ketones. IV fluids were discontinued, and a rapidacting insulin was administered SC 1 hour before the insulin infusion was

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.

TREATMENT OF TYPE 2 DIABETES:

ANTIDIABETIC AGENTS

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

p. 1111

p. 1112

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

possible.

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

chapter.

Biguanides

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

reviewed.

160

MECHANISM OF ACTION

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

concentrations by decreasing hepatic gluconeogenesis, but it also increases insulinstimulated glucose uptake by skeletal muscle and adipose tissue and also decreases

intestinal absorption of glucose.

160

Metformin has been shown to activate 5′ adenosine monophosphate-activated

protein kinase (AMPK), a major regulator of glucose and lipid metabolism.

161 The

primary cellular site of metformin is thought to be complex I in the mitochondria,

whose inhibition by metformin leads to the activation of AMPK.

162 Through 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

glucose uptake.

161,163

Metformin modestly lowers total cholesterol and triglycerides and may maintain or

improve HDL-C levels.

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).

164

PHARMACOKINETICS

Approximately 50% to 60% of metformin is absorbed from the small intestine, and

peak plasma concentrations are achieved at approximately 2.5 hours.

164

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.

164

It

is not bound to plasma proteins.

ADVERSE EFFECTS

Gastrointestinal Effects

Transient side effects include diarrhea and other GI disturbances such as nausea,

abdominal discomfort, metallic taste, flatulence and anorexia.

164 Relative to placebo,

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).

Lactic Acidosis

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

1977.

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

production.

166 However, it may decrease conversion of lactate to glucose (decreased

gluconeogenesis) and increase lactate production in the gut and liver.

166,167 Metformin

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

mg/dL for men

164

). 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).

p. 1112

p. 1113

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

experiencing lactic acidosis.

164

DRUG INTERACTIONS

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

materials can result in acute renal failure and increase the risk of metformininduced lactic acidosis. For patients requiring such a study, metformin should be

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

determined to be normal.

EFFICACY

As monotherapy, metformin can be expected to reduce the A1C by 1.3% to 2.0% and

the FPG by 50 to 70 mg/dL.

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.

168

DOSAGE AND CLINICAL USE

Metformin is the first line of therapy for Type 2 diabetes.

7,38 The ADA recommends

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

recommends

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

mL/minute/1.73 m2

). Metformin should not be used in patients older than 80 years

unless a ClCr/eGFR demonstrates normal renal function.

7 Patients are good

candidates for treatment if the ClCr is more than 60 mL/minute (or eGFR >60

mL/minute/1.73 m2

). 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

December 2000 (Table 53-25).

MECHANISM OF ACTION

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.

PHARMACOKINETICS

Repaglinide has a bioavailability of 56% and is rapidly absorbed and excreted.

170

Its

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%.

171

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

a lesser extent, to α1

-acid glycoprotein.

ADVERSE EFFECTS

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.

170,171

Rare side effects include elevated hepatic enzymes and hypersensitivity reactions.

There has been at least one case report of repaglinide-induced hepatic toxicity.

172

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

safely at a reduced dose.

170 The clearance of nateglinide is not affected in patients

with moderate-to-severe renal insufficiency.

171

p. 1113

p. 1114

Table 53-25

Comparative Pharmacology of Antidiabetic Agents

Agent/Generic

Name (Brand

Name)/Mechanism FDA Indications A1C Efficacy

a Adverse Effects Comments

Insulin

Replaces or

augments

endogenous insulin

Monotherapy;

combined with any

oral agent

↓ A1Cb ↓FPGb

↓ PPGb

↓ TG

Hypoglycemia,

weight gain,

lipodystrophy, local

skin reactions

Offers flexible

dosing to match

lifestyle and glucose

concentrations.

Rapid onset. Safe in

pregnancy, renal

failure, and liver

dysfunction. Drug of

choice when patients

do not respond to

other antidiabetic

agents

Insulin-Augmenting Agents

Nonsulfonylurea

secretagogues

(glinides)

Repaglinide

(Prandin)

Nateglinide (Starlix)

Stimulates insulin

secretion

Monotherapy;

combined with

metformin or TZD

Monotherapy: ↓

A1C ˜1%

(repaglinide)

↓ A1C ˜0.5%

(nateglinide)

Combination:

additional 1% ↓ A1C

Hypoglycemia,

weight gain

Take only with

meals. If a meal is

skipped, skip a dose.

Flexible dosing with

lifestyle. Safe in

renal and liver

failure. Rapid onset.

Useful to lower PPG

Sulfonylureas

Various; see Table

53-26. Stimulates

insulin secretion.

May decrease

hepatic glucose

output and enhance

peripheral glucose

utilization

Monotherapy;

combined with

metformin; combined

with insulin

(glimepiride)

Monotherapy: ↓

A1C ˜1%

Combination:

additional 1% ↓ in

A1C

Hypoglycemia,

especially longacting agents;

weight gain (5–10

lb); rash,

hepatotoxicity,

alcohol intolerance,

and hyponatremia

rare

Very effective

agents. Some can be

dosed once daily.

Rapid onset of

effect (1 week)

Incretin-Based Therapies

Glucagon-like

peptide-1 receptor

agonists/incretin

mimetic

Exenatide (Byetta)

Extended-release

exenatide

(Bydureon)

Liraglutide (Victoza)

Dulaglutide

(Trulicity)

Albiglutide

(Tanzeum)

Stimulates insulin

secretion, delays

gastric emptying,

reduces postprandial

glucagon levels,

improved satiety

Monotherapy

(exenatide only)

Combined with

metformin, SFU, or

TZD; combined with

metformin + SFU;

combined with

metformin + TZD

Exenatide and

liraglutide can be

used in combination

with basal insulin

Monotherapy: ↓

A1C 0.8%–0.9%

Combination:

additional 1% ↓ in

A1C

GI: nausea, vomiting,

diarrhea;

hypoglycemia (with

SFUs); weight loss;

reports of acute

pancreatitis; URTIs

Weight loss.

Exenatide: take

within 60 minutes

before morning and

evening meals or

before 2 main meals

of the day (≥6 hours

apart).

Liraglutide,

extended-release

exenatide,

dulaglutide,

albiglutide: Do not

use if personal or

family history of

medullary thyroid

carcinoma (MTC) or

in patients with

multiple endocrine

neoplasia syndrome

type 2.

Do not use in

patients with

gastroparesis or

severe GI disease.

Administered by SC

injection; pen device

in use does not need

to be refrigerated.

Rare cases of

pancreatitis

DPP-4 inhibitors

Sitagliptin (Januvia)

Saxagliptin (Onglyza)

Linagliptin

Monotherapy;

combined with

metformin, SFU, or

TZD; insulin

Monotherapy: ↓

A1C 0.5%–0.8%

Combination: ↓ A1C

0.5%–0.9%

Headache,

nasopharyngitis,

hypoglycemia (with

SFU), rash (rare)

Dosed once daily.

Taken with or

without food. No

weight gain or

(Tradjenta)

Alogliptin

(Nesina)

Stimulates insulin

secretion and

reduces postprandial

glucagon levels

(sitagliptin, linagliptin,

and saxagliptin)

nausea. Need to

adjust sitagliptin,

saxagliptin, and

alogliptin dose in

renal dysfunction.

Reduce dose of SFU

when combined.

Rare reports of

pancreatitis

p. 1114

p. 1115

Amylin Receptor Agonists

Amylin mimetic

Pramlintide (Symlin)

Type 1: Adjunct to

mealtime insulin

T1: ↓ A1C 0.33%

T2: ↓ A1C 0.40%

GI: nausea,

decreased appetite

Take only

immediately before

meals; administered

by SC injection. Do

not use in patients

with gastroparesis.

Reduce dose of

mealtime insulin by

50% to avoid

hypoglycemia when

starting therapy

Stimulates insulin

secretion, delays

gastric emptying,

reduces postprandial

glucagon levels,

improved satiety

Type 2: Adjunct to

mealtime insulin; ±

SFU and metformin

Headache;

hypoglycemia;

weight loss (mild)

Insulin Sensitizers

Biguanides

Metformin

(Glucophage)

↓ Hepatic glucose

output; ↑ peripheral

glucose uptake

Monotherapy;

combined with SFU

or TZD; or with

insulin

Monotherapy: ↓ A1C

˜1%

Combination:

additional 1% ↓ in

A1C

GI: nausea,

cramping, diarrhea;

lactic acidosis (rare)

Titrate dose slowly

to minimize GI

effects. No

hypoglycemia or

weight gain; weight

loss possible. Mild

reduction in

cholesterol. Do not

use in patients with

renal or severe

hepatic dysfunction

Thiazolidinediones

Rosiglitazone

(Avandia)

Pioglitazone (Actos)

Enhances insulin

action in periphery;

increases glucose

utilization by muscle

and fat tissue;

Monotherapy;

combined with SFU,

TZD, or insulin;

combined with SFU

+ TZD

Monotherapy: ↓ A1C

˜1%

Combination:

additional 1% ↓ in

A1C

Mild anemia; fluid

retention and edema,

weight gain, macular

edema, fractures (in

women)

Can cause or

exacerbate HF; do

not use in patients

with symptomatic

HF or class III or IV

HF. Rosiglitazone

may increase risk of

MI. Increased risk

of distal fractures in

decreases hepatic

glucose output

older women.

Pioglitazone may

increase risk of

bladder cancer when

used for >1 year.

Slight reduction in

TG with

pioglitazone; slight

increase in LDL-C

with rosiglitazone.

LFTs must be

measured at baseline

and periodically

thereafter. Slow

onset (2–4 weeks)

Glucose Reabsorption Inhibitors

Sodium–Glucose

Cotransporter

Type 2 Inhibitors

Canagliflozin

(Invokana)

Dapagliflozin

(Farxiga)

Empagliflozin

(Jardiance)

Selectively and

reversibly bind to

SGLT-2 preventing

reabsorption of

glucose leading to

the excretion of

glucose in the urine

May be used as 2nd

or 3rd line agent or

1st line in patients

who cannot tolerate

metformin.

↓A1C 0.7-1.0%

↓FPG

↓PPG

May cause weight

loss

Genital mycotic

infections

Urinary tract

infections

↓GFR in patients

with renal failure

Low risk of

hypoglycemia

Contraindicated in

renal failure

GFR<30

p. 1115

p. 1116

Delayers of Carbohydrate Absorption

α-Glucosidase

inhibitors

Acarbose (Precose)

Miglitol (Glyset)

Slow absorption of

complex

carbohydrates

Monotherapy;

combined with

SFUs, metformin, or

insulin

Monotherapy: ↓ A1C

˜0.5%

Combination:

additional ˜0.5% ↓

A1C

GI: flatulence,

diarrhea. Elevations

in LFTs seen in

doses >50 mg TID

of acarbose

Useful for PPG

control (↓ PPG 25–

50 mg/dL).

LFTs should be

monitored every 3

months during the

first year of therapy

and periodically

thereafter. Because

miglitol is not

metabolized,

monitoring of LFTs

is not required.

Titrate dose slowly

to minimize GI

effects. No

hypoglycemia or

weight gain. If used

in combination with

hypoglycemic

agents, advise

patients to treat

hypoglycemia with

glucose tablets

because absorption

is not inhibited as

with sucrose.

Avoid use in patients

with GI disorders

(IBD, Crohn

disease, intestinal

obstruction)

Bile acid

sequestrant

Colesevelam

(Welchol)

Combined with

metformin, SFU, or

insulin

↓ A1C 0.3%–0.4% Constipation,

dyspepsia, and

nausea; ↑ TG

Added benefit of ↓

LDL-C (by 12%–

16%). Administer

certain drugs 4 hours

before. Take with a

meal and liquid

Enhancers of Dopaminergic Tone

Bromocriptine

(Cycloset)

Monotherapy;

combined with SFU

or metformin in

patients with type 2

diabetes

Monotherapy ↓ A1C

0.1%; Combo: ↓

A1C 0.5%

Hypotension,

dizziness, syncope,

nausea, somnolence,

headache,

exacerbation of

psychotic disorders

Very limited role as

a therapeutic agent

aComparative effectiveness data provided for SFUs, glinides, TZDs, and α-glucosidase inhibitors.

256

Theoretically, unlimited glucose lowering with insulin therapy.

A1C, glycosylated hemoglobin; DPP-4, dipeptidyl peptidase-4; FDA, Food and Drug Administration; FPG, fasting

plasma glucose; GI, gastrointestinal; HF, heart failure; LDL-C, low-density lipoprotein cholesterol; LFTs, liver

function tests; MI, myocardial infarction; PPG, postprandial glucose; SC, subcutaneously; SFU, sulfonylureas; TG,

triglycerides; TID, 3 times a day; T1, type 1 diabetes; T2, type 2 diabetes; TZD, thiazolidinediones.

DRUG INTERACTIONS

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

inhibit their metabolism.

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.

170 Studies have

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.

173

EFFICACY

The efficacy of repaglinide is comparable to metformin and the sulfonylureas.

174

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

placebo (−31.0

p. 1116

p. 1117

mg/dL, −47.6 mg/dL, and −0.6% compared with baseline).

170 Nateglinide as

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

baseline).

171

In comparison with metformin monotherapy, both drugs produce a

similar or slightly smaller reduction in A1C.

DOSAGE AND CLINICAL USE

Repaglinide and nateglinide are approved to treat people with Type 2 diabetes as

monotherapy or in combination with metformin or a TZD.

170,171 Because they have the

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

insufficiency.

170,171

Sulfonylureas

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.

p. 1117

p. 1118

Table 53-26

Antidiabetic Pharmacokinetic Data

Drug (Brand

Name),

Available

Tablet

Strengths

(mg)

Typical

Dosing

Regimen

(mg)

Usual

Minimum

and

Maximum

Total Daily

Dose

(TDD)/How

Divided

Mean

Half-Life

Approximate

Duration of

Activity

Bioavailability,

Metabolism,

and Excretion Comments

α-Glucosidase Inhibitors

Acarbose

(Precose) 25,

50, 100 mg

25–100 mg

with first bite

of each meal

Begin with

25 mg; ↑ by

25 mg/meal

every 4–8

weeks

Minimum: 25

mg TID

Maximum

dose is 50 mg

TID if ≤60

kg; 100 mg

TID if >60 kg

2 hours Affects

absorption of

complex

carbohydrates

in a single

meal

F = 0.5%–1.7%;

extensively

metabolized by

GI amylases to

inactive

products; 50%

excreted

unchanged in

the feces

Titrate doses

slowly to

avoid GI

effects

Miglitol

(Glyset) 25, 50,

100 mg

25–100 mg

with first bite

of each meal

Minimum: 25

mg TID

Maximum:

2 hours Affects

absorption of

complex

Dose of 25 mg

is completely

absorbed; dose

Begin with

25 mg; ↑ by

25 mg/meal

every 4–8

weeks

100 mg TID carbohydrates

in a single

meal

of 100 mg 50%–

70% absorbed;

elimination by

renal excretion

as unchanged

drug

Biguanides

Metformin

(Glucophage)

500, 850, 1000

mg; 500 mg/mL

liquid

Begin with

500 mg daily

or BID; ↑ by

500 mg daily

every 1–2

weeks

0.5–2.5 g

BID or TID

Plasma, 6.2

hours.

Whole

blood, 17.6

hours

6–12 hours F = 50%–60%;

excreted

unchanged in

urine

Take with

food. Avoid in

patients with

renal

dysfunction or

those who

could be

predisposed

to lactic

acidosis (e.g.,

alcoholism,

severe HF,

severe

respiratory

disorders,

liver failure)

Metformin

extendedrelease

(Glucophage

XR) 500, 750,

1000 mg

500–1,000

mg daily with

evening

meal; ↑ by

500 mg every

1–2 weeks

1,500–2,000

mg daily

As for

metformin,

but active

drug is

released

slowly

24 hours As for

metformin

As for

metformin

Nonsulfonylurea Insulin Secretagogues (Glinides)

Repaglinide

(Prandin) 0.5,

1, 2 mg

If A1C is

<8% or if this

is first drug,

begin with

0.5 mg with

each meal.

For others,

begin with 1–

2 mg/meal

0.5–4 mg

with each

meal (16

mg/d) TID or

QID

1 hour Cmax

is at 1

hour; duration

is

approximately

2–3 hours

F = 56%; 92%

metabolized to

inactive

products by the

liver; 8%

excreted as

metabolites

unchanged in

the urine

Take only

with meals.

Skip dose if

meal is

skipped.

Maximum

dose per meal

is 4 mg

Nateglinide

(Starlix) 60, 120

mg

120 mg TID

1–30 minutes

before meals;

60 mg TID

for patients

with nearnormal A1C

at initiation

60 or 120 mg

TID

1.5 hours Onset, 20

minutes; peak,

1 hours;

duration, 2–4

hours

F = 73%;

metabolized to

inactive

products

(predominantly)

that are

excreted in the

urine (83%) and

feces (10%)

Skip dose if

meal is

skipped

First-Generation Sulfonylureas

Acetohexamide

(Dymelor) 250,

500 mg

250 or 500

mg daily; ↑

by 250 mg

0. 25–1.5 g

daily or BID

5 hours

(active

metabolite)

12–18 hours Activity of

metabolite

greater then

Caution in

elderly and

patients with

daily every

1–2 weeks

parent drug.

Metabolite

excreted, in part,

by kidney

renal disease.

Significant

uricosuric

effects

Chlorpropamide

(Diabinese)

100, 250 mg

100 or 250

mg daily; ↑

by 100 or 250

mg every 1–

2 weeks

0.1–0.5 g

daily

≥35 hours 24–72 hours Inactive and

weakly active

metabolites;

20% excreted

unchanged;

varies widely

Caution in

elderly and

patients with

renal

impairment.

Highest

frequency of

side effects

relative to

other

sulfonylureas

Tolazamide

(Tolinase) 100,

250, 500 mg

100–250 mg

daily; ↑ by

100 or 250

mg every 1–

2 weeks

0.2–1 g daily

or BID

7 hours (4–

25)

12–24 hours Some

metabolites with

moderate

activity excreted

via kidney

Active

metabolites

may

accumulate in

renal failure

Tolbutamide

(Orinase) 250,

500 mg

250 mg BID

before meals;

↑ by 250 mg

daily every

1–2 weeks

0.5–3 g BID

or TID

7 hours 6–12 hours Metabolized to

compounds with

negligible

activity

No special

precautions

Shortestacting

sulfonylurea

Second-Generation Sulfonylureas

Glimepiride

(Amaryl) 1, 2, 4

mg

1–2 mg daily

initially; usual

maintenance

dose is 1–4

mg

1–8 mg daily 9 hours 24 hours F = 100%

completely

metabolized by

liver. Principal

metabolite is

slightly active

(30% of parent

compound).

Excreted by the

urine (60%) and

feces (40%)

Probably safe

in patients

with renal

failure, but

low initial

doses

recommended

for older

patients and

those with

renal

insufficiency.

Incidence of

hypoglycemia

may be lower

than other

long-acting

sulfonylureas

p. 1118

p. 1119

Glipizide

(Glucotrol) 5,

10 mg

2.5 mg daily in

elderly, 5 mg

daily in others;

2.5–40 mg

daily or BID

a

2–4 hours 12–24 hours Metabolized

to inactive

compounds

No special

precautions

daily dose >15

↑ by 2.5 or 5

mg every 1–2

weeks

mg should be

divided. Dose

30 minutes

before meals

Glipizide

extendedrelease

(Glucotrol XL)

5 mg

5 mg daily; ↑

by 5 mg every

1–2 weeks

5–20 mg daily 4–13 hours 24 hours Same as

glipizide

Use with

caution in

patients with

preexisting GI

narrowing

owing to

possible

obstruction

Glyburide

(Diabeta,

Micronase)

1.25, 2.5, 5 mg

1.25 mg daily

in elderly, 2.5

mg daily in

others; ↑ by

1.25 or 2.5 mg

every 1–2

weeks

1.25–20 mg

daily or BID

4–13 hours 12–24 hours Metabolized

to inactive or

weakly

inactive

compounds;

50% excreted

in urine and

50% in feces.

Caution in

elderly

patients with

renal failure

and others

predisposed to

hypoglycemia.

Daily doses

>10 mg

should be

divided

Micronized

glyburide

(Glynase

PresTab) 1.5,

3 mg

1.5 mg daily; ↑

by 1.5 mg

every 1–2

weeks

1.0–12 mg

daily

4 hours 24 hours Metabolized

to inactive or

weakly

inactive

compounds;

50% excreted

in urine and

50% in feces.

Daily doses

>6 mg should

be divided. ↑

Bioavailability

relative to

original

formulation.

Resulted in

reduced dose

Thiazolidinediones

Rosiglitazone

(Avandia) 2, 4,

8 mg

4 mg daily; ↑ to

8 mg daily (or

4 mg BID)

4–8 mg daily

in single or

divided doses

3–4 hours Onset and

duration

poorly

correlated

with half-life

because of

mechanism of

action. Onset

at 3 weeks;

max at ≥4

weeks.

Offset likely

to be similar

F = 99%;

extensively

metabolized in

liver into

inactive

metabolites;

excreted 2/3

in urine and

1/3 in feces.

Food has no

effect on

absorption.

BID dosing

may have

greater A1C

lowering

effect. No

dose

adjustments

required in

renal failure.

Avoid in

patients with

liver disease

and heart

failure

Pioglitazone

(Actos) 15, 30,

45 mg

15–30 mg

daily; ↑ to 45

mg daily. If

15–45 mg

daily

3–7 hours

(16–24 hours

for all

Same as

previous

Extensively

metabolized in

liver; 15%–

Food delays

absorption but

is not

used with

insulin, ↓ insulin

dose by 10%–

25% once FPG

<120 mg/dL

metabolites) 30% excreted

in urine,

remainder

eliminated in

the feces

clinically

significant.

No dose

adjustments

required in

renal disease.

Avoid in

patients with

liver disease

and heart

failure

GLP-1 Receptor Agonists/Incretin Mimetics

p. 1119

p. 1120

Exenatide

(Byetta)

5 mcg SC

BID; ↑ to 10

mcg SC BID

after 1 month

5–10 mcg

BID

2.4 hours Cmax

is at

2.1 hours;

duration 10

hours

Glomerular

filtration

Take within

60 minutes

before

morning and

evening meal.

Nausea

usually

subsides with

time

Exenatide ER

(Bydureon)

2mg SC once

weekly

2 mg once

weekly

10 weeks Initial Cmax

is at 2 weeks,

second peak

is at 6 to 7

weeks

Glomerular

filtration

Take daily

without

regard to

meals.

Nausea

usually

subsides with

time.

Liraglutide

(Victoza)

0.6 mg daily

for 1 week; ↑

to 1.2 mg daily

0.6–1.8 mg

daily

13 hours 24 hours;

Cmax

is 8–12

hours after

dosing

Metabolized

as other large

proteins

Take daily

without

regard to

meals.

Nausea

usually

subsides with

time

Dulaglutide

(Trulicity)

0.75 mg SC

once weekly;

can ↑ to 1.5

mg once

weekly

0.75–1.5 mg

weekly

Approximately

5 days

Cmax is at 48

hours

Degraded into

amino acids

by protein

catabolism

Take daily

without

regard to

meals.

Nausea

usually

subsides with

time

Albiglutide

(Tanzeum)

30 mg SC

once weekly;

30–50 mg

weekly

Approximately

5 days

Cmax is at 3

to 5 days

Metabolized

by ubiquitous

Take daily

without

can ↑ to 50 mg

once weekly

after

administration

proteolytic

enzymes into

small peptides

and amino

acids

regard to

meals.

Nausea

usually

subsides with

time

DPP-4 Inhibitors

Sitagliptin

(Januvia)

100 mg daily

CrCl ≥30 to

<50

mL/minute: 50

mg daily

CrCl <30

mL/minute: 25

mg daily

100 mg daily 12.4 hours 24 hours F = 87%;

79% excreted

unchanged in

urine

Requires dose

adjustment in

renal

insufficiency

Saxagliptin

(Onglyza)

5 mg daily

CrCl ≤50

mL/min: 2.5

mg daily

2.5–5 mg

daily

2.5 hours (3.1

hours for

active

metabolite)

24 hours Metabolized

by CYP

3A4/5

Excreted by

renal and

hepatic

pathways

Active

metabolite is

½ as potent

Reduce dose

to 2.5 mg

with strong

CYP 3A4/5

inhibitors

Linagliptin

(Tradjenta)

5 mg daily 5 mg daily 12 hours 24 hours F = 30%;

90% excreted

unchanged

(80%

enterohepatic

system, 5%

urine). Small

fraction

metabolized

to inactive

metabolite

No dose

adjustment

needed in

liver or renal

disease

p. 1120

p. 1121

Alogliptin

(Nesina)

25 mg daily

CrCl 30 to 59

mL/minute:

12.5 mg daily

CrCl <30

mL/minute:

6.25mg daily

25 mg daily 21 hours 24 hours F=100%, 76%

excreted

unchanged and

13%

eliminated in

feces. Small

fraction

metabolized to

inactive

metabolite

Requires dose

adjustment in

renal

insufficiency

Amylin Mimetics

Pramlintide

(Symlin)

Type 1 DM:

15 mcg SC

Type 1: 15–

60 mcg

48 minutes Cmax

is 20

minutes

F = 30%–

40%;

Reduce

mealtime

before major

meals; ↑ by

15-mcg

increments

after minimum

of 3 days

before major

meals

metabolized by

kidneys

insulin dose

by 50%.

Titrate dose if

no significant

nausea

Type 2 DM:

60 mcg SC

before major

meals; ↑ to 120

mcg after 3–7

days

Type 2: 60 or

120 mcg

before major

meals

SGLT-2 Inhibitors

Canagliflozin

(Invokana)

100 mg by

mouth before

first meal

May increase

to 300 mg

daily

10.6 hours F = ˜65%

Metabolism:

Primarily

UGT1A9 and

UGT2B4. ˜7%

Metabolized

through

CYP3A4

Dapagliflozin

(Farxiga)

5 mg by mouth

daily before

first meal

May increase

to 10 mg daily

12.9 hours F = 78%

Metabolism:

Primarily

(UGT)

isoenzyme

1A9.

Empagliflozin

(Jardiance)

10 mg by

mouth daily

before first

meal

May increase

to 25 mg daily

12.4 Hours Metabolism:

Primarily

through

glucuronidation

by UGT2B7,

UGT1A3,

UGT1A8,

UGT1A9

Bile Acid Sequestrants

Colesevelam

(Welchol)

6 tablets once

daily or 3

tablets BID

[625 mg

tablets]

3.75 g N/A N/A Drug is not

absorbed

systemically

and not

metabolized

Take with

food and

liquid. Do not

use if history

of bowel

obstruction,

TG >500

mg/dL, or

history of

pancreatitis

from ↑ TG.

p. 1121

p. 1122

Enhancers of Dopaminergic Tone

Bromocriptine

(Cycloset), 0.8

mg

1.6–4.8 mg

once daily in

the morning;

Begin with 0.8

mg daily and

increase by 1

tablet each

week until max

tolerated dose

1.6–4.8 mg

daily

6 hours F = 65%–

95%

Metabolized

extensively by

CYP3A4;

93%

undergoes

first-pass

metabolism

Excreted

primarily in

bile; 2%–6%

in urine

Take with

food to

reduce GI

side effects.