The starting dose of exenatide is 5 mcg injected SC into the abdomen, thigh, or arm

twice daily within 60 minutes before morning and evening meals. Patients who

experience severe GI side effects may try injecting just before meals initially and

then move from 30 to 60 minutes before meals. If a patient tolerates the 5-mcg dose,

then it can be titrated after 1 month of therapy to the maximal dose of 10 mcg SC

twice daily. The dose of extended-release exenatide is 2 mg given SC once weekly

without regard to meals at any time of the day. The starting dose of liraglutide is 0.6

mg injected SC into the abdomen, thigh, or arm once daily for 1 week, and then it may

be increased to 1.2 mg SC daily. If the A1C goal is not achieved with a 1.2-mg dose,

the dose can be further increased to 1.8 mg daily. The starting dose of albiglutide is

30 mg injected SC into the abdomen, thigh, or upper arm once weekly without regard

to meals at any time of the day. The dose can be increased to 50 mg once weekly in

patients who have not achieved adequate glycemic control. The starting dose of

dulaglutide is 0.75 mg injected SC into the abdomen, thigh, or upper arm once

weekly given at any time of the day and may be increased to 1.5 mg once weekly if

adequate glycemic control is not achieved.

211–215

When any of these agents are added to the treatment regimen of a patient who is

also taking a sulfonylurea or glinide, the insulin secretagogue dose may need to be

lowered (by about half) to reduce the risk of hypoglycemia. If used in combination

with basal insulin, the insulin dose may need to be decreased.

211–215

Dipeptidyl Peptidase-4 Inhibitors

Currently, four DPP-4 inhibitors are available in the United States: sitagliptin,

saxagliptin, linagliptin, and alogliptin.

218,222–224

MECHANISM OF ACTION

The DPP-4 inhibitors inhibit the degradation of GIP and GLP-1 on entering the GI

vasculature, thus increasing the effects of these endogenous incretins on first-phase

insulin secretion and glucagon inhibition.

225 They are all competitive inhibitors of

DPP-4. Sitagliptin, at a 100-mg dose, reduces DPP-4 activity by 80% for up to 24

hours,

222 whereas saxagliptin, at a 2.5-mg dose, reduces DPP-4 activity by 50% for

up to 24 hours.

223 Alogliptin, at a dose of at least 25 mg, has been shown to reduce

DPP-4 activity by more than 80% at a dose of at least 25 mg for at least 24 hours.

224

Linagliptin, at the standard dose of 5 mg, has been shown to reduce DPP-4 activity by

more than 80% for up to 24 hours.

218

In contrast to GLP agonists, which increase

GLP-1 levels by 6- to 10-fold,

226

these agents only modestly increase GLP-1 levels

(2- to 3-fold), but also increase GIP levels. As a result, DPP-4 inhibitors have

minimal-to-no effect on satiety and delaying gastric emptying.

PHARMACOKINETICS

Sitagliptin is rapidly absorbed, with an absolute bioavailability of 87%.

222

Absorption is unaffected by food. Peak plasma concentrations occur in 1 to 4 hours,

and its terminal half-life is 12.4 hours. Only

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38% of sitagliptin is plasma protein bound. Eighty-seven percent of the parent drug is

excreted unchanged in the urine, primarily by active renal tubular secretion, and may

involve P-glycoprotein and human organic anion transporter-3. Metabolism by CYP

3A4, and to a much lesser extent, CYP2C8, plays a minimal role in the excretion of

metabolites in the feces.

227

Saxagliptin is well absorbed with a bioavailability estimated to be 75%.

223

Although food increases absorption by 27%, it can be administered with or without

food. Peak plasma concentrations occur at 2 hours for saxagliptin and 4 hours for the

active metabolite. Saxagliptin is metabolized by CYP 3A4/5 to a major metabolite

that is one-half as potent.

228 Protein binding of saxagliptin and its active metabolite is

negligible. The mean plasma terminal half-lives of saxagliptin and its active

metabolite are 2.5 and 3.1 hours, respectively. Saxagliptin is excreted primarily by

the kidneys, with 25% excreted unchanged in the urine, and 36% of the active

metabolite found in urine. Approximately 22% of drug and metabolite are excreted in

feces.

227

Linagliptin is well absorbed and has a bioavailability of 30%. A high-fat meal can

decrease the absorption by 15%; however, this is not clinically significant.

Therefore, linagliptin may be administered with or without food. Peak plasma

concentrations occur at approximately 1.5 hours after a dose of 5 mg. Linagliptin has

a long terminal half-life (>100 hours) due to biphasic decline in plasma

concentrations, which is related to the binding of DPP-4. Approximately 90% of

linagliptin is excreted unchanged in the urine, and a small percentage is metabolized

to an inactive metabolite.

218

Alogliptin is well absorbed and has a bioavailability of 100%. A high-fat meal

results in no significant change in absorption; therefore, it may be administered with

or without food. Alogliptin is 20% plasma protein bound, with 60% to 71% of the

dose excreted unchanged in urine and 13% excreted in the feces. Limited metabolism

occurs via CYP2D6 and CYP3A4. The terminal half-life of alogliptin is

approximately 21 hours after the administration of a 25-mg dose.

224

ADVERSE EFFECTS

Because these agents differ significantly in chemical structure from one another, some

adverse events may be unique to the individual agent and may not be indicative of a

class wide effect.

225 The most commonly reported side effects with sitagliptin and

alogliptin include nasopharyngitis, upper respiratory tract infection, hypoglycemia,

and headache.

222,224 Saxagliptin can cause these same adverse effects, as well as

urinary tract infection, whereas linagliptin adverse effects can include hypoglycemia,

nasopharyngitis, diarrhea, and cough.

218,223

It is possible that DPP-4 inhibitors may

have an effect on the immune system, because lymphocytes express DPP-4. These

medications have been suggested to increase risk for pancreatitis; however, studies

have shown this risk to be low.

229 Additional clinical experience and postmarketing

studies are needed to clearly establish the long-term safety of these agents.

CONTRAINDICATIONS AND PRECAUTIONS

All DPP-4 inhibitors should be avoided in patients with a history of serious

hypersensitivity reaction to the drug.

DRUG INTERACTIONS

Sitagliptin is not significantly protein bound.

222

It also does not inhibit CYP

isoenzymes or induce CYP 3A4; therefore, it is not expected to interact with other

drugs that are metabolized by these pathways. Patients taking digoxin, a substrate of

P-glycoprotein-like sitagliptin, should be monitored for any signs or symptoms of

digoxin toxicity, because a slight increase in the AUC (11%) and C max

(18%) has

been observed.

222,226

Saxagliptin does have significant drug interactions because it is metabolized by

CYP 3A4/5.

223 Therefore, if used with strong inhibitors of these enzymes (e.g.,

ketoconazole, itraconazole, clarithromycin, telithromycin, protease inhibitors such as

indinavir), the dose of saxagliptin is reduced to 2.5 mg daily.

Linagliptin is a weak-to-moderate inhibitor of CYP3A4 and a P-glycoprotein

substrate and inhibits P-glycoprotein-mediated transport of digoxin at high

concentrations.

218 Medications that are strong inducers of CYP3A4 or Pglycoprotein, such as rifampin, decrease linagliptin to levels that are subtherapeutic

and ineffective; therefore, if treatment with those medications is necessary, an

alternative to linagliptin should be used.

Alogliptin is not significantly protein bound, and metabolism through the

cytochrome P450 pathway is negligible; therefore, there are no significant drug

interactions with alogliptin.

224

EFFICACY

In monotherapy clinical trials versus placebo, sitagliptin lowers fasting glucose by

12 mg/dLand A1C by 0.5% to 0.6% compared with baseline (0.6%–0.8% compared

with placebo)

222

; saxagliptin is comparable, with A1C lowering by 0.5% (0.6% vs.

placebo) and FPG by 15 mg/dL.

223

In addition, both agents reduce 2-hour

postprandial glucose by approximately 45 mg/dL.

222,223,226 When used as add-on

combination therapy, A1C lowering is greater (0.7%–0.9%). Linagliptin, as

monotherapy in clinical trials versus placebo, decreased fasting glucose by 13 mg/dL

from baseline and decreased A1C by 0.4%.

218 Alogliptin, as monotherapy in clinical

trials versus placebo, decreased fasting glucose by 16 mg/dL and A1C by 0.6%.

224

Unlike the GLP-1 mimetics and analogs, DPP-4 inhibitors do not significantly affect

body weight, appetite, or satiety, and are considered weight neutral.

226 As is the case

for the GLP-1 mimetics and analogs, further studies are needed to more clearly

determine the effects of DDP-4 inhibitors on long-term preservation of β-cell

function.

DOSAGE AND CLINICAL USE

DPP-4 inhibitors are mainly used as add-on therapy in combination with other agents.

However, all are approved for use as monotherapy. Sitagliptin may be initiated at

100 mg taken once daily with or without food.

222 Renal function should be assessed

before initiation of this agent. In patients with moderate renal insufficiency (CrCl 30–

50 mL/minute), the dose for sitagliptin should be reduced to 50 mg once daily, and in

severe renal insufficiency (CrCl <30 mL/minute) or for those in end-stage renal

failure requiring dialysis, the sitagliptin dose is 25 mg once daily. Sitagliptin may be

administered without regard to the timing of hemodialysis. Only sitagliptin should be

used in patients on peritoneal dialysis.

Saxagliptin is dosed at 2.5 to 5 mg once daily with or without food.

223 Renal

function should be assessed before initiation of this agent. In patients with moderate

or severe renal impairment or end-stage renal disease with a CrCl < 50 mL/minute,

the recommended dose is 2.5 mg daily. If patients are taking strong CYP3A4/5

inhibitors, the dose of saxagliptin should be 2.5 mg daily. In hemodialysis patients,

the dose is 2.5 mg daily to be administered after hemodialysis.

Linagliptin is dosed at 5 mg once daily with or without food. No dose adjustment

is necessary for patients with renal impairment; however, patients with a CrCl <30

mL/minute may be more prone to hypoglycemia; therefore, dosing adjustments of

concomitant antidiabetic medications and frequent monitoring may be necessary.

218

Alogliptin is dosed at 25 mg once daily with or without food. Renal function

should be assessed prior to initiation of this medication. In patients with moderate

renal impairment with a CrCl of 30 to 60 mL/minute, the recommended dose is 12.5

mg once

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daily. In patients with severe renal impairment (CrCl <30 mL/minute) or end-stage

renal disease, the dose is 6.25 mg once daily. Patients on hemodialysis should be

given 6.25 mg once daily and it may be administered without regard to the timing of

dialysis.

224

When any of these agents are added to a patient also on a sulfonylurea or glinide,

the insulin secretagogue dose may need to be lowered (by about half) to reduce the

risk of hypoglycemia. Similarly, when sitagliptin is added to a patient already on

insulin therapy, the dose(s) of insulin may need to be lowered initially and then

readjusted depending on the response to sitagliptin.

Amylin Receptor Agonists (Amylinomimetics)

MECHANISM OF ACTION

Amylin is a hormone found in the β-cells where it is comanufactured, stored, and

released with insulin in response to food intake.

230

Its actions seem to be centrally

mediated and include slowing gastric emptying, suppressing glucagon secretion, and

modulating the regulation of appetite. Amylin is absent in patients with Type 1

diabetes. In patients with Type 2 diabetes, its concentrations are altered to mirror

those of insulin at different points in the progression of the disease. Pramlintide, a

synthetic amylin analog, is available in the United States for the adjunctive treatment

of both Type 1 and Type 2 diabetes who use mealtime insulin.

PHARMACOKINETICS

The absolute bioavailability of SC injected pramlintide is 30% to 40%.

231

Subcutaneous injection into the abdomen and thigh allows for more predictable

absorption and distribution than when administered into the arm. Approximately 40%

of the drug is unbound in plasma. The half-life is about 48 minutes, and time to

maximum concentration is approximately 20 minutes. Pramlintide is metabolized by

the kidneys to an active metabolite with a half-life similar to the parent drug.

ADVERSE EFFECTS

GI symptoms—including mild-to-moderate nausea (28%–48%), vomiting (8%–

11%), and anorexia (9%–17%)—are the most frequently reported adverse reactions

associated with therapy.

231 GI symptoms are usually transient, subsiding after 4 to 8

weeks of treatment or with dose reduction and slow dose escalation. Hypoglycemia

can occur in up to 16.8% of Type 1 diabetes patients receiving pramlintide and

insulin therapy, and in 8.2% of Type 2 diabetes patients receiving pramlintide and

insulin.

CONTRAINDICATIONS AND PRECAUTIONS

Pramlintide is contraindicated in patients with known cresol hypersensitivity,

hypoglycemic unawareness, and gastroparesis.

231 Severe hypoglycemia can occur

when it is used in combination with insulin and medications that can slow gastric

emptying. Drugs that can alter glucose metabolism when administered with

pramlintide, and therefore cause hypoglycemia, include oral antidiabetics, fibrates,

fluoxetine, salicylates, and ACE inhibitors, and should be used with caution if

administered concomitantly. Pramlintide has a black box warning for severe

hypoglycemia, which can occur within 3 hours following an injection of pramlintide.

Caution individuals while driving, those who operate heavy machinery, and those

who engage in other high-risk activities due to potential serious injuries that may

result during a hypoglycemic episode.

DRUG INTERACTIONS

As noted, severe hypoglycemia can occur in patients who are concurrently taking an

oral hypoglycemic agent (e.g., sulfonylurea) or insulin (see Dosage and Clinical Use

section).

231 Because pramlintide can delay the absorption of medications that are

administered concomitantly, medications that require rapid onset for effectiveness,

such as antibiotics, oral contraceptives, and analgesics, should be administered at

least 2 hours after or 1 hour prior to the pramlintide injection.

EFFICACY

In clinical studies of patients with Type 2 diabetes with doses up to 150 mcg/day for

52 weeks, pramlintide combined with insulin decreased A1C by 0.3% and weight by

2.57 kg.

231 Clinical studies of patients with Type 1 diabetes taking insulin in

combination with pramlintide or placebo demonstrated A1C reductions of 0.2% to

0.4% and weight loss of 0.4 to 1.3 kg.

56

DOSAGE AND CLINICAL USE

In clinical practice, pramlintide is considered an add-on agent primarily for patients

with Type 1 diabetes who have failed to achieve target BG goals on insulin therapy

alone. Its practical use is more limited to obese patients with Type 2 diabetes who

have failed to achieve target BG levels with a regimen that includes a sulfonylurea or

insulin. Pramlintide is available in a pen device (SymlinPen). It cannot be mixed

with any type of insulin. The pens (60 pen-injector for 15-, 30-, 45-, or 60-mcg doses

and 120 pen-injector for 60- and 120-mcg doses) in use may be stored at room

temperature (86°F or 30°C) for up to 30 days.

231

For patients with Type 1 diabetes, the initial dose is 15 mcg, and for patients with

Type 2 diabetes, the initial dose is 60 mcg. Pramlintide is injected SC into the

abdomen or thigh immediately before every major meal. A major meal is one that

contains 30 g or more of carbohydrate or 250 kcal or more. If a meal is skipped, the

pramlintide dose should be skipped. When initiating pramlintide therapy, the dose of

premeal insulins must be reduced by at least 50%. Patients should be closely

followed and instructed to intensively monitor and record BG (fasting, preprandial,

and postprandial) levels and any hypoglycemic episodes until control has stabilized.

Pramlintide is titrated based on achieving optimal glucose control with minimal side

effects (e.g., nausea). The dose can be increased when no clinically significant

nausea has occurred for 3 to 7 days. For patients with Type 1 diabetes, doses may be

increased in 15-mcg increments up to a maximum meal dose of 60 mcg. For patients

with Type 2 diabetes, the dose may be increased to 120 mcg before every major

meal.

231

Sodium–Glucose Transporter 2 (SGLT2) Inhibitors

SGLT2 inhibitors reduce BG by decreasing tubular reabsorption of glucose in the

kidney, thereby increasing the excretion of urinary glucose.

231 These agents are highly

selective, reversible inhibitors of SGLT2. Currently, there are three agents in this

class: canagliflozin, dapagliflozin, and empagliflozin, which are available as

individual agents or in combination with other antidiabetic agents.

232–234 Because

their mechanism of action is independent of insulin resistance or β-cell function,

these medications can be used in combination with all antidiabetic agent classes,

including insulin, for the treatment of Type 2 DM in addition to diet and exercise.

These agents have added benefits of weight loss, increase in HDL, and decrease in

blood pressure; however, genital and urinary infections may be an adverse effect of

these agents.

235

PHARMACOKINETICS

Canagliflozin has a bioavailability of 65%, and peak plasma concentrations occur

within 1 to 2 hours after the dose is administered.

232 There was no effect on

absorption when administered with a high-fat meal; therefore, canagliflozin may be

administered with or without food. Canagliflozin is 99% protein bound, primarily to

albumin. This agent is metabolized primarily by glucuronidation

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