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.
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.
Dipeptidyl Peptidase-4 Inhibitors
Currently, four DPP-4 inhibitors are available in the United States: sitagliptin,
saxagliptin, linagliptin, and alogliptin.
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
222 whereas saxagliptin, at a 2.5-mg dose, reduces DPP-4 activity by 50% for
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.
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.
In contrast to GLP agonists, which increase
GLP-1 levels by 6- to 10-fold,
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.
Sitagliptin is rapidly absorbed, with an absolute bioavailability of 87%.
Absorption is unaffected by food. Peak plasma concentrations occur in 1 to 4 hours,
and its terminal half-life is 12.4 hours. Only
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
Saxagliptin is well absorbed with a bioavailability estimated to be 75%.
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
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
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
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.
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
225 The most commonly reported side effects with sitagliptin and
alogliptin include nasopharyngitis, upper respiratory tract infection, hypoglycemia,
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.
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.
Sitagliptin is not significantly protein bound.
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
Saxagliptin does have significant drug interactions because it is metabolized by
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
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
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
; saxagliptin is comparable, with A1C lowering by 0.5% (0.6% vs.
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%.
Unlike the GLP-1 mimetics and analogs, DPP-4 inhibitors do not significantly affect
body weight, appetite, or satiety, and are considered weight neutral.
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
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.
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.
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
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
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)
Amylin is a hormone found in the β-cells where it is comanufactured, stored, and
released with insulin in response to food intake.
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.
The absolute bioavailability of SC injected pramlintide is 30% to 40%.
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.
GI symptoms—including mild-to-moderate nausea (28%–48%), vomiting (8%–
11%), and anorexia (9%–17%)—are the most frequently reported adverse reactions
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
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.
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
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.
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
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.
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.
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
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.
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.
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
Canagliflozin has a bioavailability of 65%, and peak plasma concentrations occur
within 1 to 2 hours after the dose is administered.
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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