| Agent | Mechanism of Action | Dosage | Benefits | Side Effects | Notes |
|---|
| Insulin (regular insulin;
insulin aspart;
insulin lispro;
insulin glulisine;
isophane insulin [NPH];
lente insulin;
ultralente insulin;
insulin glargine;
insulin detemir;
insulin lispro, insulin lispro protamine;
insulin aspart, insulin aspart protamine;
regular insulin, isophane insulin [NPH];
semilente insulin;
protamine zinc insulin [PZI]) | Direct action of hormone | Starting
dose is highly variable; weight-based algorithms can be used, with a
typical total starting dose of 0.1 to 0.15 units/kg (NPH, lente, or
glargine insulin) divided into two doses | Insulin can improve HbA1c by 1%-2%; in some studies, titrated doses can result in all patients achieving HbA1c <7% | Hypoglycemia, weight gain | May be used alone or in combination with oral agents
|
| Sulfonylureas |  pancreatic secretion of insulin in response to glucose | See table Dosages for Various Types of Sulfonylureas. |  HbA1c by 1%-2% | Often associated with initial weight gain. Control may deteriorate over time, requiring doses or additional modes of therapy. |
First-line agent |
| Biguanide (Metformin) | Suppresses hepatic glucose production and insulin sensitivity in muscle and liver | 500 mg/d; may be weekly to 2500 mg/d in bid or tid dosaging |
HbA1c by 1%-2% (84). May lipid levels and BP; avoid weight loss; may macrovascular disease in obese patients | Gastrointestinal side effects such as nausea, diarrhea, bloating, and flatulence.
Increased risk of lactic acidosis, primarily in those with
renal insufficiency (serum creatinine >1.4 mg/dL), decompensated
congestive heart failure, liver failure, and in alcoholics or those who
binge drink. Clinicians should avoid the use of metformin in these
settings. Furthermore, in clinical situations with a high risk of these
situations developing, metformin should be discontinued or used with
extreme caution; for example, metformin should be discontinued prior to
the use of contrast media in imaging studies | May mortality when used in combination with sulfonylureas (controversial) (84);
overweight patients in a randomized, controlled trial showed 32%
reduction in any diabetes-related end point, including 36% reduction in
all-cause mortality (84). Combination of glyburide and metformin, glipizide and metformin, and metformin and rosiglitazone are also available |
Nonsulfonylurea insulin secretagogue:
Repaglinide
Nateglinide
| Stimulates insulin production; postprandial hyperglycemia | Repaglinide: 0.5 mg just before meals; can be to 4 mg qid. Nateglinide: 120 mg just before meals | More rapid onset than with sulfonylureas; short-acting; useful in patients who skip meals or drug doses | Hypoglycemia, headache with repaglinide | Glyburide is more effective at mean glucose, but repaglinide is more effective at
postprandial glucose and results in less hypoglycemia; can be used as
monotherapy; long-term effects on glycemic control are not well defined |
| Alpha-glucosidase inhibitor (acarbose, miglitol) | postprandial hyperglycemia by GI absorption of carbohydrates | 25 mg qd (starting dosage) to tide; titrate to maximum of 100 mg tid | HbA1c by 0.5%-1.0% | GI (bloating, flatulence, diarrhea) | Less effective than other agents; not generally used as monotherapy in patients with hyperglycemia (HbA1c >9%); qd dosing tends to minimize GI side effects |
| Thiazolidinediones (rosiglitazone, pioglitazone) | muscle sensitivity to insulin | Rosiglitazone:
4 mg qd (starting dose), titrate to maximum 8 mg qd or 4 mg bid.
Pioglitazone: 15 mg (starting dosage), titrate to maximum 45 mg qd | HbA1c by 1%-2% when added to other agents (102; 168) | Weight gain, edema. Need to check LFTs at baseline and whenever clinically indicated thereafter.
The thiazolidinediones can cause fluid retention when used
alone or in combination with other antidiabetic agents, including
insulin. Fluid retention may lead to or exacerbate heart failure.
Patients should be observed for signs and symptoms of heart failure, and
the thiazolidinedione should be discontinued if any deterioration in
cardiac status occurs. Thiazolidinediones should not be used in patients
with class III/IV NYHA heart failure.
The FDA's joint Endocrinologic and Metabolic Drugs Advisory
Committee and Drug Safety and Risk Management Committee concluded that
the use of rosiglitazone for the treatment of type 2 diabetes was
associated with a greater risk of myocardial ischemic events than
placebo, metformin, or sulfonylureas. This conclusion was based on
several independently conducted meta-analyses showing an increase in the
relative risk of myocardial infarction, angina, or sudden death among
patients taking rosiglitazone. Presentations by FDA staff members
suggested that a subgroup of patients with type 2 diabetes who are at
higher risk for these events includes those with long-term nitrate use
and those receiving concomitant insulin therapy. The FDA committee
report acknowledged that there were several caveats inherent in the
meta-analyses, including the facts that most of the clinical trials
lasted only 6 months (although the two largest trials, which contributed
most of the end points, were longer), that there were relatively few
myocardial events overall, and that differences existed in adjudication
of ischemic events. Ultimately, the committee voted to recommend that
rosiglitazone not be removed from the market but rather that label
warnings and extensive educational efforts be instituted immediately.
The committee also requested further studies, but noted that none of the
several proposed analyses of the ongoing clinical trials is likely to
define an absolute risk for myocardial ischemic events in patients with
diabetes who are taking this drug (110; 109)
The FDA has received postmarketing reports of new onset and worsening
diabetic macular edema in patients receiving rosiglitazone. In most
cases, the patients also reported concurrent peripheral edema. In some
cases, macular edema resolved or improved after discontinuation of
therapy, and in one case macular edema resolved after dose reduction.
An FDA alert
has been issued regarding safety data indicating an increased risk for
fractures of the upper arm, hand, and foot in women taking rosiglitazone
and pioglitazone as compared to those taking metformin or glyburide.
| As monotherapy, most useful in patients
with mild hyperglycemia; as adjunct, most useful to patients on insulin
(insulin dosage must be by 10%-25% to avoid hypoglycemia), sulfonylureas, or metformin |
| Exenatide | Glucose-dependent
enhancement of inulin secretion, suppression of inappropriately high
glucagon secretion, slowing of gastric emptying, reduction of food
intake | 5 µg sc 60 min before morning and evening meals; increase to 10 µg after 1 month | HbA1c by ~1%
weight | Nausea, vomiting
In October 2007, the FDA
reported that it had reviewed 30 postmarketing reports of acute
pancreatitis in patients taking exenatide. In some cases, an association
between exenatide and acute pancreatitis has been suspected. Health
care professionals should be alert to the signs and symptoms of acute
pancreatitis and instruct patients taking exenatide to seek prompt
medical care if they experience unexplained, persistent, severe
abdominal pain, which may or may not be accompanied by vomiting. If
pancreatitis is suspected, exenatide should be discontinued. Amylin
Pharmaceuticals has agreed to include information about acute
pancreatitis in the precautions section of the product label | May only be used in combination with metformin, a sulfonylurea, or a combination of metformin and sulfonylurea |
| Pramlintide | Modulation of emptying, prevention of the postprandial increase in plasma glucagon, and increased satiety | 60 µg sc just before each major meal ( 250 kcal or containing >30 g carbohydrate); increase as tolerated to 120 µg | HbA1c by ~0.5%
weight | Nausea | Use
in patients with suboptimal glycemic control on insulin with or without
concurrent metformin-sulfonylurea therapy. Because of its effect on
gastric emptying, pramlintide may delay the absorption of concomitantly
administered oral drugs and reduce their peak plasma concentrations |
| DPP-IV inhibitors (Sitagliptin) | Prevent
the rapid degradation of incretin hormones, thereby resulting in
increased postprandial levels of active incretin hormons, GLP-1 and GIP.
By enhancing incretin action, DPP-IV inhibitors lower blood glucose in a
glucose-dependent manner, enhance β-cell mass, and promote satiety | 100 mg qd; 50 mg daily if creatinine clearance is 30-50 mL/min; and 25 mg daily if creatinine clearance is <30 mL/min | HbA1c by ~0.7% | None | May be used as monotherapy or in combination with metformin or thiazolidinediones in patients with type 2 diabetes |
