Ketosis-Prone Type 2 Diabetes 

Updated: Jan 06, 2016
Author: Richard S Krause, MD; Chief Editor: George T Griffing, MD 

Overview

Background

The original schema for classifying diabetes mellitus (DM) consisted of 2 categories known as type 1 diabetes mellitus and type 2 diabetes mellitus. Type 1 diabetes was also known as insulin-dependent diabetes. Patients with this type of diabetes were considered prone to develop diabetic ketoacidosis (DKA).

Patients with type 1 diabetes were found to have an absolute insulin deficiency due to autoimmune destruction of pancreatic beta cells. Patients with type 2 diabetics, or noninsulin-dependent diabetes, were not considered to be at risk for DKA. Type 2 diabetes is strongly associated with obesity and a family history of diabetes. These patients have peripheral insulin resistance with initially normal or elevated circulating levels of endogenous insulin.

Pathophysiology

Since the mid-1990s, the number of patients who presented with DKA but did not require long-term insulin therapy has increased. Many such patients had conditions that resembled traditionally defined type 2 diabetes, in that they were obese and often had a family history of diabetes. Subsequent to these observations, new ways to classify diabetes were devised.

The system of classification that most accurately predicts the need for insulin treatment 12 months after presentation with DKA is known as the Aß system. This system classifies diabetics into 4 groups as follows:

  • A+ß- - Autoantibodies present, β cell function absent

  • A+ß+ - Autoantibodies present, β cell function present

  • A-ß- - Autoantibodies absent, β cell function absent

  • A-ß+ - Autoantibodies absent, β cell function present

The commonest ketosis-prone diabetes (KPD) subgroup in a longitudinal study was A-ß+ (54%), followed by A-ß- (20%) A+ß- (18%) and A+ß+ (8%).[1] As noted above, in the A-ß+ subgroup of patients with KPD β cell antibodies are absent and β cell function is present. The triggering mechanisms leading to DKA in these patients are not well defined. Viral infections, other metabolic factors such as oxidative stress with concomitant G6PD deficiency, and genetic factors have been implicated. Patients who are in the A+ß+ and A-ß+ subgroups have clinical characteristics of type 2 diabetes. The American Diabetes Association (ADA) system classifies them as having type 2 diabetes.[2] Patients with this metabolic and clinical profile who experience DKA have ketosis prone type 2 diabetes.

There is also a modified ADA system and a system based on body mass index (BMI).[3]

Etiology

The etiology of different diabetic conditions is an area of active research. Antibodies to glutamic acid decarboxylase exhibit different epitopes (antigenic determinants). The differences in antigenic specificity of these epitopes are related to the degree of beta-cell destruction and thus to the severity of the clinical syndrome.[4]

When antibodies are absent (A-ß+ phenotype), multiple etiologies have been proposed. These include viral infection, genetic variations, and oxidative stress.[5]

 

Prognosis

The long term prognosis of KPD varies with the Aß status. Patients who are ß- require long term insulin therapy for glycemic control. Most patients in the A-ß+ subgroup have-long term remission (do not continue to require insulin) after treatment of an initial DKA episode followed by a period of insulin therapy.

Patient Education

Patient education materials are available from various sources; an excellent resource is the American Diabetes Association.

Epidemiology

Ketosis-prone type 2 diabetes is prevalent in the United States among blacks and Hispanics, who account for 20%-50% of newly diagnosed patients.[6]  As with type 2 diabetes, most patients with ketosis-prone type 2 diabetes are obese and have a family history.

 

Presentation

History

The presentation of DKA does not differ markedly according to the Aß phenotype. Typical features of polydipsia, polyuria, and fatigue are seen. In patients who already require insulin, the onset of DKA can be rapid when, for example, insulin is abruptly discontinued or a major stressor such as acute myocardial infarction occurs.

Patients with previously undiagnosed ketosis-prone type 2 diabetes may have a less abrupt onset of symptoms. Symptoms related to an underlying precipitating event, such as myocardial infarction or infection (eg, pneumonia, urinary tract infection) may be noted. Abdominal pain is also a common complaint associated with DKA, especially in children. The cause of abdominal pain in DKA is not well understood but appears to relate to the severity of the acidosis. Failure of abdominal pain to resolve with treatment of DKA or marked abdominal tenderness should lead to consideration of other causes. Shortness of breath in spite of normal pulse oximetry and clear lungs is common.

Physical Examination

Physical signs in DKA are associated with the severity of the metabolic derangement and dehydration and may include the following:

  • Tachypnea/hyperpnea

  • Tachycardia

  • Dry mucous membranes

  • Poor skin turgor

  • Altered mental status

  • Nausea, vomiting

  • Hypotension

  • Signs related to a precipitating illness

 

DDx

Diagnostic Considerations

The main differential diagnostic consideration when DKA is considered is a hyperosmolar hyperglycemic state (HHS). The main metabolic differences between HHS and DKA are the extreme elevations of glucose seen in HHS and the lack of significant ketoacidosis. Although overlap is observed, glucose levels tend to be higher in HHS than in DKA. Levels of more than 1000 mg/dL are not uncommon, and levels are almost always more than 600 mg/dL. In DKA, glucose levels are typically between 500-800 mg/dL and seldom exceed 900 mg/dL.

Of greater differentiating value are acidosis and ketonemia. Metabolic acidosis is absent or mild with HHS and if present, ketonemia is mild. Anion gap is normal or minimally elevated in HHS. In contrast, the triad of hyperglycemia, elevated anion gap acidosis, and ketonemia is expected in DKA.

Clinically, patients with HHS are much more likely to have altered mental status than patients with DKA. Altered mental status in HHS is related to the degree of effective plasma osmolality elevation. Effective plasma osmolality can be calculated using the formula below. Values of more than approximately 320 mosmol/kg are usually seen in HHS. Both DKA and HHS are known stroke mimics because they may be associated with focal neurologic findings. The formula is as follows:

  • Effective plasma osmolality (in mosmol/kg) = [2 x Na (mmol/L)] + glucose (mmol/L)

Another cause of ketoacidosis is alcoholic ketoacidosis. Ketoacidosis in an alcoholic without significant hyperglycemia is diagnostic of this state. It is seen in chronic alcoholics who are malnourished. In the right setting, toxic alcohol (eg, methanol, ethylene glycol) ingestion may be considered. Poisoning with toxic alcohols also causes an elevated anion gap metabolic acidosis with altered mental status. For additional discussion of toxic alcohol poisoning see Methanol Toxicity, Ethylene Glycol Toxicity.

Many other causes of metabolic acidosis are noted besides DKA and the other diagnoses mentioned above. For a detailed discussion, see the Medscape Reference articles Metabolic Acidosis in Emergency Medicine, Metabolic Acidosis, and Pediatric Metabolic Acidosis.

The signs and symptoms of DKA can overlap with other illnesses. In the case of known diabetes, DKA should always be considered when the patient presents with a systemic illness. Patients not known to have diabetes can be more of a diagnostic challenge, especially when they present early before metabolic derangements are severe.

Hints that a presentation may represent new onset DKA in type 2 diabetes include obesity and a strong family history of diabetes. If no other reason to obtain laboratory tests is suggested, a finger stick blood sugar can be used as a screening test.

Although euglycemic DKA occurs, it is unusual. It has been described in type 1 diabetes and also in patients with diabetes who are pregnant or who are experiencing starvation. For practical purposes, a normal or near normal random blood sugar rules out DKA. The renal threshold for glucose in healthy people is approximately 180 mg/dL. This varies, but new onset DKA in ketosis-prone type 2 diabetes should have elevated sugar and ketones on a urine dipstick test. Thus, a urine dipstick can also be used at the bedside to rule out most cases of DKA.

Typical patients appear significantly ill, leading to suspicion of the diagnosis or at least a less directed laboratory investigation, which reveals the characteristic hyperglycemia with an elevated anion gap acidosis (see the Anion Gap calculator). In that setting, DKA is confirmed by the finding of significant ketonemia.

 

Workup

Approach Considerations

When DKA is being considered in the acute setting, the following tests are indicated:

  • Bedside serum glucose

  • Urine dipstick

  • Basic metabolic profile

  • Serum ketones

  • Venous or ABG (if the serum bicarbonate is severely depressed)

  • CBC count with differential

Other tests should be ordered according to the clinical picture. Most hospitals routinely obtain an EKG and a chest radiograph in most patients with serious illness. The yield is low in the absence of other clinical indications for testing.

After acute treatment and resolution of DKA, patients with new-onset ketosis-prone type 2 diabetes should be considered for additional testing. Evaluating for β cell autoimmunity and functional reserve is useful for prognostication and guiding treatment. These tests, especially autoimmune testing, may be expensive and are not strictly necessary. Fasting C-peptide levels are used to classify patients as ß+ or ß-. ß+ status is established when the fasting C-peptide level is 1 ng/mL or more. This testing should not be done during the acute phase of DKA. Measuring β-cell function shows transient secretory defect of β cells during the acute phase, with 60- 80% improvement in insulin-secreting capacity during remission. Measurement of the GAD65 and IA-2 antibodies is used to establish A+ or A- status.[7]

 

Treatment

Approach Considerations

The treatment of patients who present with DKA is fairly standardized and does not differ according to their Aß phenotype. Detailed discussion of DKA treatment can be found in the following Medscape Reference articles: Diabetic Ketoacidosis and Pediatric Diabetic Ketoacidosis.

At the time of initial presentation with new-onset diabetes and DKA, determining what "type" of diabetes is present is not possible or needed; predicting the need for long-term insulin treatment is also impossible. Therefore, after an initial episode of DKA, all patients should be continued on insulin treatment for some period of time (typically weeks to months). Patients who are found to be ß- should be continued on insulin indefinitely.

Patient Disposition

No generally accepted guidelines are available for disposition of DKA after initial treatment. Clinical experience and practice suggests that patients with mild DKA may be safely discharged with close follow-up after successful initial treatment. One large, multicenter study of US EDs found that 13% of patients were discharged; approximately one fourth were admitted to an ICU.[8] Appropriate initial treatment may decrease length of stay and the need for ICU admission.[9]

Long-Term Monitoring

Patients who are ß+ need outpatient assessment of the need for long-term insulin treatment. If glucose levels are under control on an insulin regimen, the dose of insulin can be decreased by 50% and the patient reassessed at 1-2 weeks. If glycemic control is maintained, insulin can be discontinued with close monitoring. Other agents can be continued or added as needed. New onset of diabetes, older age at onset and higher levels of ß cell function all are associated with less likelihood of requiring long-term insulin treatment.

For newly diagnosed patients discharged after a first episode of DKA, a typical insulin regimen is a total of 0.6-0.7 units of insulin/kg/d. Typically, two thirds of the total daily dose is given before breakfast, and one third is given before dinner. Two thirds of the dose is given as intermediate-acting insulin (NPH), and one third is given as short-acting (regular insulin).

Long-term management of diabetes is discussed in the following Medscape reference articles: Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus, Pediatric Type 1 Diabetes Mellitus, and Pediatric Type 2 Diabetes Mellitus.

 

Medication

Medication Summary

Insulin injected subcutaneously is the first-line treatment of type 1 diabetes mellitus. The different types of insulin vary with respect to onset and duration of action. Short-, intermediate-, and long-acting insulins are available. Short-acting and rapid-acting insulins are the only types that can be administered intravenously (IV). Human insulin currently is the only species of insulin available in the United States; it is less antigenic than the previously used animal-derived varieties.

Pharmacologic therapy of type 2 diabetes has changed dramatically in the last 10 years, with new drugs and drug classes becoming available. These drugs allow for the use of combination oral therapy, often with improvement in glycemic control that was previously beyond the reach of medical therapy.

Agents used in diabetic therapy include the following:

  • Biguanides

  • Sulfonylureas

  • Meglitinide derivatives

  • Alpha-glucosidase inhibitors

  • Thiazolidinediones (TZDs)

  • Glucagonlike peptide–1 (GLP-1) agonists

  • Dipeptidyl peptidase IV (DPP-4) Inhibitors

  • Insulins

  • Amylinomimetics

  • Bile acid sequestrants

  • Dopamine agonists

Traditionally, diet modification has been the cornerstone of diabetes management. Weight loss is more likely to control glycemia in patients with recent onset of the disease than in patients who are significantly insulinopenic. Medications that induce weight loss, such as orlistat, may be effective in highly selected patients but are not generally indicated in the treatment of the average patient with type 2 diabetes mellitus.

Patients who are symptomatic at initial presentation with diabetes may require transient treatment with insulin to reduce glucose toxicity (which may reduce beta-cell insulin secretion and worsen insulin resistance) or an insulin secretagogue to rapidly relieve symptoms such as polyuria and polydipsia.

Antidiabetics, Insulins

Class Summary

Rapid-acting insulins are used whenever a rapid onset and short duration are appropriate (eg, before meals or when the blood glucose level exceeds target and a correction dose is needed). Rapid-acting insulins are associated with less hypoglycemia than regular insulin.

Currently, short-acting insulins are less commonly used than the rapid-acting insulins in patients with type 1 DM. They are used when a slightly slower onset of action or a greater duration of action is desired.

Intermediate-acting insulins have a relatively slow onset of action and a relatively long duration of action. They are usually combined with faster-acting insulins to maximize the benefits of a single injection.

Long-acting insulins have a very long duration of action and, when combined with faster-acting insulins, provide better glucose control for some patients. In patients with type 1 DM, they must be used in conjunction with a rapid-acting or short-acting insulin given before meals.

Premixed insulins contain a fixed ratio of rapid-acting insulins with longer-acting insulin, which can restrict their use. Premixed insulin is usually not recommended in type 1 DM patients, because of their need for frequent adjustments of premeal insulin doses.

Insulin aspart (NovoLog)

Insulin aspart has a rapid onset of action, 5-15 minutes. The peak effect occurs within 30-90 minutes, and the usual duration of action is 2-4 hours. Insulin aspart is approved by the US Food and Drug Administration (FDA) for use in insulin pumps.

Insulin glulisine (Apidra)

Insulin glulisine has a rapid onset of action, 5-15 minutes. The peak effect occurs within 30-90 minutes, and the usual duration of action is 2-4 hours. Insulin glulisine is FDA-approved for use in insulin pumps.

Insulin lispro (Humalog)

Insulin lispro has a rapid onset of action, 5-15 minutes. The peak effect occurs within 30-90 minutes, and the usual duration of action is 2-4 hours.

Regular insulin (Humulin R, Novolin R)

Regular insulin has a short onset of action, 0.5 hour. Its peak effect occurs within 2-4 hours, and its usual duration of action is 5-8 hours. Preparations that contain a mixture of 70% neutral protamine Hagedorn (NPH) insulin and 30% regular human insulin (eg, Novolin 70/30 and Humulin 70/30) are available, but the fixed ratios of intermediate-acting to rapid-acting insulin may restrict their use.

Insulin detemir (Levemir)

Insulin detemir is indicated for once-daily or twice-daily subcutaneous administration in individuals with type 1 DM who require long-acting basal insulin for hyperglycemia control. Its duration of action ranges from 5.7 hours (low dose) to 23.2 hours (high dose). The prolonged action results from slow systemic absorption of detemir molecules from the injection site. Its primary activity is regulation of glucose metabolism.

Insulin detemir binds to insulin receptors and lowers blood glucose levels by facilitating cellular uptake of glucose into skeletal muscle and fat; it also inhibits glucose output from the liver. The drug inhibits lipolysis in adipocytes, inhibits proteolysis, and enhances protein synthesis.

Insulin glargine (Lantus)

Insulin glargine stimulates proper utilization of glucose by the cells and reduces blood sugar levels. It has no pronounced peaks of action, because a small amount of insulin is gradually released at a constant rate over 24 hours. A possible association of insulin glargine with an increased risk of cancer has been reported.

Insulin aspart protamine/insulin aspart (NovoLog 70/30)

The combination of insulin aspart protamine with insulin aspart includes 30% rapid-onset insulin (ie, insulin aspart) and 70% intermediate-acting insulin (ie, insulin aspart protamine). Insulin aspart is absorbed more rapidly than regular human insulin, and insulin aspart protamine has a prolonged absorption profile after injection.

Insulin lispro protamine/insulin lispro (Humalog 75/25)

The combination of insulin lispro protamine with insulin lispro includes 75% insulin lispro protamine, which has a prolonged duration of action, and 25% insulin lispro, which is a rapid-onset insulin.

Antidiabetics, Biguanides

Class Summary

These agents are considered the first choice for oral type 2 diabetes treatment. They reduce hyperglycemia by decreasing hepatic gluconeogenesis (primary effect) and increasing peripheral insulin sensitivity (secondary effect). They do not increase insulin levels or cause weight gain. Alone, they rarely cause hypoglycemia.

Biguanides are absorbed from the intestines and are not bound to plasma proteins. They are not metabolized and are rapidly eliminated by the kidneys. Drug levels increase markedly in renal insufficiency. Lactic acidosis is a rare, but serious, complication that may occur with drug accumulation.

Metformin (Glucophage)

Metformin is used as monotherapy or in combination with sulfonylureas, thiazolidinediones, or insulin. It is taken with food to minimize adverse GI effects. Metformin is available in immediate-release and extended-release formulations, as well as in combination with other antidiabetic drugs.

Metformin is contraindicated in patients with impaired renal function, as indicated by a serum creatinine level of greater than 1.5 mg/dL in men or of more than 1.4 mg/dL in women, or an estimated GFR of less than 60 mL/min. It also should not be used within 48 hours of IV iodinated contrast medium.

Antidiabetics, Amylinomimetics

Class Summary

These amylinomimetic agents elicit endogenous amylin effects by delaying gastric emptying, decreasing postprandial glucagon release, and modulating appetite.

Pramlintide acetate (Symlin)

Pramlintide acetate is a synthetic analogue of human amylin, a naturally occurring hormone made in pancreatic beta cells that is deficient in people with type 1 DM. It slows gastric emptying, suppresses postprandial glucagon secretion, and regulates food intake through centrally mediated appetite modulation.

Antidiabetics, Sulfonylureas

Class Summary

Sulfonylureas are time-honored insulin secretagogues (ie, oral hypoglycemic agents). They have been used as monotherapy and in combination with other oral hypoglycemic agents or with insulin, although glimepiride is the only sulfonylurea approved by the FDA for combination therapy. Sulfonylureas function by stimulating the release of insulin from pancreatic beta cells and can usually reduce HbA1c by 1-2% and blood glucose concentrations by about 20%.

Glyburide (Micronase, DiaBeta, Glynase)

Glyburide is a second-generation sulfonylurea. It is more potent and exhibits fewer drug interactions than first-generation agents. It also has a longer half-life than most sulfonylureas. Glyburide has been used as an alternative to insulin for the treatment of gestational diabetes, although it is not FDA approved for this indication. Glyburide (known as glibenclamide in the United Kingdom) was one of the sulfonylureas used in the United Kingdom Prospective Diabetes Study (UKPDS).

Glipizide (Glucotrol, Glucotrol XL)

Glipizide is also a second-generation sulfonylurea. It is more potent and exhibits fewer drug interactions than first-generation agents. It may cause more physiologic insulin release with less risk for hypoglycemia and weight gain than other sulfonylureas.

Hypoglycemia Antidotes

Class Summary

Pancreatic alpha cells of the islets of Langerhans produce glucagon, a polypeptide hormone. Glucagon increases blood glucose levels by promoting hepatic glycogenolysis and gluconeogenesis.

Glucagon (GlucaGen)

Glucagon elevates blood glucose levels by inhibiting glycogen synthesis and enhancing the formation of glucose from noncarbohydrate sources such as proteins and fats (gluconeogenesis). It increases hydrolysis of glycogen to glucose in the liver and accelerates hepatic glycogenolysis and lipolysis in adipose tissue. Glucagon also increases the force of contraction in the heart and has a relaxant effect on the gastrointestinal tract.

Antidiabetics, Meglitinide Derivatives

Class Summary

Meglitinides are much more short-acting insulin secretagogues than sulfonylureas. Preprandial dosing potentially achieves more physiologic insulin release and less risk for hypoglycemia. Meglitinide monotherapy has efficacy similar to that of sulfonylureas.

Repaglinide (Prandin)

Repaglinide is probably most useful in patients at increased risk for hypoglycemia who still need an insulin secretagogue. It works by stimulating insulin release from pancreatic beta cells. Better control of postprandial glycemic excursions also may be achieved with repaglinide. It is FDA approved for monotherapy and for combination therapy with metformin or thiazolidinediones.

Nateglinide (Starlix)

Nateglinide mimics endogenous insulin patterns, restores early insulin secretion, and controls mealtime glucose surges. It works by stimulating insulin release from pancreatic beta cells. It is indicated as monotherapy for type 2 diabetes or as combination therapy with metformin or a thiazolidinedione. Nateglinide is available in 60-mg and 120-mg tablets.

Antidiabetics, Alpha-Glucosidase Inhibitors

Class Summary

Alpha-glucosidase inhibitors prolong the absorption of carbohydrates and thus help to prevent postprandial glucose surges. Their induction of flatulence greatly limits their use. Doses of these agents should be titrated slowly to reduce GI intolerance. Their effect on glycemic control is modest, affecting primarily postprandial glycemic excursions.

Miglitol (Glyset)

Miglitol is not absorbed, so liver function abnormalities do not occur. It is FDA approved for use as monotherapy or in combination with sulfonylureas. Its modest effect on glycemia and high degree of GI adverse effects (flatulence) limit its use.

Acarbose (Precose)

Acarbose was the first alpha-glucosidase inhibitor approved by the FDA. It is absorbed to a small degree, so liver function abnormalities can occur rarely. It can be used as monotherapy or in combination with other treatment modalities. The modest effect of acarbose on glycemia and its high degree of GI adverse effects (flatulence) limit its use.

Antidiabetics, Thiazolidinediones

Class Summary

Thiazolidinediones are a newer class of drugs that reduce insulin resistance in the periphery (ie, they sensitize muscle and fat to the actions of insulin) and perhaps to a small degree in the liver (ie, insulin sensitizers, antihyperglycemics). They activate peroxisome proliferator–activated receptor (PPAR) gamma, a nuclear transcription factor that is important in fat cell differentiation and fatty acid metabolism. The major action of thiazolidinediones is probably actually fat redistribution. These drugs may have beta-cell preservation properties.

Thiazolidinediones have moderate glycemic efficacy, between that of alpha-glucosidase inhibitors and sulfonylureas. They are the most expensive oral agents.

Pioglitazone (Actos)

Pioglitazone is indicated as an adjunct to diet and exercise to improve glycemic control. It improves target-cell response to insulin without increasing insulin secretion from the pancreas. It also increases insulin-dependent glucose use in skeletal muscle and adipose tissue. Pioglitazone lowers triglycerides more than rosiglitazone, probably because of its PPAR-alpha effect.

Long duration of pioglitazone use and high cumulative doses have been linked with slightly increased risk for bladder cancer. The FDA currently recommends not prescribing pioglitazone for patients with active bladder cancer and using it with caution in patients with a history of bladder cancer.

Rosiglitazone (Avandia)

Rosiglitazone is an insulin sensitizer with a major effect on the stimulation of glucose uptake in skeletal muscle and adipose tissue. It lowers plasma insulin levels. It is indicated for type 2 diabetes associated with insulin resistance, as monotherapy and in conjunction with sulfonylureas and/or metformin and insulin. It may preserve beta-cell function and yields positive effects on vasculature and inflammation. It changes LDL and HDL particle size.

Because of data suggesting an elevated risk of myocardial infarction in patients treated with rosiglitazone, this agent is currently available only via a restricted access program. Patients currently taking rosiglitazone and benefiting from the drug are permitted to continue using it if they choose to do so. Rosiglitazone is available to new patients only if they are unable to achieve glucose control on other medications and are not willing to take pioglitazone, the only other thiazolidinedione.

As of November 18, 2011, rosiglitazone was no longer available in retail pharmacies. It can be purchased only through specially certified pharmacies participating in the Avandia-Rosiglitazone Medicines Access Program.

Antidiabetics, Glucagonlike Peptide-1 Agonists

Class Summary

Glucagonlike peptide–1 (GLP-1) agonists have a novel mechanism of action: they mimic the endogenous incretin GLP-1, stimulating glucose-dependent insulin release (as opposed to oral insulin secretagogues, which may cause non–glucose-dependent insulin release and hypoglycemia), reducing glucagon, and slowing gastric emptying.

Exenatide injectable solution (Byetta)

Exenatide is a GLP-1 agonist that improves glycemic control in patients with type 2 diabetes mellitus. Like endogenous incretins, it enhances glucose-dependent insulin secretion by pancreatic beta cells, suppresses inappropriately elevated glucagon secretion, and slows gastric emptying. The drug's 39–amino acid sequence partially overlaps that of the human incretin GLP-1.

Exenatide is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes who have not achieved glycemic control with metformin or a sulfonylurea. The solution is administered by subcutaneous injection twice daily.

Exenatide injectable suspension (Bydureon)

This formulation of exenatide allows once-weekly dosing by subcutaneous injection. Glycemic control attained with once-weekly long-acting exenatide injections may be superior to that achieved with the twice-daily injections.

Liraglutide (Victoza)

Liraglutide is a once-daily injectable GLP-1 receptor agonist that stimulates G-protein in pancreatic beta cells. It increases intracellular cyclic adenosine monophosphate (cAMP), leading to insulin release in the presence of elevated glucose concentrations. Liraglutide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The drug has not been studied in combination with insulin.

Liraglutide is not recommended as first-line pharmacologic therapy, because of potential serious adverse effects. Liraglutide is contraindicated in patients with a history or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2, as dose- and duration-dependent thyroid C-cell tumors have occurred in animal studies of liraglutide.

In addition, clinical studies suggest that liraglutide may cause pancreatitis, although conclusive evidence has not been established. Nevertheless, patients should be monitored for unexplained, persistent, severe abdominal pain, with or without vomiting, and liraglutide should be discontinued if pancreatitis is suspected.

Antidiabetics, Dipeptidyl Peptidase IV Inhibitors

Class Summary

Incretin hormones are part of an endogenous system involved in the physiologic regulation of glucose homeostasis. They increase insulin release and decrease glucagon levels in the circulation in a glucose-dependent manner. DPP-4 degrades numerous biologically active peptides, including the endogenous incretins GLP-1 and glucose-dependent insulinotropic peptide (GIP). DPP-4 inhibitors prolong the action of incretin hormones.

The FDA has approved 3 oral DDP-4 inhibitors: sitagliptin, saxagliptin, and linagliptin. A fourth, vildagliptin, is currently under FDA review.

Sitagliptin (Januvia)

Sitagliptin demonstrates selectivity for DPP-4 and does not inhibit DPP-8 or DPP-9 activity in vitro at concentrations approximating those from therapeutic doses. Sitagliptin can be used as a monotherapy or in combination with metformin or a thiazolidinedione. It is given once daily and is weight neutral.

Saxagliptin (Onglyza)

Saxagliptin inhibits DPP-4 and thereby increases concentrations of GLP-1 and GIP, which stimulate insulin release in response to increased blood glucose levels following meals. This action enhances glycemic control. Saxagliptin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Linagliptin (Tradjenta)

Linagliptin is a DPP-4 inhibitor that increases and prolongs incretin hormone activity. It is indicated for adults with type 2 diabetes mellitus, along with diet and exercise, to lower blood glucose levels. It may be used as monotherapy or in combination with other common antidiabetic medications, including metformin, sulfonylurea, or pioglitazone; it has not been studied in combination with insulin.

Bile Acid Sequestrants

Class Summary

Colesevelam is FDA approved as an adjunctive therapy to improve glycemic control in adults with type 2 diabetes mellitus.

Colesevelam (WelChol)

Colesevelam is a high-capacity bile acid sequestrant. It is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. The precise mechanism by which colesevelam improves glycemic control is largely unknown.

Antidiabetics, Intermediate-Acting Insulins

Class Summary

Intermediate-acting insulins have a slow onset of action and a longer duration of action. These agents are commonly combined with faster-acting insulins to maximize the benefits of a single injection.

Insulin NPH (Humulin N, Novolin N)

Insulin neutral protamine Hagedorn (NPH) has an onset of action of 3-4 hours. The peak effect occurs within 8-14 hours, and its usual duration of action is 16-24 hours. The drug appears cloudy and must be gently mixed and checked for clumping; if clumping occurs, the insulin should be discarded.

Antiparkinson Agents, Dopamine Agonists

Class Summary

Quick-release bromocriptine acts on circadian neuronal activities within the hypothalamus to reset the abnormally elevated hypothalamic drive for increased plasma glucose, triglyceride, and free fatty acid levels in fasting and postprandial states in patients with insulin resistance.

Bromocriptine (Cycloset)

This quick- release formulation is the only bromocriptine product indicated for type 2 diabetes mellitus. It is indicated as an adjunct to diet and exercise to improve glycemic control.