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Detail-Document #221103
−This Detail-Document accompanies the related article published in− PHARMACIST'S LETTER / PRESCRIBER'S LETTER
November 2006 Volume 22 Number 221103 American Diabetes Association Treatment Algorithm for Type 2 Diabetes
Diagnosis of type 2 diabetes
Counsel patients regarding lifestyle modification (weight loss, exercise)
(expected decrease in HbA1c 1-2%)
initiate metformin [Glucophage, others] 500 mg once or twice daily,
titrate to 850 mg to 1000 mg twice daily (expected decrease in HbA1c 1.5%)

HbA1c 7% or greater
three months later

rosiglitazone [Avandia] or pioglitazone [Actos] (expected decrease in HbA1c 0.5-1.4%)
sulfonylurea (expected decrease in HbA1c 1.5%)
basal insulin (bedtime intermediate-acting insulin or bedtime or morning long-acting insulin)
(expected decrease in HbA1c 1.5-2.5%)
HbA1c 7% or greater
three months later

additional agent (glitazone or sulfonylurea or insulin)
intensify insulin for those on insulin*

HbA1c 7% or greater
three months later

In patients not yet receiving insulin, add basal insulin or intensify insulin in those already receiving insulin*
HbA1c 7% or greater
three months later
Metformin + intensive insulin with/without glitazone
*When prandial rapid or very-rapid acting insulin is added, insulin secretagogues such as the
sulfonylureas or the glinides (repaglinide, nateglinide) should be discontinued.
Consider insulin as initial therapy (with lifestyle modification) in patients with fasting glucose greater
than 250 mg/dL or HbA1c greater than 10% or those with ketonuria or symptoms of hyperglycemia.
When initiating insulin, start with a bedtime dose of an intermediate-acting insulin or once-daily
long-acting insulin. Initiate with 10 units or 0.2 units per kg. Check fasting glucose concentrations
and increase by approximately 2 units (4 units if fasting glucoses are greater than 180 mg/dL) every 3
days, until fasting glucoses are less than 130 mg/dL. If HbA1c continues to be 7% or greater after 2
to 3 months, with well-controlled fasting glucose concentrations, consider checking pre-meal glucose

The algorithm does not include pramlintide [Symlin], exenatide [Byetta], alpha-glucosidase inhibitors
[Precose, Glyset], glinides [Prandin, Starlix], or sitagliptin [Januvia] due to generally lower overall
affect on HbA1c, limited information, and/or cost. However, these agents may be appropriate for
certain patients.

Copyright 2006 by Therapeutic Research Center Pharmacist's Letter / Prescriber's Letter P.O. Box 8190, Stockton, CA 95208 Phone: 209-472-2240 Fax: 209-472-2249 (Detail-Document #221103: Page 2 of 4)
Treatment of Type 2 Diabetes Mellitus
gastrointestinal adverse effects have not occurred, The incidence of diabetes is growing and is the dose can be increased to 850 to 1,000 mg with now considered an epidemic. A number of breakfast and dinner. The maximum effective studies have demonstrated that control of blood dose is 850 mg twice daily (AWP for one month glucose can reduce the morbidity associated with supply of generic immediate-release 850 mg twice diabetes. The recent development of a number of daily is $71.43),2 with only modest improvements new medications to control blood glucose has of blood glucose up to three grams daily.2 enlarged the armamentarium of agents used to Although the guidelines from the American treat this disease. However, the role of these Diabetes Association suggest that the maximum newer agents has been unclear. The American dose of regular-release metformin is three grams Diabetes Association and European Association daily, the U.S. prescribing information states that for the Study of Diabetes recently released a the maximum daily dose is 2,550 mg in adults and consensus algorithm for the initiation and 2,000 mg in adolescents ten to sixteen years of adjustment of therapy in patients with type 2 age.3 The expected reduction in HbA1c is approximately 1.5%. Advantages of metformin The goal of therapy is to maintain a HbA1c include lack of weight gain and lower cost, while level of less than 7%. This goal was selected the major disadvantages are GI adverse effects because of the practicality and potential for and the rare potential for lactic acidosis. reduction in complications. According to the new Preliminary evidence from the United Kingdom guidelines, a HbA1c of 7% or higher should be "a Prospective Diabetes Study (UKPDS) indicates call to action to initiate or change therapy with the that metformin may have a beneficial effect on goal of achieving an A1c level as close to the cardiovascular disease outcomes, but more nondiabetic range as possible or at a minimum, research is needed. decreasing the A1c to less than 7%." In addition, If glucose control is not achieved with lifestyle careful attention to controlling blood pressure and modification and the maximal dose of metformin cholesterol has been shown to reduce morbidity tolerated by the patient within two to three associated with diabetes. months, a second medication should be added. Second-line medications include sulfonylureas, a Selecting an Initial Agent
thiazolidinedione, or insulin. The decision of Following lifestyle modification, the selection which agent to use should depend on the degree of of the initial agent to treat patients with diabetes necessary A1c lowering. In patients with an A1c should be based on effectiveness, safety, of greater than 8.5% or those who are tolerability, and cost. Other than the effects on symptomatic, insulin should be considered. glucose and HbA1c, there is very little Advantages of insulin include lack of maximum information on the long-term benefits and risks of dose, improvement in cholesterol profile, and the agents. Consequently, decisions must be cost. Disadvantages of insulin include the need made based on their glucose and HbA1c effects. for injections and close monitoring of blood The most recent recommendations from the glucose concentrations, and the potential for American Diabetes Association recognize that weight gain and hypoglycemic reactions. lifestyle changes alone are often ineffective for While most sulfonylureas are available long-term control of blood glucose because of generically and are therefore less expensive (for failure to lose weight, the high rate of weight example, 20 mg of generic, extended-release regain, and progression of the disease. glipizide daily has an AWP of $48.32 per month)2 Consequently, it is recommended that metformin than the newer agents for patients with type 2 be started at the time of diagnosis, along with diabetes; weight gain of about 2 kg and lifestyle modification. Metformin is usually well hypoglycemia may limit their use. The longer- tolerated, especially if the dose is gradually acting sulfonylurea agents such as chlorpropamide titrated to the effective dose. Patients should be (Diabinese, others), glyburide (Micronase, started on a low-dose (i.e., 500 mg) once or twice others), and sustained-release glipizide (Glucotrol daily with breakfast and/or dinner. If XL, others) are more likely to cause Copyright 2006 by Therapeutic Research Center Pharmacist's Letter / Prescriber's Letter P.O. Box 8190, Stockton, CA 95208 Phone: 209-472-2240 Fax: 209-472-2249 (Detail-Document #221103: Page 3 of 4)
hypoglycemia. Additionally, elderly patients are expected reduction in HbA1c of approximately at higher risk for hypoglycemia than younger 0.5% to 0.8%. The major advantage of these agents is a lack of effect on weight. Though the thiazolidinediones, pioglitazone Disadvantages include the high incidence of GI (Actos) and rosiglitazone (Avandia) are less adverse effects, especially gas and bloating. effective than insulin or the sulfonylureas in Adverse effects lead to discontinuation in up to reducing HbA1c (0.5% to 1.4% compared with 45% of patients. These agents are contraindicated 1.5% to 2.5% for insulin and 1.5% for the in patients with intestinal or bowel disease, or sulfonylureas), they have been shown to have a intestinal obstruction. Additionally, these agents beneficial effect on serum lipid profiles. must be dosed three times daily with meals and Disadvantages include the potential for fluid are expensive (AWP for one month supply of retention, weight gain, and expense (AWP for one maximal dose of Precose 100 mg three times month supply of maximal dose of 45 mg once daily is $89.38 and 100 mg three times daily of daily for Actos Glyset is $87.62). 2 8 mg once daily for Avandia is $188.93).2 Due to The glinides, repaglinide and nateglinide, are the risk of fluid retention leading to an acute effective at lowering HbA1c (expected reduction exacerbation of congestive heart failure, it is in HbA1c approximately 1.5% with repaglinide recommended that these agents not be used in and approximately 1% with nateglinide), but each patients with New York Heart Association Class 3 must be given three times daily and these are or 4 heart failure.5 expensive (AWP for one month supply maximal In patients who continue to experience dose of 4 mg three times daily of Prandin is hyperglycemia despite lifestyle modification, $250.42 and 120 mg three times daily of Starlix is metformin and either a sulfonylurea, glitazone or $124.86).2 As with the sulfonylureas, there is a insulin, a third pharmacological agent (either a risk of weight gain with the glinides. sulfonylurea or a thiazolidinedione) can be Only one agent of the glucagon-like peptide started. Another oral agent should be added only (GLP)-1 agonists, exenatide (Byetta), is approved in patients where the HbA1c is close to the target for use in the United States. There is less goal. In patients with an HbA1c of 8% or greater, published clinical information on exenatide consideration should be given to adding insulin in compared with other agents commonly used to those who are not receiving it, or intensifying treat type 2 diabetes. Exenatide is considered an insulin in those who are already receiving insulin. "incretin mimetic." It works by a number of Intensifying insulin usually involves adding mechanisms including stimulation of insulin injections of short-acting or rapid-acting insulin production in response to high blood glucose prior to selected meals. When mealtime insulin is levels, inhibition of the release of glucagon after added, insulin secreatagogues such as the meals, and slowing the rate of gastric emptying. sulfonylureas or the glinides (repaglinide It is thought that the expected reduction in HbA1c [Prandin], nateglinide [Starlix]) should be is approximately 0.5% to 1%, a value lower than discontinued since these agents do not act that of the other recommended agents. An synergistically with insulin. advantage of exenatide is the weight loss that is commonly noted in patients who take the Other Agents
medication. In clinical trials, patients typically In addition to the agents included in the lost 2 kg to 3 kg of weight, some of which may algorithm, there are a number of other agents for have been due to the GI adverse effects associated diabetes which are generally less effective in with the medication. Disadvantages include the lowering the HbA1c, have limited clinical data, or need for twice daily injections, the high incidence are more expensive than other agents. In general, of GI adverse effects such as nausea, vomiting or these agents should be considered for patients diarrhea, and cost (AWP for one month supply who are close to their HbA1c goal, yet continue to maximal dose of 10 mcg twice daily of Byetta is experience postprandial hyperglycemia. $219.42).2 It is currently only approved for use The alpha-glucosidase inhibitors, acarbose with metformin and/or a sulfonylurea. (Precose) and miglitol (Glyset), are considered Pramlintide (Symlin) is the only approved less effective than other available agents with an agent in the class of medications known as the Copyright 2006 by Therapeutic Research Center Pharmacist's Letter / Prescriber's Letter P.O. Box 8190, Stockton, CA 95208 Phone: 209-472-2240 Fax: 209-472-2249

(Detail-Document #221103: Page 4 of 4)
amylin agonists. It is only indicated for use with insulin. The expected reduction in HbA1c is lower The incidence of type 2 diabetes continues to with pramlintide (approximately 0.5% to 0.7%) grow. Because of the morbidity and mortality than other agents. It is given subcutaneously associated with the disease, aggressive therapy is before meals. The most common adverse effect is required to rapidly achieve and maintain glycemic nausea. Weight loss often occurs with this agent, levels as close to normal as possible. The newest but may be due to the gastrointestinal adverse recommendations of the American Diabetes effects. As with many of the newer agents, Association emphasize these principles and will pramlintide is expensive, with the AWP of a 5 mL assist the clinician in achieving these goals. vial (containing 25 x 120 mcg doses) of $103.03.2 Patients with type 2 diabetes typically inject Users of this document are cautioned to use their own 60 mcg to 120 mcg with major meals. Preprandial professional judgment and consult any other necessary rapid-acting or short-acting insulin doses must be or appropriate sources prior to making clinical reduced when initiating pramlintide in order to judgments based on the content of this document. Our reduce the risk of hypoglycemia. editors have researched the information with input The newest class of medication for the from experts, government agencies, and national treatment of type 2 diabetes is the dipeptidyl organizations. Information and Internet links in this peptidase IV (DPP-4) inhibitors. Like exenatide, article were current as of the date of publication. these agents work by enhancing the incretin system in the body. The incretin system is one of Project Leader in preparation of this Detail-
the mechanisms in the body which lowers blood Document: Neeta Bahal O'Mara, Pharm.D.,
glucose. When the body senses hyperglycemia, incretins stimulate the pancreas to release insulin and signal the liver to cease glucose production. DPP-4 inhibitors increase the active levels of 1. Nathan DM, Buse JB, Davidson MB, et al. incretin hormones in the body while exenatide is Management of hyperglycemia on type 2 diabetes: a consensus algorithm for the initiation and an "incretin mimetic" and works by stimulating adjustment of therapy. Diabetes Care the GLP-1 receptor. Sitagliptin (Januvia) is an 2006;29:1963-72. orally active, once-daily DPP-4 inhibitor which 2. Red Book, 2005 edition and August 2006 update. has been approved by the FDA and vildagliptin Volume 25, Montvale, NJ:Thomson PDR. (Galvus) is expected to be approved in the near 3. Product information for metformin (Glucophage). Bristol-Myers Squibb. Princeton, New Jersey future. The role in therapy for the DPP-4 08543. March 2004. inhibitors has not yet been determined. Like 4. Anon. FDA approves once-daily Januvia, the first exenatide, the expected reduction in HbA1c is and only DPP-4 inhibitor available in the United lower than other agents (approximately 0.6% to States for type 2 diabetes. October 17, 2006. 0.8%). However, sitagliptin does not appear to ia/hcp/press/index.jsp. (Accessed October 18, cause weight loss or nausea commonly seen with exenatide. According to the manufacturer, a 30- 5. The use of glitazones in patients with congestive day supply of 100 mg once daily will be about heart failure. Pharmacist's Letter/Prescriber's Letter 2006;22(9):220909.
Cite this Detail-Document as follows: Treatment of type 2 diabetes mellitus. Pharmacist's Letter/Prescriber's
Letter 2006;22(11):221103.

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