• Agents for the treatment of thyroid disorders:
• Thyroglobulin (Proloid),Levothyroxine sodium (Synthroid, Levothroid, Levoxine), Liothyronine sodium (Cytomel)
• Antithyroid drugs: Propylthiouracil (PTU),  Methimazole (Tapazole), Iodide,  Radioactive Iodine, Propranolol (Inderal)
• Calcium & related: gluconate (Kalcinate),gluceptate,chloride, carbonate (TUMS, etc.), citrate (Citracal, etc.), glubionate (Neo-Calglucon), lactate phosphate, Dicalcium phosphate, Vitamin D₂/ergocalciferol (Deltalin, Drisdol, Calciferol), Calcitriol/1,25-(OH)₂-cholecalciferol (Rocaltrol)
• Bisphosphonates: Sodium etidronate (Didronel), Pamidronate (Aredia), Alendronate (Fosamax)
• Insulins: Regular insulin, Isophane insulin suspension (NPH insulin), Insulin Zn (Lente insulin), Extended insulin zinc suspension (Ultralente insulin).
• Oral antidiabetic drugs: Tolbutamide (Orinase), Chlorpropramide (Diabinese), Glyburide (Micronase), Glipizide (Glucotrol), Metformin (Glucophage), Acarbose (Precose), Troglitazone

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Comparative Effectiveness Review.

Premixed Insulin Analogues for Adults With Type 2 Diabetes

Premixed insulin preparations are an alternative that may permit a smaller number of daily insulin injections.

Although oral diabetes medicines are used as first-line treatments in patients with type 2 diabetes, insulin is often required to achieve the desired level of glucose control. According to the National Health Interview Survey, 28 percent of patients with type 2 diabetes use insulin either alone (16 percent) or in combination with oral diabetes medicines (12 percent).

To mimic the release of insulin from the pancreas in response to food intake, insulin replacement regimens involve giving insulin at mealtimes along with a longer-acting insulin that provides a slow release of insulin throughout the day. However, these insulin regimens may decrease a person’s flexibility in the timing of meals and activities, increase the frequency of blood glucose monitoring, and increase the risk of hypoglycemia. Also, the requirement of multiple injections may affect patients’ overall satisfaction with their treatment regimen.

Premixed insulin preparations are an alternative that may permit a smaller number of daily insulin injections. They combine both mealtime insulin and a longer lasting insulin. The newest premixed insulin preparations use insulin analogues, which are insulins with amino acid substitutions that alter their rate of entering the bloodstream after a subcutaneous injection. It is important to evaluate the evidence for the safety and effectiveness of these premixed insulins compared with other regimens for managing blood glucose. The EHC Program commissioned the Evidence-based Practice Center at Johns Hopkins University to perform a systematic review of premixed insulin analogues. The review found that:

There is more evidence available on some comparisons than others. When compared with premixed NPH (neutral protamine Hagedorn) and regular insulin, people who use premixed insulin analogues achieve similar reductions in A1c (average blood glucose) and fasting glucose levels, but those who use premixed insulin analogues achieve lower glucose levels after meals. Rates of hypoglycemia are also similar.

People who use premixed insulin analogues achieve lower A1c levels than people who use long-acting insulin analogues alone, but rates of hypoglycemia are higher.
People who use premixed insulin analogues experience more episodes of hypoglycemia but also achieve better glycemic control than those who use oral diabetes drugs.

Evidence was insufficient to determine whether the effectiveness or harms of premixed insulin analogues vary by demographic factors. There was insufficient evidence to draw conclusions about the effectiveness of premixed insulin analogues for people with poor glycemic control or coexisting medical conditions. There was also insufficient evidence about the impact of premixed insulin analogues on quality of life and treatment satisfaction. Most available studies of premixed insulin analogues lasted 1 year or less and focused on short-term outcomes. Therefore, evidence was insufficient to determine the effects of premixed insulin analogues on long-term outcomes, such as mortality and cardiovascular disease.

Further information about the CER, including both an Executive Summary and the complete report, is available here: http://effectivehealthcare.ahrq.gov/healthInfo.cfm?infotype=rr&ProcessID=18&DocID=108.

“The Journal of the Canadian Medical Association (CMAJ) has published the results of a systematic review and meta-analysis that aimed to quantify the fracture risk associated with glitazone therapy. There is also an accompanying editorial. This study has also reached the general media (BBC).

The analysis examined data from 10 studies involving 13,715 patients. The trials varied in duration from one to four years, collected data on fracture rates and were all double blind randomised trials. The overall risk of fracture was significantly increased by glitazone therapy with an odds ratio of 1.45 (95% confidence interval 1.18 – 1.79). When analysed separately it was found that there was no significant increase in risk among men but remained significant among women; odds ratio 2.23 (95% CI 1.65 – 3.01).

The authors note that the findings of this study have several limitations. None of the included trials were designed to measure the risk of fractures and a number of trials were excluded from the final analysis because they did not report fracture data.

Despite these limitations the rates of fractures reported were consistent with those observed in observational epidemiologic studies. The authors conclude that, “the relatively modest benefits of thiazolidinediones (glitazones) must be balanced against their significant long-term effects on bone and the cardiovascular system“. In addition the authors quote the current NICE guideline recommendations that advise clinicians to “not commence or continue a thiazolidinedione (glitazone) in people who have evidence of heart failure, or who are at higher risk of fracture“.

Action: This new analysis further confirms the current third line position for glitazones after metformin and sulphonylureas.”

See a related animation on thiazolidinediones  mechanism of action.

• Rosiglitazone improves glycaemic control but there is a lack of evidence that it improves diabetes–related clinical complications and mortality. Prescribers should consider this —along with recently emerging safety information — when assessing the ratio of potential harms and benefits for each patient.

• Rosiglitazone is no longer indicated in combination with insulin or for triple oral therapy in combination with metformin and a sulfonylurea.

• Rosiglitazone is a third-line choice. It may still be considered as part of dual therapy when either metformin or a sulfonylurea is contraindicated or not tolerated.

• Insulin should also be considered instead of rosiglitazone in these scenarios.

• Do not use rosiglitazone in people with heart failure or a history of heart failure.

• Avoid using rosiglitazone in people with ischaemic heart disease. Take particular care when prescribing the drug to people with a high risk of cardiovascular events.

• Bear in mind the possibility that rosiglitazone may increase the risk of a myocardial infarction.

• A large clinical trial found an increased rate of fractures of the upper arm (humerus), hand and foot among women using rosiglitazone.

• Wait 8 weeks before increasing the dose, as the full effect of the drug may not be seen before this time. In clinical trials of glitazone treatment, 25% to 30% of patients had no improvement in glycaemic control.

• Establish the effective and tolerated dose of each component as single drugs before considering the rosiglitazone with metformin combination tablet. Do not use combination tablets for patients taking more than 2 g/day of metformin because the maximum recommended daily dose of rosiglitazone will be exceeded.

Source: Rosiglitazone (Avandia) and rosiglitazone with metformin (Avandamet) for type 2 diabetes mellitus. NPS RADAR

The primary mechanism of action of the sulfonylureas is direct stimulation of insulin release from the pancreatic beta cells. In the presence of viable pancreatic Beta-cells, sulfonylureas enhance the release of endogenous insulin, thereby reducing blood glucose levels. At higher doses, these drugs also decrease hepatic glucose production, and the second-generation sulfonylureas may possess additional extrapancreatic effects that increase insulin sensitivity, though the clinical significance of these pharmacological effects is unclear.

Classification of sulfonylureas

Insuline secretion and sulfonylureas

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Mechanism of action on insulin secretion

In the basal state, the plasma membrane of the β cell is hyperpolarized, and the rate of insulin secretion from the cell is low. When glucose is available, it enters the cell via GLUT2 transporters in the plasma membrane and is metabolized to generate intracellular ATP. ATP binds to and inhibits the plasma membrane K+/ATP channel. Inhibition of the K+/ATP channel decreases plasma membrane K+ conductance; the resulting depolarization of the membrane activates voltage-gated Ca2+ channels and thereby stimulates an influx of Ca2+. Ca2+ mediates fusion of insulin-containing secretory vesicles with the plasma membrane, leading to insulin secretion.

The K+/ATP channel, an octamer composed of Kir6.2 and SUR1 subunits, is the target of several physiologic and pharmacologic regulators. ATP binds to and inhibits Kir6.2, while sulfonylureas bind to and inhibit SUR1; these agents promote insulin secretion.

Therapeutic uses, side effects and contraindications [2]

Sulfonylureas are used to control hyperglycemia in type 2 Diabetes mellitus affected patients who cannot achieve appropriate control with changes in diet alone. In all patients, continued dietary restrictions are essential to maximize the efficacy of the sulfonylureas.

The major adverse effect is hypoglycemia resulting from oversecretion of insulin; therefore, should be used cautiously in patients who are unable to recognize or respond to hypoglycemia

Contraindications to the use of these drugs include type 1 DM, pregnancy, lactation, and for the older preparations, significant hepatic or renal insufficiency.

Below is a transcript of the latest statement (December 2008) published on Diabetes Care about the titration of metformin in the medical management of hyperglycemia in type 2 diabetes.

TITRATION OF METFORMIN

1. Begin with low-dose metformin (500 mg) taken once or twice per day with meals (breakfast and/or dinner) or 850 mg once per day.

2. After 5–7 days, if gastrointestinal side effects have not occurred, advance dose to 850, or two 500 mg tablets, twice per day (medication to be taken before breakfast and/or dinner).

3. If gastrointestinal side effects appear as doses advanced, decrease to previous lower dose and try to advance the dose at a later time.

4. The maximum effective dose can be up to 1,000 mg twice per day but is often 850 mg twice per day. Modestly greater effectiveness has been observed with doses up to about 2,500 mg/day. Gastrointestinal side effects may limit the dose that can be used.

5. Based on cost considerations, generic metformin is the first choice of therapy. A longer-acting formulation is available in some countries and can be given once per day.

Free full text: Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care 31:1–11, 2008

Below is a transcript of the latest statement (December 2008) published on Diabetes Care, about the role of Glucagon-like peptide-1 agonists (exenatide) in the medical management of hyperglycemia in type 2 diabetes.

Glucagon-like peptide-1 agonists (exenatide).

Glucagon-like peptide-1 (GLP-1) 7–37, a naturally occurring peptide produced by the L-cells of the small intestine, potentiates glucose-stimulated insulin secretion. Exendin-4 has homology with the human GLP-1 sequence but has a longer circulating half-life. It binds avidly to the GLP-1 receptor on the pancreatic beta-cell and augments glucose-
mediated insulin secretion (32). Synthetic exendin-4 (exenatide) was approved for use in the U.S. in 2005 and is administered twice per day by subcutaneous injection. Although there are less published data on this new compound than the other blood glucose–lowering medications, exendin-4 appears to lower A1C levels by 0.5–1 percentage points, mainly by lowering postprandial blood glucose levels (78–81).

Exenatide also suppresses glucagon secretion and slows gastric motility. It is not associated with hypoglycemia but causes a relatively high frequencyof gastrointestinal disturbances, with 30-45% of treated patients experiencing one or more episodes of nausea, vomiting, or diarrhea (78–81). These side effects tend to abate over time. In published trials, exenatide is associated with weight loss of aprox.  2–3 kg over 6 months, some of which may be a result of its gastrointestinal side effects. Recent reports have suggested a risk for pancreatitis associated with use of GLP agonists; however, the number of cases is very small and whether the relationship is causal or coincidental is not clear at this time.

Currently, exenatide is approved for use in the U.S. with sulfonylurea, metformin, and/or a TZD.

Several other GLP-1 agonists and formulations are under development

Free full text: Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care 31:1–11, 2008

Below is a transcript of the latest statement (December 2008) published on Diabetes Care about the role of dipeptidyl peptidase four inhibitors in the medical management of hyperglycemia in type 2 diabetes.

Dipeptidyl peptidase four inhibitors.

GLP-1 and glucose-dependent insulinotropic peptide (GIP), the main insulinotropic peptides of intestinal origin (incretins), are rapidly degraded by dipeptidyl peptidase four (DPP-4). DPP-4 is a member of a family of cell membrane proteins that are expressed in many tissues, including immune cells (34). DPP-4 inhibitors are small molecules that enhance the effects of GLP-1 and GIP, increasing glucose-mediated insulin secretion and suppressing glucagon secretion (83,84). The first oral DPP-4 inhibitor, sitagliptin, was approved by the Food and Drug Administration in October 2006 for use as monotherapy or in combination with metformin or TZDs.

Another DPP-4 inhibitor, vildagliptin, was approved in Europe in February 2008, and several other compounds are under development. In clinical trials performed to date, DPP-4 inhibitors lower A1Clevels by 0.6–0.9 percentage points and are weight neutral and relatively well tolerated (83,84). They do not cause hypoglycemia when used as monotherapy.

A fixed-dose combination pill with metformin is available. The potential for this class of compounds to interfere with immune function is of concern; an increase in upper respiratory infections has been reported (34).

Free full text: Medical Management of Hyperglycemia in Type 2 Diabetes: A Consensus Algorithm for the Initiation and Adjustment of Therapy. Diabetes Care 31:1–11, 2008

DPP IV inhibitors mechanism of action. Via Clinical Cases Blog