The clinical bottom line of the summary:

Premixed insulin analogues and premixed human insulin have similar effects on glycosylated hemoglobin (A1c), and rates of hypoglycemia are similar.

Premixed insulin analogues help achieve lower postprandial glucose levels than premixed human insulin.

Premixed insulin analogues help achieve lower A1c levels than long-acting insulin analogues used alone, but rates of hypoglycemia are higher.

Premixed insulin analogues are linked with more episodes of hypoglycemia than oral diabetes drugs.

Premixed insulin analogues help achieve lower A1c levels than oral diabetes drugs used alone.

Premixed Insulin Analogues: A Comparison With Other Treatments for Type 2 Diabetes. Clinician Summary Guide

The U.S. Food and Drug Administration today issued an alert to health care professionals reminding them that single-patient insulin pens and insulin cartridges should not be used to administer medication to multiple patients due to the potential risk of transmitting blood-borne pathogens such as HIV and the hepatitis viruses.

Insulin pens are pen-shaped injector devices that contain a disposable needle and either an insulin reservoir or an insulin cartridge. The devices typically contain enough insulin for a patient to self-administer several doses of insulin before the reservoir or cartridge is empty. All insulin pens are approved only for single-patient use (one device for only one patient).

 

Amy Egan, M.D., deputy director of safety at the FDA’s Division of Metabolism and Endocrinology Products in the Center for Drug Evaluation and Research declared:

“Insulin pens are not designed, and are not safe, for one pen to be used by more than one patient, even if needles are changed between patients due to the risk of transmitting blood-borne pathogens.”

Further information on the CDER website: Information for Healthcare Professionals: Risk of Transmission of Blood-borne Pathogens from Shared Use of Insulin Pens

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

Wolfgang C. Winkelmayer, MD, ScD; Soko Setoguchi, MD, DrPH; Raisa Levin, MS; Daniel H. Solomon, MD, MPH

Arch Intern Med. 2008;168(21):2368-2375.

Background

Recent meta-analyses have raised the possibility that rosiglitazone maleate may increase the risk of ischemic cardiovascular events, whereas pioglitazone hydrochloride could not be linked to such a risk. We compared cardiovascular outcomes and mortality between patients initiating pioglitazone vs rosiglitazone therapy.

Methods

We assembled an inception cohort of Medicare beneficiaries older than 65 years with state-sponsored prescription drug benefits who had diabetes mellitus and initiated treatment with rosiglitazone or pioglitazone between January 1, 2000, and December 31, 2005. The study outcomes included all-cause mortality, myocardial infarction, stroke, and hospitalization for congestive heart failure.

Results

Of 28 361 patients selected, 50.3% initiated treatment with pioglitazone and 49.7% with rosiglitazone. Most baseline characteristics were similar between the groups. As preferred in drug safety research, we censored patients at crossover or at 60 days after discontinuation of therapy with their study drug; during 29 060 person-years of follow-up, 1869 patients died. After adjustment for a large number of patient characteristics, Cox regression models revealed 15% greater mortality among patients who initiated therapy with rosiglitazone compared with pioglitazone (95% confidence interval, 5%-26%). Use of rosiglitazone was also associated with a 13% greater risk of congestive heart failure (95% confidence interval, 1%-26%). No differences between the 2 drugs were found in their rates of myocardial infarction or stroke.

Conclusions

Our findings from a large population-based cohort of US seniors are compatible with an increased risk of all-cause mortality and congestive heart failure in patients initiating therapy with rosiglitazone compared with similar patients initiating therapy with pioglitazone. Limitations of this study include residual confounding due to its nonrandomized nature.

Author Affiliations: Division of Pharmacoepidemiology and Pharmacoeconomics (Drs Winkelmayer, Setoguchi, and Solomon and Ms Levin), Renal Division (Dr Winkelmayer), and Division of Rheumatology (Dr Solomon), Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts.

Source: Arch Intern Med. 2008;168(21):2368-2375.

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.

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Some official information about the trial:

Rosuvastatin to Prevent Vascular Events in Men and Women with Elevated C-Reactive Protein.N Engl J Med. 2008 Nov 20;359(21):2195-2207

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 metformin in the medical management of hyperglycemia in type 2 diabetes.

Metformin

In most of the world, metformin is the only biguanide available. Its major effect is to decrease hepatic glucose output and lower fasting glycemia. Typically, metformin monotherapy will lower A1C levels by ~ 1.5 percentage points (27,49). It is generally well tolerated, with the most common adverse effects being gastrointestinal. Metformin monotherapy is not usually accompanied by hypoglycemia and has been used safely, without causing hypoglycemia, in patients with prediabetic hyperglycemia (50). Metformin interferes with vitamin B12 absorption but is very rarely associated with anemia (27).

The major nonglycemic effect of metformin is either weight stability or modest weight loss, in contrast with many of the other blood glucose lowering medications. The UKPDS demonstrated a beneficial effect of metformin therapy on CVD outcomes (7), which needs to be confirmed. Renal dysfunction is considered a contraindication to metformin use because it may increase the risk of lactic acidosis, an extremely rare (less than 1 case per 100,000 treated patients) but potentially fatal complication (51). However, recent studies have suggested that metformin is safe unless the estimated glomerular filtration rate falls to < 30 ml/min (52).

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