Insulin Regimens in Type 2 Diabetes
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In this issue: Efficacy of once-daily insulin, aldo-sterone use in heart failure, erectile dysfunction Clinical Practice Guidelines, and FDA Actions.
Efficacy of once-daily insulin
Most type 2 diabetics, even those on oral medications, will eventually require insulin for glycemic control. A new study suggests that simple once-a-day insulin may be as effective as more complex regimens. Researchers from England evaluated 708 patients who had suboptimal hemoglobin A1c (HbA1c) levels while taking metformin and a sulfonylurea.
Patients were randomly assigned to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily with an increase to twice daily if needed. Sulfonylurea therapy was replaced by a second type of insulin if hyperglycemia became unacceptable during the first year of this study or if HbA1c levels were > 6.5%. Outcomes measures were HbA1c levels, the proportion of patients with HbA1c ≤ 6.5%, the rate of hypoglycemia, and weight gain. After 3 years, median HbA1c levels were similar in all 3 groups. More patients had HbA1c levels < 6.5% in the prandial and basal groups, although more than 80% of patients in the basal group required a second type of insulin. The median number of hypoglycemic events per patient per year during the trial was lowest in the basal group (1.7) compared to the the biphasic (3.0) and prandial (5.7) groups (P < 0.001). Weight gain was highest in the prandial group. The authors conclude that the basal or prandial insulin-based regimens added to oral therapy resulted in better HbA1c levels compared to a biphasic insulin regimen. In addition, the basal group also had fewer hypoglycemic episodes and less weight gain. The authors state that the "results support the initial addition of a basal insulin to oral therapy, with subsequent intensification to a basal-prandial regimen..." (published at www.nejm.org Oct. 22, 2009).
In an accompanying editorial, Michael Roden, MD, points out that regardless of group, most subjects were accelerated to multiple doses of insulin per day. The study was sponsored by a manufacturer of insulin analogues, and only their analogue products were used in the study, whereas current consensus statements recommend regular human insulin. The editorial also points out that blood sugar control is only part of the equation with diabetics. Aggressive blood pressure control and use of statins and aspirin are equally important. Still, more studies are suggesting an early intensification of treatment with insulin may effectively reduce complications in type 2 diabetes (published at www.nejm.org Oct. 22, 2009).
For updated guidelines on the treatment of type 2 diabetes, see the recently released one-page algorithm from the American Association of Clinical Endocrinologists: www.aace.com/pub/pdf/GlycemicControlAlgorithm.pdf.
Aldosterone use in heart failure
Aldosterone antagonists are underused in patients with moderate-to-severe heart failure (HF) and systolic dysfunction according to a new study in the Journal of the American Medical Association. Aldosterone antagonists (spironolactone and eplerenone) have been shown to be very effective in the treatment of HF such that they were designated class I (useful and recommended) in the recent American College of Cardiology/American Heart Association Chronic HF Guidelines. Despite this, the drugs are underused in eligible patients.
The current study was an observational analysis of more than 43,000 patients admitted to the hospital with HF and discharged home from 241 hospitals participating in the Get With The Guidelines — HF quality improvement registry between 2005 and 2007. Among 12,565 patients eligible for aldosterone antagonist therapy, only 4087 (32.5%) received one of the drugs at discharge. There was wide variation in aldosterone antagonist usage among hospitals (0%-90.6%) and was more likely to be used in younger patients, African Americans, those with lower blood pressure, history of implantable cardioverter-defibrillator, depression, alcohol use, pacemaker implantation, and those having no history of renal insufficiency. Inappropriate use of aldosterone antagonist therapy was low. The authors conclude that use of aldosterone antagonist therapy is underutilized in HF patients, occurring in only one-third of eligible patients, although the rate of use increased gradually throughout the course of the study. They also state that use of evidence-based guidelines in hospitals may be warranted to improve treatment of HF patients (JAMA 2009;302:1658-1665).
Many clinicians shy away from use of aldosterone antagonists because of concerns regarding hyperkalemia, especially since many of these patients are also on ACE inhibitors or ARBs. Aldosterone inhibitor use in HF is not part of the Joint Commission/Centers for Medicare and Medicaid Services core performance measures. Regardless, aldosterone antagonists have been shown to benefit patients with HF and they are clearly underutilized.
Erectile dysfunction guidelines
The American College of Physicians has published a Clinical Practice Guidelines regarding hormonal testing and pharmacologic treatment of erectile dysfunction (ED) in men. The guideline recommends that clinicians initiate therapy with a PDE-5 inhibitor (sildenafil, vardenafil, or tadalafil) in men who seek treatment for ED and do not have a contraindication such as concomitant nitrate use. They rate this a strong recommendation with high-quality evidence. The choice of a PDE-5 should be based on preference, including ease of use, cost, and adverse effects profile. The guideline does not recommend for or against routine use of hormonal blood tests or hormonal treatment in the management of patients with erectile dysfunction due to insufficient evidence to determine benefits and harm. The guideline reviewed more than 100 randomized controlled trials that showed that PDE-5 inhibitors improved successful sexual intercourse and improved erections in men with ED (Ann Intern Med 2009 Oct 19;).
FDA Actions
The FDA has authorized emergency use of IV antiviral peramivir for treatment of 2009 H1N1 influenza in hospitalized patients. The drug is not yet approved for use in this country, but was authorized in response to a request from the CDC. IV peramivir is approved only for hospitalized adult and pediatric patients for whom an IV drug is clinically appropriate because the patient is not responding to either oral or inhaled antiviral therapy, because enteral or respiratory therapy is not feasible, or in adults when a clinician judges that IV therapy is appropriate due to other circumstances. This is the first available IV antiviral available for 2009 H1N1 infections. For more information see www.cdc.gov/h1n1flu/eua/.
The FDA has approved the quadrivalent human papilloma virus (HPV) vaccine (Gardasil®) for use in boys and young men. The vaccine is approved for males ages 9-26 as 3 injections given over a 3- month period. HPV is the most common sexually transmitted disease in the United States with 1 of 500 men infected every year. Previously, the vaccine had only been approved for use in females ages 9-26 years. In related news, a recent study from the National Cancer Institute, CDC, and American Cancer Society has suggested that the vaccine is not cost-effective for women older than age 30 who undergo annual or biennial screening for cervical cancer (Ann Intern Med 2009;151:538-545). Similarly, a study from Harvard found that HPV vaccination for 12-year-old girls was cost-effective, but the same vaccination for 12-year-old boys was not (BMJ 2009 Oct. 8).
The FDA has also approved a bivalent HPV vaccine for use in females, which protects against HPV types 16 and 18. The vaccine is being marketed as a "cervical cancer vaccine" by Glaxo-SmithKline under the trade name Cevarix®.
This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. Dr. Elliott reports no financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: [email protected].
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