Clinical Briefs

By Louis Kuritzky, MD, Clinical Assistant Professor, University of Florida, Gainesville. Dr. Kuritzky is a consultant for GlaxoSmithKline and is on the speaker's bureau of GlaxoSmithKline, 3M, Wyeth-Ayerst, Pfizer, Novartis, Bristol-Myers Squibb, AstraZeneca, Jones Pharma, and Boehringer Ingelheim.

HbA1c Following Successful Initial Metformin Therapy

Appropriate initial treatments for type 2 diabetes (DM2) include a diversity of oral agents and/or insulins. One of the most popular current initial treatments is metformin (MET), due to its efficacy, tolerability, and weight-neutrality. Because diabetes is typically a progressive disorder, most patients progress to require intensification of treatment. Nichols et al studied a large cohort of DM2 patients (n = 1,288) who had received MET as their initial treatment, and had achieved an A1c level of < 8%. Subjects were followed to evaluate which factors predicted loss of control of DM2, defined as the addition of other agents for glucose control, or finding an A1c > 8%.

MET failure occurred within 36 months in 50% of individuals who initially attained an A1c 7-7.9% on MET alone. In comparison, there was a steep linear relationship between degree of initial control and likelihood of secondary drug failure: those who initially attained better control on MET monotherapy (A1c 6-6.9%) did not experience drug failure until at least 60 months, and those with the best degree of control (A1c < 6%), maintained MET as successful monotherapy for greater than 84 months. Another critical factor discerned amongst this population was that weight gain had a major impact upon failure. As little as 1 kg increase in weight was associated with a 4-6% increased likelihood of treatment failure. Hence, vigilance in glucose control combined with maintenance of weight both factor significantly into long-term treatment success.

Nichols GA, et al. Diabetes Care. 2006;29:504-509.

Triple Therapy in Type 2 Diabetes

The most commonly used agents for the treatment of type 2 diabetes are metformin and a sulfonylurea. Despite adequate doses of both of these medications, many patients remain uncontrolled, or progress to inadequate control over time. The next best step after dual therapy fails is indeterminate. It is tempting to place patients on a third oral agent, usually a thiazolidinedione (TZD), but this enthusiasm must be tempered by two cold realities: 1) that usual A1c reductions rarely exceed 1.4-1.7% on triple therapy, hence patients with baseline above 8.7% are unlikely to achieve their goal, and 2) the expense of adding a TZD is not inconsiderable. On the other hand, there is a substantial resistance to utilization of insulin, or any other injectable medications (eg, exenatide) for that matter.

To compare the utility of adding a TZD (rosiglitazone) vs insulin (glargine) to the regimen of persons uncontrolled with dual oral therapy, Rosenstock et al randomized 217 patients. In the glargine group, dose was titrated to a fasting glucose less than 120 mg/dL; in the TZD group, rosiglitazone was increased up to 8 mg/d if fasting glucose was above 120 mg/dL.

The overall reduction in A1c was similar in both groups, averaging a 1.7% reduction from baseline. However, in the group further from goal (A1c > 9.5%), the reduction in A1c with insulin was far greater than with TZD: 3.6% vs 2.6%. Although hypoglycemic events were more frequent with insulin, weight gain and lipid changes were more favorable with insulin. When faced with a challenge of best next-step treatment, there is solid evidence to provide guidance, dependent upon the degree of baseline control, risk of hypoglycemia, weight control, and cost issues.

Rosenstock J, et al. Diabetes Care. 2006;29:554-559.

Calcium, Vitamin D, and Fractures

Calcium (cal) and vitamin d (VITD) are commonly considered a cornerstone of customary treatment for postmenopausal women to prevent osteoporosis and fractures. In placebo-controlled trials of other osteoporosis therapies such as bisphosphonates and selective estrogen receptor modulators, inclusion of CAL and VITD supplementation has been standard.

The Women's Health Initiative, the same trial from we learned the limitations of postmenopausal hormone replacement therapy, included a large cohort of postmenopausal women (n = 36,282) between the ages of 50-79 who were randomly assigned to CAL/VITD or placebo, and followed for 7 years.

Although bone density was favorably affected by CAL/VITD, fractures were not. Neither hip fracture, spine fracture, nor total fractures achieved statistical significance when CAL/VITD was compared with placebo. Discouragingly, the incidence of kidney stones was increased by 17%. This data would suggest that healthy women do not experience a clinically beneficial reduction in fractures from CAL/VITD. Sensitivity analysis indicated that the subgroup of women with the highest adherence to the treatment regimen did experience a fracture reduction, but the absolute benefit was small: 4 fewer hip fractures per 10,000 women.

Jackson RD, et al. N Engl J Med. 2006;354:669-683. Erratum in: N Engl J Med. 2006;354:1102.