New RANK ligant target reduces significant osteoporotic fractures

From NEJM

Background Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-B ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis.

Methods We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures.

Results As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001) — a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04) — a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) — a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab.

Conclusions Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791 [ClinicalTrials.gov] .)

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Don’t send asymptomatic diabetics with CAD for cath (BARI 2D)

according to this study (http://content.nejm.org/cgi/content/full/NEJMoa0805796v1).

Name Reminds me of a Starbucks “Barista” with a Double Shot espresso. Alert enough to remember this.

Revascularization with PCI or CABG is not superior to medical therapy in patients with diabetes and CAD. Beware of the exclusion criteria: “Patients were excluded if they required immediate revascularization or had left main coronary disease, a creatinine level of more than 2.0 mg per deciliter (177 µmol per liter), a glycated hemoglobin level of more than 13.0%, class III or IV heart failure, or hepatic dysfunction or if they had undergone PCI or CABG within the previous 12 months.”

Expert international committe supports HbA1c for diagnosis of diabetes

… but they seem not to care enough to publish a free abstract and people need to pay to read this (expept if your institutution has subscription).  What is the number? 6.5. Repeat testing necessary unless the pt has symptoms and glucose more than 200.

http://care.diabetesjournals.org/content/early/2009/06/01/dc09-9033.abstract

“If you don’t control your diabetes you will die of a heart attack” How true is this statement?

Partly, this meta-analysis from Lancet shows that intensive glucose control does prevent heart-events but does not affect mortality. Still pretty good reason to keep glucose tight.

quoting Lancet below

Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials

Background

Whether intensive control of glucose reduces macrovascular events and all-cause mortality in individuals with type 2 diabetes mellitus is unclear. We undertook a meta-analysis of randomised controlled trials to determine whether intensive treatment is beneficial.

How good is metformin with insulin? Excellent!

Long-term Effects of Metformin on Metabolism and Microvascular and Macrovascular Disease in Patients With Type 2 Diabetes Mellitus

Adriaan Kooy, MD, PhD; Jolien de Jager, MD; Philippe Lehert, PhD; Daniël Bets, MSc; Michiel G. Wulffelé, MD, PhD; Ab J. M. Donker, MD, PhD; Coen D. A. Stehouwer, MD, PhD

Arch Intern Med. 2009;169(6):616-625.

Background We investigated whether metformin hydrochloride has sustained beneficial metabolic and (cardio) vascular effects in patients with type 2 diabetes mellitus (DM2).

Methods We studied 390 patients treated with insulin in the outpatient clinics of 3 hospitals in a randomized, placebo-controlled trial with a follow-up period of 4.3 years. Either metformin hydrochloride, 850 mg, or placebo (1-3 times daily) was added to insulin therapy. The primary end point was an aggregate of microvascular and macrovascular morbidity and mortality. The secondary end points were microvascular and macrovascular morbidity and mortality, as separate aggregate scores. In addition, effects on hemoglobin A_1c (HbA_1c), insulin requirement, lipid levels, blood pressure, body weight, and body mass index were analyzed.

Results Metformin treatment prevented weight gain (mean weight gain, –3.07 kg [range, –3.85 to –2.28 kg]; P < .001), improved glycemic control (mean reduction in HbA_1c level, 0.4% percentage point [95% CI, 0.55-0.25]; P < .001) (where CI indicates confidence interval), despite the aim of similar glycemic control in both groups, and reduced insulin requirements (mean reduction, 19.63 IU/d [95% CI, 24.91-14.36 IU/d]; P < .001). Metformin was not associated with an improvement in the primary end point. It was, however, associated with an improvement in the secondary, macrovascular end point (hazard ratio, 0.61 (95% CI, 0.40-0.94; P = .02), which was partly explained by the difference in weight. The number needed to treat to prevent 1 macrovascular end point was 16.1 (95% CI, 9.2-66.6).

Conclusions Metformin, added to insulin in patients with DM2, improved body weight, glycemic control, and insulin requirements but did not improve the primary end point. Metformin did, however, reduce the risk of macrovascular disease after a follow-up period of 4.3 years. These sustained beneficial effects support the policy to continue metformin treatment after the introduction of insulin in any patient with DM2, unless contraindicated.

Targeting Glucose in the ICU NICE-SUGAR study

ABSTRACT

Background The optimal target range for blood glucose in critically ill patients remains unclear.

Methods Within 24 hours after admission to an intensive care unit (ICU), adults who were expected to require treatment in the ICU on 3 or more consecutive days were randomly assigned to undergo either intensive glucose control, with a target blood glucose range of 81 to 108 mg per deciliter (4.5 to 6.0 mmol per liter), or conventional glucose control, with a target of 180 mg or less per deciliter (10.0 mmol or less per liter). We defined the primary end point as death from any cause within 90 days after randomization.

Results Of the 6104 patients who underwent randomization, 3054 were assigned to undergo intensive control and 3050 to undergo conventional control; data with regard to the primary outcome at day 90 were available for 3010 and 3012 patients, respectively. The two groups had similar characteristics at baseline. A total of 829 patients (27.5%) in the intensive-control group and 751 (24.9%) in the conventional-control group died (odds ratio for intensive control, 1.14; 95% confidence interval, 1.02 to 1.28; P=0.02). The treatment effect did not differ significantly between operative (surgical) patients and nonoperative (medical) patients (odds ratio for death in the intensive-control group, 1.31 and 1.07, respectively; P=0.10). Severe hypoglycemia (blood glucose level, 40 mg per deciliter [2.2 mmol per liter]) was reported in 206 of 3016 patients (6.8%) in the intensive-control group and 15 of 3014 (0.5%) in the conventional-control group (P<0.001). There was no significant difference between the two treatment groups in the median number of days in the ICU (P=0.84) or hospital (P=0.86) or the median number of days of mechanical ventilation (P=0.56) or renal-replacement therapy (P=0.39).

Conclusions In this large, international, randomized trial, we found that intensive glucose control increased mortality among adults in the ICU: a blood glucose target of 180 mg or less per deciliter resulted in lower mortality than did a target of 81 to 108 mg per deciliter. (ClinicalTrials.gov number, NCT00220987 [ClinicalTrials.gov] .)

From: http://content.nejm.org/cgi/content/short/360/13/1283

Want to assess their fracture risk? Simple ask them about their balance.

The principal causal components of an osteoporotic fracture are a fall and weakened bone strength. While bone quality measures have been frequently studied, the ability of simple measures of impaired balance to predict fracture risk has received less attention. Computer-assisted telephone interviews were conducted between 1998 and 2000 among 24,598 Swedish twins aged 55 years or older. Impaired balance at the time of interview was reported by 2,890 (12%) of the twins. Twin pairs who were discordant with regard to impaired balance were selected for analysis and followed for fractures through 2005. In a pairwise analysis, the odds ratio for hip fracture was 3.13 (95% confidence interval (CI): 1.62, 6.05) among twins with impaired balance as compared with their co-twins with normal balance. When previously recognized clinical risk factors for osteoporotic fracture were considered in the model, the odds ratio for hip fracture with impaired balance was 3.88 (95% CI: 1.40, 10.72). Approximately 40% of all hip fractures were attributable to impaired balance. The odds ratios for any fracture and any osteoporotic fracture for twins with impaired balance were 2.00 (95% CI: 1.29, 3.11) and 2.39 (95% CI: 1.49, 3.82), respectively. These results imply that self-reported impaired balance is a novel and readily assessed risk factor for future fractures in the elderly.

Link to the full article

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