Robert G. Josse

Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial.

BACKGROUND The worldwide increase in type 2 diabetes mellitus is becoming a major health concern. We aimed to assess the effect of acarbose in preventing or delaying conversion of impaired glucose tolerance to type 2 diabetes. METHODS In a multicentre, placebo-controlled randomised trial, we randomly allocated patients with impaired glucose tolerance to 100 mg acarbose or placebo three times daily. The primary endpoint was development of diabetes on the basis of a yearly oral glucose tolerance test (OGTT). Analyses were by intention to treat. FINDINGS We randomly allocated 714 patients with impaired glucose tolerance to acarbose and 715 to placebo. We excluded 61 (4%) patients because they did not have impaired glucose tolerance or had no postrandomisation data. 211 (31%) of 682 patients in the acarbose group and 130 (19%) of 686 on placebo discontinued treatment early. 221 (32%) patients randomised to acarbose and 285 (42%) randomised to placebo developed diabetes (relative hazard 0.75 [95% CI 0.63-0.90]; p=0.0015). Furthermore, acarbose significantly increased reversion of impaired glucose tolerance to normal glucose tolerance (p<0.0001). At the end of the study, treatment with placebo for 3 months was associated with an increase in conversion of impaired glucose tolerance to diabetes. The most frequent side-effects to acarbose treatment were flatulence and diarrhoea. INTERPRETATION Acarbose could be used, either as an alternative or in addition to changes in lifestyle, to delay development of type 2 diabetes in patients with impaired glucose tolerance.

Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes

BACKGROUND Data are lacking on the long-term effect on cardiovascular events of adding sitagliptin, a dipeptidyl peptidase 4 inhibitor, to usual care in patients with type 2 diabetes and cardiovascular disease. METHODS In this randomized, double-blind study, we assigned 14,671 patients to add either sitagliptin or placebo to their existing therapy. Open-label use of antihyperglycemic therapy was encouraged as required, aimed at reaching individually appropriate glycemic targets in all patients. To determine whether sitagliptin was noninferior to placebo, we used a relative risk of 1.3 as the marginal upper boundary. The primary cardiovascular outcome was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina. RESULTS During a median follow-up of 3.0 years, there was a small difference in glycated hemoglobin levels (least-squares mean difference for sitagliptin vs. placebo, -0.29 percentage points; 95% confidence interval [CI], -0.32 to -0.27). Overall, the primary outcome occurred in 839 patients in the sitagliptin group (11.4%; 4.06 per 100 person-years) and 851 patients in the placebo group (11.6%; 4.17 per 100 person-years). Sitagliptin was noninferior to placebo for the primary composite cardiovascular outcome (hazard ratio, 0.98; 95% CI, 0.88 to 1.09; P<0.001). Rates of hospitalization for heart failure did not differ between the two groups (hazard ratio, 1.00; 95% CI, 0.83 to 1.20; P=0.98). There were no significant between-group differences in rates of acute pancreatitis (P=0.07) or pancreatic cancer (P=0.32). CONCLUSIONS Among patients with type 2 diabetes and established cardiovascular disease, adding sitagliptin to usual care did not appear to increase the risk of major adverse cardiovascular events, hospitalization for heart failure, or other adverse events. (Funded by Merck Sharp & Dohme; TECOS ClinicalTrials.gov number, NCT00790205.).

INTERMITTENT ETIDRONATE THERAPY TO PREVENT CORTICOSTEROID- INDUCED OSTEOPOROSIS

BACKGROUND AND METHODS Osteoporosis is a recognized complication of corticosteroid therapy. Whether it can be prevented is not known. We conducted a 12-month, randomized, placebo-controlled study of intermittent etidronate (400 mg per day for 14 days) followed by calcium (500 mg per day for 76 days), given for four cycles, in 141 men and women (age, 19 to 87 years) who had recently begun high-dose corticosteroid therapy. The primary outcome measure was the difference in the change in the bone density of the lumbar spine between the groups from base line to week 52. Secondary measures included changes in the bone density of the femoral neck, trochanter, and radius and the rate of new vertebral fractures. RESULTS The mean (+/-SE) bone density of the lumbar spine and trochanter in the etidronate group increased 0.61 +/- 0.54 and 1.46 +/- 0.67 percent, respectively, as compared with decreases of 3.23 +/- 0.60 and 2.74 +/- 0.66 percent, respectively, in the placebo group. The mean differences between the groups after one year were 3.72 +/- 0.88 percentage points for the lumbar spine (P = 0.02) and 4.14 +/- 0.94 percentage points for the trochanter (P = 0.02). The changes in the femoral neck and the radius were not significantly different between the groups. There was an 85 percent reduction in the proportion of postmenopausal woman with new vertebral fractures in the etidronate group as compared with the placebo group (1 of 31 patients vs. 7 of 32 patients, P = 0.05), and the etidronate-treated postmenopausal women also had significantly fewer vertebral fractures per patient (P = 0.04). CONCLUSIONS Intermittent etidronate therapy prevents the loss of vertebral and trochanteric bone in corticosteroid-treated patients.

IOF position statement: vitamin D recommendations for older adults

This position paper of the International Osteoporosis Foundation makes recommendations for vitamin D nutrition in elderly men and women from an evidence-based perspective.

Nibbling versus Gorging: Metabolic Advantages of Increased Meal Frequency

We studied the effect of increasing the frequency of meals on serum lipid concentrations and carbohydrate tolerance in normal subjects. Seven men were assigned in random order to two metabolically identical diets. One diet consisted of 17 snacks per day (the nibbling diet), and the other of three meals per day (the three-meal diet); each diet was followed for two weeks. As compared with the three-meal diet, the nibbling diet reduced fasting serum concentrations of total cholesterol, low-density lipoprotein cholesterol, and apolipoprotein B by a mean (+/- SE) of 8.5 +/- 2.5 percent (P less than 0.02), 13.5 +/- 3.4 percent (P less than 0.01), and 15.1 +/- 5.7 percent (P less than 0.05), respectively. Although the mean blood glucose level and serum concentrations of free fatty acids, 3-hydroxybutyrate, and triglyceride were similar during both diets, during the nibbling diet the mean serum insulin level decreased by 27.9 +/- 6.3 percent (P less than 0.01) and the mean 24-hour urinary C-peptide output decreased by 20.2 +/- 5.6 percent (P less than 0.02). In addition, the mean 24-hour urinary cortisol excretion was lower by 17.3 +/- 5.9 percent (P less than 0.05) at the end of the nibbling diet than at the end of the three-meal diet. The blood glucose, serum insulin, and C-peptide responses to a standardized breakfast and the results of an intravenous glucose-tolerance test conducted at the end of each diet were similar. We conclude that in addition to the amount and type of food eaten, the frequency of meals may be an important determinant of fasting serum lipid levels, possibly in relation to changes in insulin secretion.

Effect of a Low–Glycemic Index or a High–Cereal Fiber Diet on Type 2 Diabetes: A Randomized Trial

CONTEXT Clinical trials using antihyperglycemic medications to improve glycemic control have not demonstrated the anticipated cardiovascular benefits. Low-glycemic index diets may improve both glycemic control and cardiovascular risk factors for patients with type 2 diabetes but debate over their effectiveness continues due to trial limitations. OBJECTIVE To test the effects of low-glycemic index diets on glycemic control and cardiovascular risk factors in patients with type 2 diabetes. DESIGN, SETTING, AND PARTICIPANTS A randomized, parallel study design at a Canadian university hospital research center of 210 participants with type 2 diabetes treated with antihyperglycemic medications who were recruited by newspaper advertisement and randomly assigned to receive 1 of 2 diet treatments each for 6 months between September 16, 2004, and May 22, 2007. INTERVENTION High-cereal fiber or low-glycemic index dietary advice. MAIN OUTCOME MEASURES Absolute change in glycated hemoglobin A(1c) (HbA(1c)), with fasting blood glucose and cardiovascular disease risk factors as secondary measures. RESULTS In the intention-to-treat analysis, HbA(1c) decreased by -0.18% absolute HbA(1c) units (95% confidence interval [CI], -0.29% to -0.07%) in the high-cereal fiber diet compared with -0.50% absolute HbA(1c) units (95% CI, -0.61% to -0.39%) in the low-glycemic index diet (P < .001). There was also an increase of high-density lipoprotein cholesterol in the low-glycemic index diet by 1.7 mg/dL (95% CI, 0.8-2.6 mg/dL) compared with a decrease of high-density lipoprotein cholesterol by -0.2 mg/dL (95% CI, -0.9 to 0.5 mg/dL) in the high-cereal fiber diet (P = .005). The reduction in dietary glycemic index related positively to the reduction in HbA(1c) concentration (r = 0.35, P < .001) and negatively to the increase in high-density lipoprotein cholesterol (r = -0.19, P = .009). CONCLUSION In patients with type 2 diabetes, 6-month treatment with a low-glycemic index diet resulted in moderately lower HbA(1c) levels compared with a high-cereal fiber diet. Trial Registration clinicaltrials.gov identifier: NCT00438698.

Relation between fractures and mortality: results from the Canadian Multicentre Osteoporosis Study

Background: Fractures have largely been assessed by their impact on quality of life or health care costs. We conducted this study to evaluate the relation between fractures and mortality. Methods: A total of 7753 randomly selected people (2187 men and 5566 women) aged 50 years and older from across Canada participated in a 5-year observational cohort study. Incident fractures were identified on the basis of validated self-report and were classified by type (vertebral, pelvic, forearm or wrist, rib, hip and “other”). We subdivided fracture groups by the year in which the fracture occurred during follow-up; those occurring in the fourth and fifth years were grouped together. We examined the relation between the time of the incident fracture and death. Results: Compared with participants who had no fracture during follow-up, those who had a vertebral fracture in the second year were at increased risk of death (adjusted hazard ratio [HR] 2.7, 95% confidence interval [CI] 1.1–6.6); also at risk were those who had a hip fracture during the first year (adjusted HR 3.2, 95% CI 1.4–7.4). Among women, the risk of death was increased for those with a vertebral fracture during the first year (adjusted HR 3.7, 95% CI 1.1–12.8) or the second year of follow-up (adjusted HR 3.2, 95% CI 1.2–8.1). The risk of death was also increased among women with hip fracture during the first year of follow-up (adjusted HR 3.0, 95% CI 1.0–8.7). Interpretation: Vertebral and hip fractures are associated with an increased risk of death. Interventions that reduce the incidence of these fractures need to be implemented to improve survival.

Bisphosphonate Associated Osteonecrosis of the Jaw

In 2003, the first reports describing osteonecrosis of the jaw (ONJ) in patients receiving bisphosphonates (BP) were published. These cases occurred in patients with cancer receiving high-dose intravenous BP; however, 5% of the cases were in patients with osteoporosis receiving low-dose bisphosphonate therapy. We present the results of a systematic review of the incidence, risk factors, diagnosis, prevention, and treatment of BP associated ONJ. We conducted a comprehensive literature search for relevant studies on BP associated ONJ in oncology and osteoporosis patients published before February 2008.All selected relevant articles were sorted by area of focus. Data for each area were abstracted by 2 independent reviewers. The results showed that the diagnosis is made clinically. Prospective data evaluating the incidence and etiologic factors are very limited. In oncology patients receiving high-dose intravenous BP, ONJ appears to be dependent on the dose and duration of therapy, with an estimated incidence of 1%–12% at 36 months of exposure. In osteoporosis patients, it is rare, with an estimated incidence < 1 case per 100,000 person-years of exposure. The incidence of ONJ in the general population is not known. Currently, there is insufficient evidence to confirm a causal link between low-dose BP use in the osteoporosis patient population and ONJ. We concluded BP associated ONJ is associated with high-dose BP therapy primarily in the oncology patient population. Prevention and treatment strategies are currently based on expert opinion and focus on maintaining good oral hygiene and conservative surgical intervention.

Low bone mineral density and fracture burden in postmenopausal women

Background: The study objectives were to determine fracture rates in relation to bone mineral density at various central skeletal sites, using the World Health Organization definition for osteoporosis (T-score –2.5 or less), and to contrast fracture patterns among women 50 to 64 years of age with those among women 65 years of age and older. Methods: Historical cohort study with a mean observation period of 3.2 (standard deviation [SD] 1.5) years. The study group (16 505 women 50 years of age or older) was drawn from the Manitoba Bone Density Program database, which includes all bone mineral density results for Manitoba. Baseline density measurements for the lumbar spine and hip were performed with dual-energy x-ray absorptiometry. Outcomes included the percentage of osteoporotic fractures and the rates of fracture and excess fracture (per 1000 person-years) among postmenopausal women with osteopenia and osteoporosis relative to those with normal bone mineral density (according to the classification of the World Health Organization). Results: The mean age was 65 (SD 9) years, and the mean T-scores for all sites fell within the osteopenic category. There were 765 incident fractures (fracture rate 14.5 [95% confidence interval, CI, 13.5–15.6 [per 1000 person-years). Fracture rates were significantly higher among women 65 years of age or older than among women 50–64 years of age (21.6 [95% CI 19.7–23.4] v. 8.6 [95% CI 7.5–9.7] per 1000 person-years, p < 0.001). Although fracture rates were significantly higher among women with osteoporotic T-scores, most fractures occurred in women with nonosteoporotic values (min–max: 59.7%–67.8%). Interpretation: In this study, most of the postmenopausal women with osteoporotic fractures had nonosteoporotic bone mineral density values. This finding highlights the importance of considering key clinical risk factors that operate independently of bone mineral density (such as age) when assessing fracture risk.

Beneficial Effect of Low-Glycemic Index Diet in Overweight NIDDM Subjects

Objectives To determine whether low-glycemic index (GI) diets have clinical utility in overweight patients with non-insulin-dependent diabetes mellitus (NIDDM). Research Design and Methods Six patients with NIDDM were studied on both high- and low-GI diets of 6-wk duration with metabolic diets with a randomized crossover design. Both diets were of similar composition (57% carbohydrate, 23% fat, and 34 g/day dietary fiber), but the low-GI diet had a GI of 58 compared with 86 for the high-GI diet. Results Small and similar amounts of weight were lost on both diets: 2.5 kg on high-GI diet and 1.8 kg on low-GI diet. On the low-GI diet, the mean level of serum fructosamine, as an index of overall blood glucose control, was lower than on the high-GI diet by 8% (P <0.05), and total serum cholesterol was lower by 7% (P <0.01). Conclusions In overweight patients with NIDDM, reducing diet GI improves overall blood glucose and lipid control.