Clinical Question:
Does metformin slow the progression of puberty and increase the adult height of girls with history of low birth weight and early-normal onset of puberty?

Bottom Line:
Metformin treatment for 36 months in LBW girls with early-normal puberty normalized their pubertal progression to menarche and increased height gains up to adult stature. These data support the concept that insulin is a major codeterminant of the pubertal tempo and pubertal height gain in girls.

Reference:
Ibanez L, Valls C, Ong K, Dunger DB, de Zegher F. Metformin therapy during puberty delays menarche, prolongs pubertal growth, and augments adult height: a randomized study in low-birth-weight girls with early-normal onset of puberty. J Clin Endocrinol Metabol 2006;91:2068-2073.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
Hyperinsulinemia and insulin resistance in girls with history of LBW is thought to play a role in early onset of puberty. This study conducted in Spain enrolled 22 girls with history of LBW and onset of puberty in the early-normal age range of 8 to 9 years. LBW was defined as less than 1.5 standard deviation (SD) score for gestational age, which is less than 2.8 kg at term for the corresponding population. Onset of puberty was defined as Tanner stage 2 breast development, and had to occur at age 8 years or 9 years and within 1 year prior to enrollment in the study. Additional criteria for enrollment included height at enrollment of at least 1 SD above mid-parental height for chronological age and bone age of at least 1 SD above chronological age. Girls were excluded if they had personal or family history of diabetes or precocious puberty, signs of androgen excess, evidence of thyroid dysfunction, glucose intolerance, or were taking a medication that could affect gonadal function or carbohydrate metabolism. Treatment consisted of once-daily metformin 850 mg at dinnertime or no treatment. Assessments were made at 6-month intervals for a 36-month treatment period, and for an additional 6 months after the treatment stopped. Treated girls had a mean height gain of 3.5 cm more than untreated girls by the study’s conclusion (19.5 cm vs 16.0 cm; P < .01). Since treated girls still had a higher height velocity in the final observation interval, it is expected that adult height gains will be even greater. Treated girls also had a longer time to menarche by a mean of 1 year (3 yearsr vs 2 years; P < .01) and a leaner body composition. Treatment was well tolerated and there were no cases of abnormality of liver function or kidney function during the study.

Clinical Question:
In patients with type 2 diabetes, does fenofibrate prevent coronary events?

Bottom Line:
Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations. The higher rate of starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit.

Reference:
Keech A, Simes RJ, Barter P, et al, for the FIELD study investigators. Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial. Lancet 2005;366:1849-61.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing to dyslipidaemia, which can be amenable to fibrate therapy. We designed the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study to assess the effect of fenofibrate on cardiovascular disease events in these patients. They did a multinational, randomised controlled trial with 9795 participants aged 50-75 years, with type 2 diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, we randomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total-cholesterol concentration of 3.0-6.5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4.0 or more or plasma triglyceride of 1.0-5.0 mmol/L to micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900). Our primary outcome was coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecified subgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke, and coronary and carotid revascularisation). Analysis was by intention to treat. The study was prospectively registered (number ISRCTN 64783481). Vital status was confirmed on all but 22 patients. Averaged over the 5 years’ study duration, similar proportions in each group discontinued study medication (10% placebo vs 11% fenofibrate) and more patients allocated placebo (17%) than fenofibrate (8%; p<0.0001) commenced other lipid treatments, predominantly statins. 5.9% (n=288) of patients on placebo and 5.2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazard ratio [HR] 0.89, 95% CI 0.75-1.05; p=0.16). This finding corresponds to a significant 24% reduction in non-fatal myocardial infarction (0.76, 0.62-0.94; p=0.010) and a non-significant increase in coronary heart disease mortality (1.19, 0.90-1.57; p=0.22). Total cardiovascular disease events were significantly reduced from 13.9% to 12.5% (0.89, 0.80-0.99; p=0.035). This finding included a 21% reduction in coronary revascularisation (0.79, 0.68-0.93; p=0.003). Total mortality was 6.6% in the placebo group and 7.3% in the fenofibrate group (p=0.18). Fenofibrate was associated with less albuminuria progression (p=0.002), and less retinopathy needing laser treatment (5.2%vs 3.6%, p=0.0003). There was a slight increase in pancreatitis (0.5%vs 0.8%, p=0.031) and pulmonary embolism (0.7%vs 1.1%, p=0.022), but no other significant adverse effects.

Clinical Question:
How should diabetes be managed in patients who choose to fast during Ramadan?

Bottom Line:
These expert-derived guidelines (there is little study in this area) outline prudent methods of managing Muslim patients with type 2 diabetes who insist on fasting during Ramadan. Details are outlined in the synopsis; see the original paper for managing patients with type 1 diabetes or who are pregnant.

Reference:
Al-arouj M, Bouguerra R, Buse J, et al. Recommendations for management of diabetes during Ramadan. Diabetes Care 2005;28:2305-11.

Study Design:
Practice guideline

Funding:
Industry + govt

Setting:
Various (guideline)

Synopsis:
Fasting during the holy month of Ramadan is an obligatory duty for all healthy adult Muslims. During Ramadan, Muslims will abstain from eating, drinking, and taking oral medications from predawn until after sunset. Most people eat one meal after sunset and the other just before dawn. Although patients with diabetes are exempt from fasting since it might place them at risk for complications, many patients will insist on fasting. As would be expected, hypoglycemia, hyperglycemia, diabetic ketoacidosis, and dehydration and thrombosis are associated with fasting. No research has been conducted to stratify patients by risk for complications or for providing guidance for management; these guidelines are based on expert opinion. Patients at high risk for complications should frequently monitor glucose levels during the day and must end their fast if hypoglycemia occurs (that is, less than 60 mg/dL (3.3 mmol/l) at any time, or less than 70 mg/dL (3.9 mmol/L) in the first few hours of a fast). Also, the fast should be broken if the blood glucose exceeds 300 mg/dL (16.7 mmol/l). Fasting should not occur on “sick days.” Patients taking metformin (Glucophage) should take two thirds of the daily dose before the sunset meal and the remaining one third before the predawn meal. No change is required for the glitazones. Sulfonylureas may be taken with the sunset meal, with the dose adjusted based on the risk of hypoglycemia. Twice-daily sulfonylureas should be given as half the normal dose before the predawn meal and the full dose at the sunset meal. Chlorpropamide should never be used. Repaglinide and nateglinide may be used before each meal. Insulin can be given once daily with the sunset meal or individualized and given twice daily, with the larger dose given with the sunset meal.