Clinical Health Updates

Diet, exercise, drugs may prevent diabetes in high-risk patients

Clinical Question:
Can the onset of diabetes be delayed or prevented in people with impaired glucose tolerance?

Bottom Line:
Diet, exercise, or diet and exercise changes, at least those in study situations, will slow the progression of diabetes by approximately 50% in patients with impaired glucose tolerance. Drug therapy with either oral diabetes drugs or the weight loss drug orlistat (Xenical) will also slow progression. The preventive effect of the drugs is not maintained when they are stopped, and research has not been conducted for long enough to determine whether diabetes onset is prevented or just delayed.

Reference:
Gillies CL, Abrams KR, Lambert PC, et al. Pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance: systematic review and meta-analysis. BMJ 2007;334:299.

Study Design:
Systematic review

Synopsis:
To quantify the effectiveness of pharmacological and lifestyle interventions to prevent or delay type 2 diabetes in people with impaired glucose tolerance. The authors searched on Medline, Embase, and the Cochrane library up to July 2006. Expert opinions sought and reference lists of identified studies and any relevant published reviews had been checked. Randomised controlled trials that evaluated interventions to delay or prevent type 2 diabetes in individuals with impaired glucose tolerance. 21 trials met the inclusion criteria, of which 17, with 8084 participants with impaired glucose tolerance, reported results in enough detail for inclusion in the meta-analyses. From the meta-analyses the pooled hazard ratios were 0.51 (95% confidence interval 0.44 to 0.60) for lifestyle interventions v standard advice, 0.70 (0.62 to 0.79) for oral diabetes drugs v control, 0.44 (0.28 to 0.69) for orlistat v control, and 0.32 (0.03 to 3.07) for the herbal remedy jiangtang bushen recipe v standard diabetes advice. These correspond to numbers needed to treat for benefit (NNTB) and harm (NNTH) of 6.4 for lifestyle (95% credible interval, NNTB 5.0 to NNTB 8.4), 10.8 for oral diabetes drugs (NNTB 8.1 to NNTB 15.0), 5.4 for orlistat (NNTB 4.1 to NNTB 7.6), and 4.0 for jiangtang bushen (NNTH 16.9 to NNTB 24.8).

Chromium treatment has no effect in Patients with Type 2 Diabetes Mellitus

Clinical Question:
Does Chromium treatment improve glycemic control in patients with type 2 diabetes?

Bottom Line:
There is no evidence that chromium in the form of chromium yeast is effective in improving glycemic control in western patients with type 2 diabetes who are taking oral hypoglycemic agents

Reference:
Chromium treatment has no effect in Patients with Type 2 Diabetes Mellitus in a Western Population: A Randomized, Double-Blind, Placebo-Controlled Trial. Kleefstra N, Houweling ST, Bakker SJ, Verhoeven S, Gans RO, Meyboom-de Jong B, Bilo HJ. Diabetes Centre, Isala Clinics, Zwolle, The Netherlands.Diabetes Care. 2007 Feb 15

Study Design:
Randomized Controlled Trial (Double-Blind)

Synopsis:
Chromium treatment has been reported to improve glycemic control in patients with type 2 diabetes. However, concern exists about possible toxic effects of chromium picolinate. The authors determined the effect of chromium treatment in the form of chromium yeast on glycemic control in a western population of patients with type 2 diabetes who were being treated with oral hypoglycemic agents. In this 6-month, double-blind study, patients with moderate glycemic control, being treated with oral hypoglycemic agents, were randomly assigned to receive either a placebo or treatment with 400 mug of chromium daily in the form of chromium yeast. The primary efficacy parameter was a change in HbA1c. Secondary endpoints were changes in lipid profile, BMI, blood pressure, body fat, and insulin resistance. No differences were found for the change in HbA1c between the intervention and placebo groups. Nor were any differences found between the groups for the secondary endpoints.

Duloxetine decreases pain of diabetic neuropathy

Clinical Question:
Does duloxetine reduce pain in patients with diabetic peripheral neuropathy?

Bottom Line:
This study confirms previous findings that duloxetine at 60 mg QD and 60 mg BID is effective and safe in the management of diabetic peripheral neuropathic pain.Higher doses of duloxetine didn’t provide much additional benefit. The biases in this study favor treatment, so it is likely that the real benefit is less than what these investigators observed. Finally, we don’t know if duloxetine is any more effective than other treatments used for painful diabetic neuropathy.

Reference:
Wernicke JF, Pritchett YL, D’Souza DN, et al. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Neurology 2006;67:1411-1420.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Serotonin (5-HT) and norepinephrine (NE) are involved in pain modulation via descending inhibitory pathways in the brain and spinal cord. The authors assess the efficacy of duloxetine, a dual reuptake inhibitor of 5-HT and NE, on the reduction of pain severity, as well as secondary outcome measures in patients with diabetic peripheral neuropathic pain (DPNP). In this double-blind study, patients with DPNP and without comorbid depression were randomly assigned to treatment with duloxetine 60 mg once daily (QD), duloxetine 60 mg twice daily (BID), or placebo for 12 weeks. The primary outcome measure was the weekly mean score of 24-hour average pain severity on the 11-point Likert scale. Secondary measures and health outcome measures were also assessed. Duloxetine 60 mg QD and 60 mg BID demonstrated improvement in the management of DPNP and showed rapid onset of action, with separation from placebo beginning at week 1 on the 24-hour average pain severity score. For all secondary measures for pain (except allodynia), mean changes showed an advantage of duloxetine over placebo, with no significant difference between 60 mg QD and 60 mg BID. Clinical Global Impression of Severity and Patient’s Global Impression of Improvement evaluation demonstrated greater improvement on duloxetine- vs placebo-treated patients. Duloxetine showed no notable interference on diabetic controls, and both doses were safely administered.

Treating prediabetes does not affect progression

Clinical Question:
Does treatment of postprandial hyperglycemia in patients with early, asymptomatic diabetes delay progression to frank fasting hyperglycemia?

Bottom Line:
The jury is still out regarding the identification and treatment of patients with prediabetes. According to this study, a similar percentage of patients with early diabetes will develop frank diabetes whether or not they receive therapy to lower postprandial glucose levels. A larger, though shorter, study has shown a difference, but it looks like early benefit is lost over time. Ameliorating postprandial hyperglycemia did not appear to delay progression of early type 2 diabetes. Factors other than postprandial hyperglycemia may be greater determinants of progression of diabetes. Alternatively, once FPG exceeds 126 mg/dl, beta-cell failure may no longer be remediable.

Reference:
Kirkman MS, Shankar RR, Shankar S. Treating postprandial hyperglycemia does not appear to delay progression of early type 2 diabetes. Diabetes Care 2006;29:2095-2101.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
Postprandial hyperglycemia characterizes early type 2 diabetes. Researcher investigated whether ameliorating postprandial hyperglycemia with acarbose would prevent or delay progression of diabetes, defined as progression to frank fasting hyperglycemia, in subjects with early diabetes (fasting plasma glucose [FPG] <140> or =200 mg/dl). Two hundred nineteen subjects with early diabetes were randomly assigned to 100 mg acarbose t.i.d. or identical placebo and followed for 5 years or until they reached the primary outcome (two consecutive quarterly FPG measurements of > or =140 mg/dl). Secondary outcomes included measures of glycemia (meal tolerance tests, HbA(1c), annual oral glucose tolerance tests [OGTTs]), measures of insulin resistance (homeostasis model assessment [HOMA] of insulin resistance and insulin sensitivity index from hyperglycemic clamps), and secondary measures of beta-cell function (HOMA-beta, early- and late-phase insulin secretion, and proinsulin-to-insulin ratio). Acarbose significantly reduced postprandial hyperglycemia. However, there was no difference in the cumulative rate of frank fasting hyperglycemia (29% with acarbose and 34% with placebo; P = 0.65 for survival analysis). There were no significant differences between groups in OGTT values, measures of insulin resistance, or secondary measures of beta-cell function. In a post hoc analysis of subjects with initial FPG <126> or =126 mg/dl (27 vs. 50%; P = 0.04).

Rosiglitazone delays developing DM (DREAM)

Clinical Question:
Does rosiglitazone delay the development of diabetes in patients with impaired glucose tolerance or impaired fasting glucose levels?

Bottom Line:
Rosiglitazone at 8 mg daily for 3 years substantially reduces incident type 2 diabetes and increases the likelihood of regression to normoglycaemia in adults with impaired fasting glucose or impaired glucose tolerance, or both.

Reference:
DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators; Gerstein HC, Yusuf S, Bosch J, et al. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006;368:1096-1105.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Rosiglitazone is a thiazolidinedione that reduces insulin resistance and might preserve insulin secretion. The authors assessed prospectively the drug’s ability to prevent type 2 diabetes in individuals at high risk of developing the condition. 5269 adults aged 30 years or more with impaired fasting glucose or impaired glucose tolerance, or both, and no previous cardiovascular disease were recruited from 191 sites in 21 countries and randomly assigned to receive rosiglitazone (8 mg daily; n=2365) or placebo (2634) and followed for a median of 3 years. The primary outcome was a composite of incident diabetes or death. Analyses were done by intention to treat. This trial is registered at ClinicalTrials.gov, number NCT00095654. At the end of study, 59 individuals had dropped out from the rosiglitazone group and 46 from the placebo group. 306 (11.6%) individuals given rosiglitazone and 686 (26.0%) given placebo developed the composite primary outcome (hazard ratio 0.40, 95% CI 0.35-0.46; p<0.0001); 1330 (50.5%) individuals in the rosiglitazone group and 798 (30.3%) in the placebo group became normoglycaemic (1.71, 1.57-1.87; p<0.0001). Cardiovascular event rates were much the same in both groups, although 14 (0.5%) participants in the rosiglitazone group and two (0.1%) in the placebo group developed heart failure (p=0.01).

Carotid Intima-Media Thickness in Atherosclerosis Using Pioglitazone

Clinical Question:
Does treatment with pioglitazone reduced Carotid Intima-Media Thickness (CIMT) compared with glimepiride among patients with type 2 diabetes.

Bottom Line:
Among patients with type 2 diabetes, treatment with pioglitazone for 18 months was associated with a reduction in CIMT progression compared with glimepiride.

Diabetics are at higher risk of development of cardiovascular disease. The effect of the slowing of CIMT progression with pioglitazone over glimepiride on clinical outcomes is not known from the present study, given the small sample size and low event rate.

A much larger trial would be necessary to evaluate the clinical efficacy of these therapies. The recent PROactive study demonstrated a reduction in death, MI, or stroke, but no significant difference in the primary endpoint with pioglitazone over placebo plus usual care, but large clinical studies of two active therapies are not yet available. Results of the present study are similar to those by Langenfeld et al., who also showed pioglitazone was associated with a greater reduction in carotid IMT at 24 weeks compared with glimepiride in diabetic patients.

Reference:
Mazzone T, et al. Effect of Pioglitazone Compared With Glimepiride on Carotid Intima-Media Thickness in Type 2 Diabetes. JAMA 2006;296:epub before print.
Presented by Dr. Theodore Mazzone at the American Heart Association Annual Scientific Sessions, Chicago, IL, November 2006.

Study Design:
Randomized. Blinded

Synopsis:
The goal of the trial was to evaluate the effect of treatment with pioglitazone compared with glimepiride on carotid artery intima-media thickness (CIMT) among patients with type 2 diabetes.Patients were randomized in a double-blind manner to pioglitazone (15-45 mg/d; n = 232) or glimepiride (1-4 mg/d; n = 230). Patients were treated for 72 weeks and study drugs were titrated to maintain glycemic goals of fasting glucose ≤140 mg/dl. Patients underwent carotid artery ultrasound at baseline and 24-, 48-, and 72-week follow-up. A single reviewer blinded to treatment assignment analyzed the ultrasounds. The study was completed in 68% of the pioglitazone group and 72% of the glimepiride group. Baseline mean HbA1c was 7.4% and fasting plasma glucose was 150 mg/dl. Average duration of diabetes was 7.7 years. Oral diabetic treatment regimen was used in 90% of patients at baseline. Baseline CIMT was 0.771 mm for pioglitazone and 0.779 mm for glimepiride.The primary endpoint of mean change in CIMT at 72 weeks was smaller with pioglitazone compared with glimepiride (-0.001 mm vs. +0.012 mm, p = 0.02). Results were similar at 24 and 48 weeks. Maximum CIMT was also smaller with pioglitazone compared with glimepiride (0.002 mm vs. 0.026 mm, p = 0.008). Absolute difference in HbA1c levels at final visit between the pioglitazone and glimepiride groups was -0.32% (p = 0.002). For high-density lipoprotein cholesterol levels at final visit, the absolute difference was 6.4 mg/dl higher with pioglitazone (p < 0.001). The composite of cardiovascular death, myocardial infarction (MI), stroke, coronary revascularization, carotid intervention, or hospitalization for unstable angina or congestive heart failure occurred in 1.7% of the pioglitazone group and 4.4% of the glimepiride group. Adverse events leading to study drug discontinuation were similar between groups (11.3% for pioglitazone vs. 8.3% for glimepiride). Weight gain was higher in the pioglitazone group (3.2 kg vs. 1.0 kg, p < 0.001). Peripheral edema was also more common with pioglitazone (13.0% vs. 7.0%).

Effectiveness and efficacy of self-measurement of capillary blood glucose in patients with type 2 diabetes mellitus

Clinical Question:
Is self-measurement of capillary blood glucose (SMBG) in patients with type 2 diabetes mellitus effective and efficient?

Bottom Line:
SMBG is a tool that, although can improve the metabolic control of type 2 diabetes, requires a careful selection of patients and, therefore, cannot be utilized in an indiscriminate way. The time of evolution of the illness and fundamentally, the presence of a deficient metabolic control of the disease should be the factors that determine a good selection. Therefore, its extended use among the type 2 diabetic population, without a prior selection, does not seem to be justified.

Reference:
Effectiveness and efficacy of self-measurement of capillary blood glucose in patients with type 2 diabetes mellitus Oria-Pino A, Montero-Perez FJ, Luna-Morales S, del Campo-Vazquez P, Sanchez-Guijo P. Med Clin (Barc). 2006 May 20;126(19):728-35

Study Design:
Randomized controlled trial

Synopsis:
The efficacy of self-measurement of capillary blood glucose (SMBG) in patients with type 2 diabetes mellitus is not fully established.

  • The objectives of the study were:
  1. to verify the efficacy of the SMBG in patients with type 2 diabetes mellitus in the primary care set
  2. to investigate the possible causes that explain the lack of effectiveness of the method, in their case, and
  3. to deduce the predictive variables that permit to select good utilizador of the SMBG.

Clinical trial controlled and randomized carried out in the environment of the primary care, on type 2 diabetic patients. The patients were assigned, of random form and stratified, according to the type of treatment for diabetes that received, in 2 groups: SMBG group (SMBG-G) and control group (CG). The period of monitoring was of 12 months. The efficacy of the SMBG was analyzed, and also its effectiveness. 100 patients were included in the study. Out of them, 51 were assigned to SMBG-G and 49 to CG. The SMBG was efficient in the 21.6% of SMBG-G and in 14.3% patients of the CG (p = 0.44). The SMBG efficacy was greater in patients with combined treatment and in those who received only insulin (50% in both cases). No improvement was observed in patients on treatment with diet (p = 0.006). The effectiveness for the cut off from value the HbA1c was of 59.2% and of 29.58% for the totality of the European criteria of metabolic control. The independent predictor variables of the SMBG efficacy were: the evolution years number of the diabetes mellitus and a deficient control of the illness at the start of the study. The global precision of the mathematical model obtained was of 88.24% with sensibility of 54.5%, especificity of 97.5%, positive predictor value of 85.7% and negative predictive value of 11.4% (p < 0.001). The area under the ROC curve was of 89.9% (p < 0.001) (95% confidence interval, 81.2-98.5%). According to the ROC curve, the point of cut that better the SMBG efficacy discriminated was that of 74% (sensibility: 72.7%; especificity: 77.5%).

Rapid HbA1C testing doesn’t improve outcomes or save money

Clinical Question:
Does a rapid assay for glycated hemoglobin improve outcomes and save money?

Bottom Line:
Rapid testing of glycated hemoglobin in office settings does not save money or improve glycemic control compared with usual care.

Reference:
Khunti K, Stone MA, Burden AC, et al. Randomised controlled trial of near-patient testing for glycated haemoglobin in people with type 2 diabetes mellitus. Br J Gen Pract 2006;56:511-17.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
Tight glycaemic control in people with type 2 diabetes can lead to a reduction in microvascular and possibly macrovascular complications. The use of near-patient (rapid) testing offers a potential method to improve glycaemic control. To assess the effect and costs of rapid testing for glycated haemoglobin (HbA1c) in people with type 2 diabetes. The authors did a pragmatic open randomised controlled trial to eight practices in Leicestershire, UK. Patients were randomised to receive instant results for HbA1c or to routine care. The principal outcome measure was the proportion of patients with an HbA1c <7% at 12 months. We also assessed costs for the two groups. Of the 681 patients recruited to the study 638 (94%) were included in the analysis. The mean age at baseline was 65.7 years (SD = 10.8 years) with a median (interquartile range) duration of diabetes of 4(1-8) years. The proportion of patients with HbA1c < 7% did not differ significantly between the intervention and control groups (37 versus 38%, odds ratio 0.95 [95% confidence interval = 0.69 to 1.31]) at 12 months follow up. The total cost for diabetes-related care was 390 UK pounds per patient for the control group and 370 UK pounds for the intervention group. This difference was not statistically significant.

Levothyroxine reduces preterm birth in euthyroid women w/ autoantibodies

Clinical Question:
Does treatment with levothyroxine improve birth outcomes for pregnant euthyroid women who tested positive for thyroid peroxidase antibodies?

Bottom Line:
Euthyroid pregnant women who are positive for TPOAb develop impaired thyroid function, which is associated with an increased risk of miscarriage and premature deliveries. Substitutive treatment with LT(4) is able to lower the chance of miscarriage and premature delivery.

Reference:
Negro R, Formoso G, Mangieri T, Pezzarossa A, Dazzi D, Hassan H. Levothyroxine treatment in euthyroid pregnant women with autoimmune thyroid disease: Effects on obstetrical complications. J Clin Endocrinol Metab 2006;91:2587-2591.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Caucasian women receiving care in an academic obstetrical clinic in Italy were screened for thryroid peroxidase antibodies (TPOAb), free T4, and thyroid-stimluating hormone (TSH) levels. Of the 1074 women tested, 45 were excluded from the study because of overt hypothyroidism or hyperthyroidism; 984 completed the study. The 115 women with TPOAb+ and normal T4 and TSH levels were randomized to treatment with levothyroxine or placebo. Treatment allocation was concealed and treatment began within 1 week of the initial visit for prenatal care. Medication dosing for women taking active treatment was calculated according to body weight and TSH level, and was a mean of 50 mcg. The participating women and the physicians providing obstetric care were blinded to treatment assignment. Treated women had a significant reduction in spontaneous abortion (4% vs 14%; number needed to treat [NNT] = 10). Preterm births were also reduced in the treated group (7% vs 22%; NNT = 6; 95% CI, 3-22). Treated women had rates of spontaneous abortion and preterm birth similar to the 869 women who screened negative for TPOAb. In this population, in which 11% of women had a positive screen result, the number needed to screen to prevent 1 preterm birth would be 56 and to prevent one miscarriage would be 93 (assuming that all TPOAb+ women would have equally positive results with treatment). This study may be confounded by the fact that the women in the control group were younger on average than those in the treatement group, which may have influenced the rate of miscarriages. Also of note is that the study was conducted in Italy where iodization of salt is not compulsory. Iodine deficiency in this population may have reduced the functional reserve needed for the physiological increase in thyroid hormone production in pregnancy.

Metformin helps kids lose weight

Clinical Question:
Does metformin lead to weight loss for obese children and adolescents?

Bottom Line:
Metformin therapy for obese insulin-resistant pediatric patients results in significant improvement in body composition and fasting insulin. Although improvement in Si was noted in many individuals, Si was a less useful parameter for analysis of group data, possibly because of effects of variable compliance and changing Si during puberty.

Reference:
Srinivasan S, Ambler GR, Baur LA, et al Randomized, controlled trial of metformin for obesity and insulin resistance in children and adolescents: Improvement in body composition and fasting insulin. J Clin Endocrinol Metab 2006;91:2074-2080.

Study Design:
Cross-over trial (randomized)

Synopsis:
Participants were obese 9- to 18-year-olds (13 boys, 15 girls) who were treated in an endocrine clinic. All had clinical evidence of insulin resistance, but did not meet the criteria for diabetes. Patients were randomized (double-blinded) to metformin 1g twice daily or placebo for 6 months. This was followed by a 6-month crossover to the other treatment, with a 2-week washout period in between. There were equal numbers of children at Tanner stages 1 and 2 as at Tanner stages 3 to 5 at study entry. Mean body mass index (BMI) was 35. Standardized information on exercise and healthy eating was given to all patients. Four patients dropped out during the study; none because of medication side effects. At the end of the active treatment period significant benefits were observed for weight, BMI, abdominal circumference, and fasting insulin levels. The mean sizes of treatment effects at the end of the 6-month period of active therapy compared with placebo were weight loss of 4.35 kg, BMI decrease of 1.3, waist circumference decrease of 2.8 cm, and fasting insulin decrease of 2 mU/L. Data were not presented to calculate a number needed to treat.