Clinical Health Updates

Intensive control of glucose does not improve T2DM outcomes (VADT)

Clinical Question:
Does intensive control of glucose improve outcomes in patients with type 2 diabetes?

Bottom Line:
Like the ACCORD and ADVANCE studies, this trial provides additional evidence that intensive glucose control does not improve outcomes in patients with type 2 diabetes mellitus. It is important to note that these patients had well-controlled hypertension (mean blood pressure = 126/68) and well-controlled hyperlipidemia (mean low-density lipoprotein = 80 mg/dL). (LOE = 1b)

Reference:
Duckworth W, Abraira C, Moritz T, et al, for the VADT Investigators. Glucose control and vascular complications in veterans with Type 2 diabetes. N Engl J Med 2009(2);360:129-139.

Study Design:
Randomized controlled trial (single-blinded)

Funding:
Industry + govt

Setting:
Outpatient (any)

Allocation:
Concealed

Summary:
The effects of intensive glucose control on cardiovascular events in patients with long-standing type 2 diabetes mellitus remain uncertain. The recent ACCORD (N Engl J Med 2008;358:2545) and ADVANCE (N Engl J Med 2008;358:2560) trials found that tight glucose control does not reduce the risk of macrovascular complications and may actually increase all-cause mortality in patients with type 2 diabetes mellitus. The authors randomly assigned 1791 military veterans (mean age, 60.4 years) who had a suboptimal response to therapy for type 2 diabetes to receive either intensive or standard glucose control. Other cardiovascular risk factors were treated uniformly. The mean number of years since the diagnosis of diabetes was 11.5, and 40% of the patients had already had a cardiovascular event. The goal in the intensive-therapy group was an absolute reduction of 1.5 percentage points in the glycated hemoglobin level, as compared with the standard-therapy group. The primary outcome was the time from randomization to the first occurrence of a major cardiovascular event, a composite of myocardial infarction, stroke, death from cardiovascular causes, congestive heart failure, surgery for vascular disease, inoperable coronary disease, and amputation for ischemic gangrene. The median follow-up was 5.6 years. Median glycated hemoglobin levels were 8.4% in the standard-therapy group and 6.9% in the intensive-therapy group. The primary outcome occurred in 264 patients in the standard-therapy group and 235 patients in the intensive-therapy group (hazard ratio in the intensive-therapy group, 0.88; 95% confidence interval [CI], 0.74 to 1.05; P=0.14). There was no significant difference between the two groups in any component of the primary outcome or in the rate of death from any cause (hazard ratio, 1.07; 95% CI, 0.81 to 1.42; P=0.62). No differences between the two groups were observed for microvascular complications. The rates of adverse events, predominantly hypoglycemia, were 17.6% in the standard-therapy group and 24.1% in the intensive-therapy group.

Basal insulin less effective, better tolerated than biphasic and prandial

Clinical Question:
Which is preferred — biphasic, prandial, or basal insulin — for patients with poorly controlled Type 2 diabetes mellitus?

Bottom Line:
Patients choosing biphasic or prandial insulin regiments should be prepared to gain approximately 10 pounds to 12 pounds and expect 4 to 8 moderate or severe episodes of hypoglycemia per year. Basal insulin was a bit less effective as measured by the change in glycated hemoglobin (Hb A1C), but resulted in less weight gain and much less hypoglycemia. Of course, we don’t know whether any of these regiments improve long-term clinical outcomes in these patients. If you are going to add insulin for a patient with poorly controlled Type 2 diabetes, it makes sense to start with a single dose of basal insulin for most patients, and to focus primarily on those patients with an initial Hb A1C of more than 8.5%.

Reference:
Holman RR, Thorne KI, Farmer AJ, et al, for the 4-T Study Group. Addition of biphasic, prandial or basal insulin to oral therapy in Type 2 diabetes. N Engl J Med 2007;357(17):1716-1730.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
Adding insulin to oral therapy in type 2 diabetes mellitus is customary when glycemic control is suboptimal, though evidence supporting specific insulin regimens is limited. In an open-label, controlled, multicenter trial, we randomly assigned 708 patients with a suboptimal glycated hemoglobin level (7.0 to 10.0%) who were receiving maximally tolerated doses of metformin and sulfonylurea to receive biphasic insulin aspart twice daily, prandial insulin aspart three times daily, or basal insulin detemir once daily (twice if required). Outcome measures at 1 year were the mean glycated hemoglobin level, the proportion of patients with a glycated hemoglobin level of 6.5% or less, the rate of hypoglycemia, and weight gain. At 1 year, mean glycated hemoglobin levels were similar in the biphasic group (7.3%) and the prandial group (7.2%) (P=0.08) but higher in the basal group (7.6%, P<0.001 for both comparisons). The respective proportions of patients with a glycated hemoglobin level of 6.5% or less were 17.0%, 23.9%, and 8.1%; respective mean numbers of hypoglycemic events per patient per year were 5.7, 12.0, and 2.3; and respective mean weight gains were 4.7 kg, 5.7 kg, and 1.9 kg. Rates of adverse events were similar among the three groups.

Angled insulin insertion with 6-mm needle best for children with Type 1 Diabetes Mellitus

Clinical Question:
What needle length and injection technique most reliably delivers insulin into subcutaneous fat in children with diabetes?

Bottom Line:
A pinched technique with angled insertion using 6-mm needles most reliably results in the appropriately placed subcutaneous injection of insulin in children with diabetes. This same needle-size used in the abdominal site also resulted in the least amount of injection pain.

Reference:
Hofman PL, Lawton SA, Peart JM, et al. An angled insertion technique using 6-mm needles markedly reduces the risk of intramuscular injections in children and adolescents. Diabetic Medicine 2007;74(12):1400-1405.

Study Design:
Non-randomized controlled trial

Synopsis:
The authors aims of this study were
(i) to establish which children with Type 1 diabetes are at risk of intramuscular or intradermal insulin injections
(ii) to determine a needle length and technique that reliably administers insulin into subcutaneous fat.
Seventy-two healthy diabetic children (age 6.3-14.3 years, body mass index standard deviation score 1.0 +/- 1.4) were recruited for study 1 and 37 of this cohort participated in study 2. In study 1, 200 microl air was injected into the abdomen and anterior thigh by a pinched skin-fold technique using either a perpendicular insertion of NovoFine(R) 31G 6-mm or an angled insertion of NovoFine(R) 30G 8-mm needles. In study 2, subjects received injections into abdomen and anterior thigh via angled 6-mm needles with either an unpinched or pinched technique. The site of air injection was visualized by ultrasound scan and measurements taken of subcutaneous fat thickness. In study 1, intramuscular injections were detected in 32% of subjects, and in a further 22% air was visualized at the muscle fascia. In study 2, intramuscular injections occurred in 3% of subjects and a further 11% had muscle fascia air detected. No intramuscular injections occurred in subjects injecting with a 6-mm needle and an angled pinched skin-fold technique. Pinching abdomen and thigh skin folds increased the subcutaneous fat thickness by 192 +/- 16% and 22 +/- 6%, respectively. In very lean subjects, pinching thighs actually reduced subcutaneous fat thickness.

ADVANCE Trial

Clinical Question:
Is perindopril plus indapamide effective in decreasing bad outcomes in patients with type 2 diabetes and existing macrovascular disease?

Bottom Line:
Perindopril (Aceon) plus indapamide (Lozol) is better than placebo in decreasing clinically relevant events in patients with type 2 diabetes who are at high risk of cardiovascular complications. Whether the combination is better than other medications — like aspirin — isn’t addressed by this study.

Reference:
Patel A, et al, and the ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 2007;370(9590):829-840.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
This study included more than 11,000 patients older than 55 years who had type 2 diabetes and either a prior cardiovascular event (eg, myocardial infarction, stroke, amputation) or at least one other risk factor for cardiovascular disease, including microvascular complications, tobacco use, an elevated cholesterol level, a low HDL cholesterol level, microalbuminuria, more than 10 years of diabetes, or more than 65 years of age. After completing a 6-week run-in period the “surviving” patients were randomly assigned to perindopril 2 mg plus indapamide 0.625 mg daily or matching placebo. Since the authors weeded out patients who didn’t comply or who were unable to tolerate the side effects, any data about drop-outs after randomization are unlikely to reflect tolerability in the real world. After 3 months of treatment, the doses were doubled. The authors were interested in a composite outcome that included cause-specific mortality, cardiovascular events, new or worsening nephropathy, retinopathy, and so forth. I dislike composite end points like this; some outcomes don’t make sense to combine. When there is no difference in the occurrence of a more frequent and devastating outcome (like death), but an improvement in some less important outcomes (like the number of photocoagulations as opposed to loss of vision), and the results all get lumped together, the devastating outcome suddenly looks good. For a more cogent example, all one has to do is look at all the bastardizations of the UKPDS trial (BMJ 2000;320:1720-23.).

After an average of 4.3 years, the researchers found that 15.5% of the treatment group had a bad outcome compared with 16.8% of the placebo group (number needed to treat [NNT] = 77; 95% CI, 37 – 10,257). All-cause mortality was also lower in the treatment group (7.3% vs 8.5%; NNT = 84; 95% CI, 47 – 790) as was the total number of coronary events (8.4% vs 9.6%; NNT = 84; 95% CI, 45 – 734). Only 15 patients were lost to follow-up after randomization. During the follow-up sessions, the randomized treatment was continued in 83% of the treatment group and 87% of the placebo group.

Metformin does not harm patients with HF and diabetes

Clinical Question:
Do oral hypoglycemics cause harm in patients with diabetes and heart failure?

Bottom Line:
Metformin may decrease mortality in patients with heart failure. Insulin is associated with increased mortality. The thiazolidinediones decreased mortality but increased hospitalization for heart failure.

Reference:
Eurich DT, McAlister FA, Blackburn DF, et al. Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review. BMJ 2007;335(7618):497.

Study Design:
Meta-analysis (other)

Synopsis:
Up to 40% of adults with diabetes will have heart failure. Diabetes worsens the outcomes from heart failure, and tight control of blood glucose is associated with worse outcomes in patients with heart failure. To investigate the role of antidiabetic agents in patients with heart failure, these Canadian researchers searched several databases for randomized controlled trials or cohort studies that evaluated the association between hypoglycemic agents and clinical outcomes in patients with diabetes and heart failure. Two authors independently selected the studies for inclusion and abstracted the data. Research results for insulin and metformin were not homogeneous and were not formally combined. Three studies found an increased mortality associated with insulin therapy; the fourth and largest study did not find an associated increase in mortality (but did not find a decrease, either). Thiazolidinedione treatment was associated with reduced all-cause mortality (odds ratio [OR] = .83; 95% CI = 0.71 – 0.97), but an increase in hospitalization for heart failure. Metformin as single therapy was associated with decreased mortality as compared with sulfonylureas (OR = .70; 95% CI, 0.54 – 0.91) or insulin (OR = .86; 95% CI, 0.78 to 0.97) after 2.5 years of treatment, as was combination therapy with metformin and a sulfonylurea. Sulfonylureas were not independently studied but were used in comparison groups for several studies of other hypoglycemic drugs. In these studies, there was no increased mortality with sulfonylureas. Most of the studies were of good quality.

Controversial evidence on value of pioglitazone (Actos) for type 2 diabetes

Clinical Question:
Is pioglitazone (Actos) useful in the management of patients with type 2 diabetes mellitus?

Bottom Line:
Based only on studies provided by and conducted directly by the drug manufacturer, this review reports a significantly reduced incidence only of the composite outcome of death, myocardial infarction, and stroke with pioglitazone (Actos) therapy. None of the same outcomes were significantly reduced on an individual basis. An earlier review of pioglitazone therapy in type 2 diabetes by the Cochrane Collaboration of all available published and peer-reviewed clinical trials found no significant evidence of improved patient-oriented outcomes. Similar to the other thiazolidinedione, rosiglitazone (Avandia), pioglitazone also increases the risk of serious heart failure in type 2 diabetics.

Reference:
Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus. A meta-analysis of randomized trials. JAMA 2007;298:1180-88.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
Pioglitazone is widely used for glycemic control in patients with type 2 diabetes mellitus, but evidence is mixed regarding the influence of medications of this class on cardiovascular outcomes. The authors evaluated the effect of pioglitazone on ischemic cardiovascular events. A database containing individual patient-level time-to-event data collected during pioglitazone clinical trials was transferred from the drug’s manufacturer for independent analysis. Trials were included if they were randomized, double-blinded, and controlled with placebo or active comparator. The primary outcome was a composite of death, myocardial infarction, or stroke. Secondary outcome measures included the incidence of serious heart failure. A fixed-effects approach was used to combine the estimates across the duration strata and statistical heterogeneity across all the trials was tested with the I2 statistic. A total of 19 trials enrolling 16 390 patients were analyzed. Study drug treatment duration ranged from 4 months to 3.5 years. Death, myocardial infarction, or stroke occurred in 375 of 8554 patients (4.4%) receiving pioglitazone and 450 of 7836 patients (5.7%) receiving control therapy (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.72-0.94; P = .005). Progressive separation of time-to-event curves became apparent after approximately 1 year of therapy. Individual components of the primary end point were all reduced by a similar magnitude with pioglitazone treatment, with HRs ranging from 0.80 to 0.92. Serious heart failure was reported in 200 (2.3%) of the pioglitazone-treated patients and 139 (1.8%) of the control patients (HR, 1.41; 95% CI, 1.14-1.76; P = .002). The magnitude and direction of the favorable effect of pioglitazone on ischemic events and unfavorable effect on heart failure was homogeneous across trials of different durations, for different comparators, and for patients with or without established vascular disease. There was no evidence of heterogeneity across the trials for either end point (I2 = 0%; P = .87 for the composite end point and I2 = 0%; P = .97 for heart failure).

Controversial evidence on value of pioglitazone (Actos) for type 2 diabetes

Clinical Question:
Is pioglitazone (Actos) useful in the management of patients with type 2 diabetes mellitus?

Bottom Line:
Based only on studies provided by and conducted directly by the drug manufacturer, this review reports a significantly reduced incidence only of the composite outcome of death, myocardial infarction, and stroke with pioglitazone (Actos) therapy. None of the same outcomes were significantly reduced on an individual basis. An earlier review of pioglitazone therapy in type 2 diabetes by the Cochrane Collaboration of all available published and peer-reviewed clinical trials found no significant evidence of improved patient-oriented outcomes. Similar to the other thiazolidinedione, rosiglitazone (Avandia), pioglitazone also increases the risk of serious heart failure in type 2 diabetics.

Reference:
Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus. A meta-analysis of randomized trials. JAMA 2007;298:1180-88.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
Pioglitazone is widely used for glycemic control in patients with type 2 diabetes mellitus, but evidence is mixed regarding the influence of medications of this class on cardiovascular outcomes.

A recently published systematic review (Nissen SE, et al. NEJM 2007;356:2457-71) reported an increased risk of adverse cardiovascular events among type 2 diabetics treated with rosiglitazone (Avandia). In the same issue of this journal a second review of rosiglitazone also similarly reports an increased risk of adverse cardiovascular events (Singh S, et al. JAMA 2007;298:1189-95). Thus, all eyes from clinicians and patients hoping to still receive benefit from treatment for type 2 diabetes with the thiazolidinediones are on the remaining drug, pioglitazone (Actos). A recent Cochrane review reporting on a meta-analysis of 22 peer-reviewed trials comprising approximately 6200 patients found no evidence of improved patient-oriented outcomes with pioglitazone treatment. The same review did, however, report a significantly increased incidence of edema among treated patients.

In this current review, the investigators were contracted to perform a meta-analysis of 19 trials, enrolling 16,390 patients, of pioglitazone therapy in type 2 diabetics conducted by the manufacturer. The authors note that at least 20 other completed trials evaluating pioglitazone therapy not conducted directly by the manufacturer were not included in their summary analysis. No formal search of the medical literature was independently completed by the authors, including not reviewing any evidence-based resources or the Cochrane Registry of Controlled Trials. In this review the composite outcome of death, nonfatal myocardial infarction, or nonfatal stroke was significantly reduced in patients treated with pioglitazone compared to placebo. However, as was also reported in the earlier Cochrane review, no significant benefit was found for any individual patient-oriented outcome, including all cause mortality, myocardial infarction, or stroke. Similarly to the two reviews of rosiglitazone, this review of pioglitazone did report a statistically significant increased incidence of serious heart failure in treated patients compared to controls.

Home glucose monitoring ineffective

Clinical Question:
In patients with type 2 diabetes under relatively good control without the use of insulin, does self-monitoring of blood glucose improve long-term control?

Bottom Line:
Evidence is not convincing of an effect of self monitoring blood glucose, with or without instruction in incorporating findings into self care, in improving glycaemic control compared with usual care in reasonably well controlled non-insulin treated patients with type 2 diabetes.

Reference:
Farmer A, Wade A, Goyder E, et al. Impact of self monitoring of blood glucose in the management of patients with non-insulin treated diabetes: open parallel group randomised trial. BMJ 2007;335:132.

Study Design:
Randomized controlled trial (nonblinded)

Synopsis:
The investigators determine whether self monitoring, alone or with instruction in incorporating the results into self care, is more effective than usual care in improving glycaemic control in non-insulin treated patients with type 2 diabetes. Three arm, open, parallel group randomised trial was done in a 48 general practices in Oxfordshire and South Yorkshire . They include 453 patients with non-insulin treated type 2 diabetes (mean age 65.7 years) for a median duration of three years and a mean haemoglobin A1c level of 7.5%. Standardised usual care with measurements of HbA1c every three months as the control group (n=152), blood glucose self monitoring with advice for patients to contact their doctor for interpretation of results, in addition to usual care (n=150), and blood glucose self monitoring with additional training of patients in interpretation and application of the results to enhance motivation and maintain adherence to a healthy lifestyle (n=151). HbA1c level measured at 12 months. At 12 months the differences in HbA1c level between the three groups (adjusted for baseline HbA1c level) were not statistically significant (P=0.12). The difference in unadjusted mean change in HbA1c level from baseline to 12 months between the control and less intensive self monitoring groups was -0.14% (95% confidence interval -0.35% to 0.07%) and between the control and more intensive self monitoring groups was -0.17% (-0.37% to 0.03%).

Rosiglitazone (Avandia) associated with increased risk of acute MI

Clinical Question:
Does rosiglitazone (Avandia) increase the risk of adverse cardiovascular events?

Bottom Line:
This study acquainted us with an evidence that short-term use of rosiglitazone may increase the risk of Myocardial Infarction and cardiovascular death. While the absolute possibilty was small, the goal of diabetes treatment is to decrease cardiovascular disease, the largest cause of death in patients with diabetes. Longer and larger studies using cardiovascular outcomes as a prespecified outcome and meta-analysis using individual patient level data are needed to more definitively answer this question. A study of pioglitazone (Actos) found no increase in cardiovascular events but did show an increase in hopsitalizations for heart failure. Aggressive attention to cardiovascular risk factors remains the most important thing we can do for our diabetic patients.

Reference:
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: epub.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
The thiazolinediones family have a patterned history: troglitazone caused hepatotoxicity and was removed from the market, while muraglitazar never made it to market because it increased the risk of cardiovasculr events and myocardial infarction (MI). Rosiglitazone, though, was thought to be safe based on the results of short, small studies submitted to the FDA. However, these studies were designed to detect changes in blood sugar, and not to detect changes in cardiovascular mortality, MI, or all-cause mortality. The authors of this meta-analysis have therefore pooled data from 42 smaller trials to determine if use of the drug increases the risk of MI or cardiovascular death. Since the studies were not specifically designed to evaluate cardiac outcomes, most did not describe how cardiac endpoints were determined. Most studies were between 24 and 52 weeks duration, with a typical dosage range for rosiglitazone of 4 to 8 mg per day. The average age of patients was 56 years and over half were men; the mean hemoglobin A1C was 8.2%.

The results showed a significant increase in the likelihood of MI (odds ratio 1.43, 95% CI 1.03 to 1.98) and a borderline increase in the risk of death from cardiovascular causes (OR 1.64, 95% CI 0.98 – 2.74). The absolute increase in risk of MI was small, approximately 0.4%. On the other hand, the studies were short and most excluded patients with pre-existing heart disease, which explains the small total number of cardiovascular events in both groups. Results were similar whether the control group took placebo or an active comparator, although the number of patients in each comparator group were relatively small. The authors used a fixed effects model to combine the studies; a more conservative approach would have been to use a random effects model, which may not have shown a significant difference in outcomes.

Glitazones may be beneficial post-PCI

Clinical Question:
Is treatment with a glitazone after angioplasty effective in decreasing the need for revascularization?

Bottom Line:
The use of a thiazolidinedione (glitazone) following percutaneous coronary intervention (PCI) will decrease the need for revascularization over the following 6 months. The effect occurs in patients with and without diabetes and is likely due to an effect other than on blood glucose control. The studies in this meta-analysis were small, and further research is necessary before putting these results into practice.

Reference:
Riche DM, Valderrama R, Henyan NN. Thiazolidinediones and risk of repeat target vessel revascularization following percutaneous coronary intervention. Diabetes Care 2007;30:384-88.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
Thiazolidinediones (TZDs) (rosiglitazone and pioglitazone) are a class of antidiabetes agents that have a high affinity for peroxisome proliferator-activated receptor-gamma. TZDs initiate a multitude of physiologic processes that may elicit benefits as systemic agents for the prevention of restenosis requiring revascularization following percutaneous coronary intervention (PCI). Numerous trials have evaluated the impact of TZDs on repeat target vessel revascularization (TVR) in patients following PCI; however, several limitations (small sample size, inconclusive results, and risk factor stratification) complicate definitive conclusions. A meta-analysis was performed to evaluate the impact of TZDs on repeat TVR following PCI. Included trials met the following criteria: 1) prospective, randomized controlled trials evaluating available TZDs versus standards of care; 2) well-described protocol; 3) minimum of 6 months of follow-up; and 4) data provided on repeat TVR. Data are presented as relative risks (RRs) with 95% CIs. Seven clinical trials (n = 608) met the inclusion criteria. Upon meta-analysis, the risk of repeat TVR was significantly reduced in patients who received TZD therapy compared with standards of care (RR 0.35 [95% CI 0.22-0.57]). In studies using rosiglitazone (0.45 [0.25-0.83]) and pioglitazone (0.24 [0.11-0.51]), risk of repeat TVR was significantly reduced. Risk of repeat TVR was also significantly reduced among patients with (0.34 [0.19-0.63]) and without (0.37 [0.18-0.77]) diabetes.