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New Insulin safety guidance issued to reduce wrong dosages

Monday, July 26th, 2010
 

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26 July 2010

Introduction
In June 2010, the National Patient Safety Agency (NPSA) issued its Rapid Response Report: Safer administration of insulin,1 which outlines supporting information2 aimed at reducing the number of wrong dose incidents involving insulin. In its supporting information2, the NPSA highlights that insulin is frequently included in the list of the top 10 high-alert medicines worldwide, indicating the high risk of patient injury if it is misused.

Action
In the report the NPSA recommends the following action points be completed by all organisations in the NHS and independent sector:

  1. All regular and single insulin (bolus) doses are measured and administered using an insulin syringe or commercial insulin pen device. Intravenous syringes must never be used for insulin administration.
  2. The term ‘units’ is used in all contexts. Abbreviations, such as ‘U’ or ‘IU’, are never used.
  3. All clinical areas and community staff treating patients with insulin have adequate supplies of insulin syringes and subcutaneous needles, which staff can obtain at all times.
  4. An insulin syringe must always be used to measure and prepare insulin for an intravenous infusion. Insulin infusions are administered in 50ml intravenous syringes or larger infusion bags. Consideration should be given to the supply and use of ready to administer infusion products e.g. prefilled syringes of fast acting insulin 50 units in 50ml sodium chloride 0.9%.
  5. A training programme should be put in place for all healthcare staff (including medical staff) expected to prescribe, prepare and administer insulin. An e-learning programme is available from NHS Diabetes: http://www.diabetes.nhs.uk/safe_use_of_insulin3
  6. Policies and procedures for the preparation and administration of insulin and insulin infusions in clinical areas are reviewed to ensure compliance with the above.

The deadline for completion of these action points is 16th December 2010.

Background
Between August 2003 and August 2009 the NPSA received 3,881 wrong dose incident reports involving insulin. These included one death and one severe harm incident due to 10-fold dosing errors from abbreviating the term ‘Unit’.1,2

Three deaths and 17 other incidents between January 2005 and July 2009 were also reported where an intravenous syringe was used to measure and administer insulin.1,2

What does this mean to medicines management?
Healthcare professionals and managers involved in the care and treatment of diabetic patients should work together to establish clear policies and procedures that meet the recommendations identified by the NPSA for the safer administration of insulin.

The training principles for safer administration of insulin need to be agreed and fully understood by all staff. To coincide with the issue of this Rapid Response Review, NHS Diabetes has launched a new e-learning course, aimed at healthcare professionals, on the safer administration of insulin. The NHS Diabetes website  supports its e-learning course with further information, advising people to check before they inject insulin, ensuring that they have the:

  • Right insulin – check the name.
  • Right dose – check strength and how much insulin to give. Check the numbers very carefully.
  • Right time – with food? At bedtime?
  • Right way – via syringe, pen or pump?  

NHS Diabetes also advises that those administering insulin should “always ask the patient – show them the insulin and what you are about to do”.

Learning from previous incidents like those reported in the Rapid Response Report supporting information is essential, and ensuing steps need to be taken to minimise those risks such as: double checking insulin doses before administration; giving staff lighter workloads at insulin administration times; and putting effective communication and recording systems in place.

How does this relate to other publications or evidence?
The NPSA’s Rapid Response Report: Reducing harm from omitted and delayed medicines in hospital4 identifies the timeliness of insulin administration to be a further critical factor for patient safety. Therefore, medicine management procedures for insulin should include guidance on the importance of prescribing, supplying and administering, timeliness issues and what to do when insulin has been omitted or delayed.

The NPC e-learning resource NPCi has a whole floor dedicated to patient safety and risk with supporting medicines management information on reducing medication errors and  reducing risk.

References
1. National Patient Safety Agency (2010). Rapid Response Report NPSA/2010/RRR013: Safer administration of insulin

2. National Patient Safety Agency (2010). Rapid Response Report NPSA/2010/RRR013: safer administration of insulin – supporting information

3. NHS Diabetes: Safe Use of Insulin. Available at:  http://www.diabetes.nhs.uk/safe_use_of_insulin

4. National Patient Safety Agency (2010). The Rapid Response Report NPSA/2010/RRR009: Reducing harm from omitted and delayed medicines in hospital

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Association found between financial conflicts of interest and authors’ views on MI risk with rosiglitazone

Monday, July 19th, 2010
MeReC Rapid Review NPC Logo

19th July 2010

A systematic review  found that there was a link between financial conflicts of interests with pharmaceutical companies and the orientation of views expressed by authors on the association of rosiglitazone with increased risk of myocardial infarction (MI) in patients with diabetes. The disclosure rates of financial conflicts of interests were found to be low (53% of the 202 included articles), with 45% of authors having financial conflicts of interest.

Level of evidence:
Level 3 (other evidence) according to the SORT criteria.

Action
This review reinforces the need for readers of scientific literature to consider the authors’ financial conflicts of interests and the potential ramifications they may have on their writing. Healthcare professionals should base their prescribing decisions on evidence-based information from organisations with a public sector ethos such as NICE, CKS, SIGN, Cochrane, CRD, Clinical Evidence, DTB and the NPC. These decisions should be based on consideration of the entire body of evidence and not merely rely on the claims made in individual publications or reports.

What is the background to this?
According to the authors of this paper, an association in published articles between conflicts of interest and pro-industry conclusions has previously been shown, and in recent years policies on disclosure of conflicts of interests have become more prevalent. As discussed in the introduction of this paper, the overall impact that disclosure of authors’ financial conflict of interest have on their expressed views and opinions is, however, unknown.  

This cross-sectional systematic review examines the relation between recommendations made in articles citing and commenting on either of two index publications ─ a meta-analysis that showed a significant increase in the MI risk associated with the use of rosiglitazone, and the manufacturer-funded RECORD trial which did not show a significant increase in MI risk.  

For each article, the review team sought information about the authors’ financial conflicts of interest in the report itself and in all publications within two years of the original publication and online. Two reviewers blinded to the authors’ financial relationships independently classified each article as presenting a favourable (that is, rosiglitazone does not increase the risk of myocardial infarction), neutral, or unfavourable view on the risk of myocardial infarction with rosiglitazone and on recommendations on the use of the drug.

What does this study claim?
Authors who had a favourable view of the risk of MI with rosiglitazone were at least three times more likely to have financial conflicts of interest with manufacturers of antihyperglycaemic agents in general, and with rosiglitazone manufacturers in particular, than authors who had an unfavourable view (rate ratio [RR] 3.38, 95% confidence interval [CI] 2.26 to 5.06 and 4.29, 2.63 to 7.02, respectively). Likewise there was a strong association between favourable recommendations on the use of rosiglitazone and financial conflicts of interest (RR 3.36, 95%CI 1.94 to 5.83).

Disclosure rates for financial conflicts of interest were unexpectedly low – of the 202 included articles, 108 (53%) had a conflict of interest statement. Ninety authors (45%) had financial conflicts of interest.

What are the limitations of this study?
This study is limited by the observational and descriptive nature of the evidence. The reviewers had to rely on classification of financial conflicts of interest articulated by the very authors they were evaluating. Even though multiple sensitivity analyses were conducted, this study was unable to establish the effect of the strength (in terms of monetary magnitude) of financial associations authors had with pharmaceutical companies.  The majority of authors (82%) had financial conflicts of interest with pioglitazone manufacturers as well as the rosiglitazone manufacturer. However, the reviewers were unable to establish what impact these contradictory associations had on authors’ expressed views. The search was limited by the lack of a formal database for reporting conflicts of interest, so there is a potential that this review underestimated the prevalence of conflicts of interest associated with authors’ view on rosiglitazone safety.

So what?
A study conducted in 1998 by Stelfox and colleagues found only 3% of studies had conflict of interest statements, so this study indicates there has been limited progress on disclosure – this study found 53% of articles had conflict of interest statements. Further studies are warranted to confirm the magnitude of the impact of  financial ties on expressed views presented in articles.  

Although this study does not necessarily indicate a causal link for authors’ positions on rosiglitazone, these findings highlight the need for vigilance in disclosure procedures by journal editors and by readers of scientific literature.

Note: The EMEA are currently carrying out an ongoing Europe-wide review of the risks and benefits of rosiglitazone due to concerns about an increased risk of cardiovascular adverse effects

Study details –
Wang AT, McCoy CP et al. Association between industry affiliation and position on cardiovascular risk with rosiglitazone: cross sectional systematic review. BMJ 2010;340:c1344

Design
The review team searched Web of Science and Scopus for articles citing and commenting on either of two index publications that contributed key data to the rosiglitazone controversy (a meta-analysis of small trials and a subsequent large trial). In order to qualify articles had to comment on rosiglitazone and the risk of MI. Guidelines, meta-analyses, reviews, clinical trials, letters, commentaries, and editorials were included.

Intervention and comparison
For each article, the review team sought information about the authors’ financial conflicts of interest in the report itself and elsewhere (that is, in all publications within two years of the original publication and online). Two reviewers blinded to the authors’ financial relationships independently classified each article as presenting a favourable (that is, rosiglitazone does not increase the risk of myocardial infarction), neutral, or unfavourable view on the risk of myocardial infarction with rosiglitazone and on recommendations on the use of the drug. Sensitivity analyses was conducted enhance the validity and robustness of the results, including investigating whether using the articles (as opposed to the authors) as units of analysis would alter the results.

Outcomes and results
Disclosure rates for financial conflicts of interest were low – of the 202 included articles, 108 (53%) had a conflict of interest statement. Ninety authors (45%) had financial conflicts of interest. Authors who had a favourable view of the risk of MI with rosiglitazone were more likely to have financial conflicts of interest with manufacturers of antihyperglycaemic agents in general, and with rosiglitazone manufacturers in particular, than authors who had an unfavourable view (rate ratio 3.38, 95% confidence interval [CI] 2.26 to 5.06 and 4.29, 2.63 to 7.02, respectively). Likewise there was a strong association between favourable recommendations on the use of rosiglitazone and financial conflicts of interest (3.36, 95% CI 1.94 to 5.83). Sensitivity analysis showed that these links persisted when articles rather than authors were used as the unit of analysis (4.69, 95% CI 2.84 to 7.72), when the analysis was restricted to opinion articles (6.29, 2.15 to 18.38) or to articles in which the rosiglitazone controversy was the main focus (6.50, 2.56 to 16.53).

Sponsorship
This study was conducted by the Mayo Clinic, and the authors state that no funding was required. The authors of this study also claim to have no competing financial or non-financial conflicts of interest.

More information can be found on the Information Mastery floor of NPCi, or in related blogs on the Information Mastery section of the blog homepage.

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CV risk reduction in diabetes: law of cumulative benefits, diminishing returns

Thursday, July 15th, 2010
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15th July 2010

Summary:
This modelling study demonstrates the “law of cumulative benefits” or conversely a “law of diminishing returns” with regard to the intensification of BP-lowering and lipid-modification therapy in patients with diabetes. It suggests a personalised, shared-care approach based on baseline CV risk could maximise a patient’s net benefit from treatment.

Level of evidence:
Level 3 (other evidence) according to the SORT criteria.

Action
Health professionals should continue to follow NICE guidance on the management of type 2 diabetes. NICE guidance recommends reducing BP to below 140/80 mmHg (below 130/80 mmHg if there is kidney, eye or cerebrovascular damage). Simvastatin 40mg is the usual choice and dose of statin, with an increase to 80mg if the total cholesterol is more than 4mmol/L and also the LDL-cholesterol is more than 2mmol/L on treatment. In people with type 2 diabetes and existing or new cardiovascular (CV) disease, or increased albumin excretion, NICE advises considering intensifying lipid lowering treatment to achieve a total cholesterol of less than 4mmol/L or an LDL-cholesterol of less than 2mmol/L. However, in line with good medical practice, such a decision should take into account the patient’s informed preference, including the benefits and risks of treatment.

Health professionals may wish to consider the implications of this modelling study and the earlier ACCORD BP and lipids trials with respect to the risks and benefits of intensifying antihypertensive and lipid-modification treatment, especially if aiming for BP and lipid targets below or at the lower end of the standard target levels set by NICE.

What is the background to this?
As the NICE full guideline for diabetes emphasises, people with type 2 diabetes are at increased CV risk, which is reduced by lowering BP and using suitable lipid modification. Clinical trials have shown that antihypertensives and statins provide significant CV benefits on average for people with type 2 diabetes. However, the recent ACCORD studies have highlighted that intensive BP control and intensive treatment with combination lipid-lowering treatments offered no survival advantage overall, and perhaps caused harm, to patients with type 2 diabetes. This mathematical modelling study aimed to examine the benefits and harms among patients with diabetes of treating high cholesterol levels to a target LDL-cholesterol of 100mg/dL (2.6mmol/L) and blood pressure to a target of 130/80mmHg. Patients were modelled to receive up to five titrations of statin therapy and eight titrations of antihypertensive therapy.

What does this study claim?
Treating to an LDL-cholesterol target of 2.6mmol/L resulted in gains of 1.50 quality-adjusted life-years (QALYs) of lifetime treatment-related benefit. Treating to a BP target of 130/80mmHg resulted in a gain of 1.35 QALYs of lifetime treatment-related benefit. These QALYs declined to 1.42 and 1.16, respectively, after accounting for treatment-related harms. Most of the total benefit was limited to the first few steps of medication intensification or to tight control for a limited group of very high-risk patients. Because of treatment-related harms (such as treatment specific adverse events and the burdens and safety risks from polypharmacy), and the diminishing benefits of combination therapy, intensifying treatment beyond the first step (simvastatin 20mg) for the LDL-cholesterol target or the third step (thiazide plus ACE inhibitor plus beta-blocker) for the BP target resulted in either limited benefit or net harm for patients with below-average risk.

So what?
Like all modelling studies, this study has limitations largely because of the numerous assumptions that had to be made regarding treatment benefits and harms. However, as the related editorial points out, the lessons to be gleaned from this simulation could be profound.

The editorial suggests that over the years, practice guidelines have advocated increasingly tighter control of blood glucose and CV risk factors. However, this model suggests that the diminishing benefits of more aggressive therapy might not only be inefficient but potentially harmful. The principle around the “law of cumulative benefits” or conversely the “law of diminishing returns” has been discussed in some detail in workshop 3 of the Information Mastery 4 – communicating risks and benefits floor of NPCi. With each preventative drug added, the absolute benefit gained becomes increasingly less. This paper refers to previous work suggesting , for example, that adding a second antihypertensive produces a 16% lower systolic BP reduction and a 35% lower diastolic BP reduction than would be expected if the treatment effects were additive. Conversely, additive drugs are likely to have more adverse effects (because third, fourth, and fifth-line drugs and high doses tend to be less well tolerated) and a high polypharmacy burden. When the benefits of treatment are small or accrue mainly to a subset of patients, treatment harms such as adverse effects can significantly lessen or negate the benefit of treatment.

The other important finding from this modelling study was that the benefit patients receive from preventative interventions is strongly related to their baseline absolute risk of the outcome. Patients with diabetes with the highest risk of CV disease accounted for nearly all of the benefits of treating to targets. Average risk patients (nearly three-quarters of the population) received very little benefit. In addition, while the benefits of treatment accrue preferentially to those at greater likelihood of the outcome, the risks of treatment are distributed more evenly among those treated. By accounting for treatment related harms, the authors identified numerous examples where intensifying treatment would be contraindicated on the basis of risk-benefit considerations, and many more instances where the expected benefits would be so small that shared patient-clinician decision making would be most appropriate.

Shared decision making is an important theme running through much of our work on NPCi, see the Information Mastery 4 – communicating risks and benefits floor and our work around patient decision aids.

NICE guidance on the management of type 2 diabetes recommends reducing BP to below 140/80 mmHg (below 130/80 mmHg if there is kidney, eye or cerebrovascular damage). For all type 2 diabetes patients apart from those at low CV risk, statins are recommended. Simvastatin 40mg is the usual choice and dose of statin, with an increase to 80mg if the total cholesterol is more than 4mmol/L and also the LDL-cholesterol is more than 2mmol/L on treatment. In people with type 2 diabetes and existing or new cardiovascular disease, or increased albumin excretion, NICE advises considering intensifying lipid lowering treatment to achieve a total cholesterol of less than 4mmol/L or an LDL-cholesterol of less than 2mmol/L. However, in line with good medical practice, such a decision should take into account the patient’s informed preference, including the benefits and risks of treatment.

Study details
Timbie JW, et al. Variation in the net benefit of aggressive cardiovascular risk factor control across the US population of patients with diabetes mellitus. Arch Intern Med 2010;170:1037–44

Design and patients
Mathematical modelling study to examine the effect among patients with diabetes mellitus of treating high cholesterol levels to a target of LDL-cholesterol 100mg/dL (2.59 mmol/L) and blood pressure to a target of 130/80mmHg. Sample comprised individuals 30 to 75 years old with diabetes mellitus participating in the National Health and Nutrition Examination Survey III. Used Monte Carlo methods to simulate a treat-to-target strategy. Patients received up to 5 titrations of statin therapy and 8 titrations of antihypertensive therapy. Treatment adverse effects and polypharmacy risks and burdens were incorporated using disutilities. Health outcomes were simulated using a Markov model.

Intervention and comparison
LDL-cholesterol lowering steps: Step 1: simvastatin 20mg, Step 2: simvastatin 40mg, Step 3: atorvastatin 40mg, Step 4: atorvastatin 80mg, Step 5: simvastatin 80mg plus ezetimibe 10mg

BP lowering steps: Step 1: thiazide, Step 2: add ACE inhibitor, Step 3: add beta-blocker, Step 4: add calcium channel blocker (CCB), Step 5: intensify thiazide, Step 6: intensify ACE inhibitor, Step 7: intensify beta-blocker, Step 8: intensify CCB

Outcomes and results
Treating to targets resulted in gains of 1.50 for LDL-cholesterol) and 1.35 (for BP) QALYs of lifetime treatment-related benefit, which declined to 1.42 and 1.16 QALYs after accounting for treatment-related harms. Most of the total benefit was limited to the first few steps of medication intensification or to tight control for a limited group of very high-risk patients. However, because of treatment-related disutility, intensifying beyond the first step (LDL-cholesterol) or third step (BP) resulted in either limited benefit or net harm for patients with below-average risk.

Sponsorship
Supported in part by the VA Health Services Research and Development Service and the Michigan Diabetes Research and Training Centre

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Higher doses of insulin glargine associated with cancer

Tuesday, July 13th, 2010
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13 July 2010

An observational study has found that higher mean daily doses of insulin glargine, but not other types of insulin, were associated with a five times higher relative risk of cancer after adjusting for confounders.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Action
Following an evaluation of the available evidence suggesting a possible association between insulin and cancer, in July 2009, the EMEA  advised that no change in practice is required at present, and patients being treated with insulin glargine can continue their treatment as normal (in accordance with NICE guidance on type 1 and type 2 diabetes). However, this paper adds to the evidence providing a further signal about the long-term safety of high doses of insulin glargine for regulators to consider.

The effect of NICE guidance ought to be that long-acting insulin analogues are not used routinely. However, the prescribing data for England shows that the uptake of insulin glargine and insulin detemir is extensive. Based on the figures for the quarter to March 2010, there are about 1,200,000 items of insulin glargine prescribed each year, and 500,000 items of insulin detemir. This equates to over 40% of all intermediate or long-acting insulin items.

What is the background to this?
As we reported in a previous blog, several studies have signalled a possible association between the long-acting human insulin analogue, insulin glargine (Lantus®) and an increased risk of developing cancer. The concerns raised by these papers were investigated in a CHMP review. The EMEA reported the conclusion of the review in a press release on 23rd July 2009. (See also September 2009 edition of Drug Safety Update). The CHMP concluded that the available data did not provide a cause for concern and that changes to the prescribing advice were therefore not necessary. Due to methodological limitations the studies were found to be inconclusive and did not allow a relationship between insulin glargine and cancer to be confirmed or excluded. In addition, the CHMP noted that the results of the studies were not consistent. The CHMP asked the manufacturer of insulin glargine to develop a strategy for generation of further research in this area.

This study was designed to overcome, to some extent, the limitations of previous studies (e.g. limited information on comorbidities, short duration of observation, the inclusion of probably pre-existing cases of cancer diagnosed shortly after initiation of insulin, and the failure to discriminate between basal and prandial human insulin used as a comparator). It aimed to assess the longer term association between incidence of cancer and use of different insulin analogues, considering different insulin doses and a larger number of confounders than those included in previous studies, in a cohort of 1,340 diabetic outpatients starting insulin.

What does this study claim?
Over a median follow-up of 75.9 months, there were 112 cases of incident cancer, which were compared with 370 controls, matched from the same cohort with respect to follow-up time, five-year age class, sex and body mass index (BMI) class.

A significantly higher mean daily dose of glargine was observed in cases, compared with controls (0.24 vs 0.16 IU/day/kg, P=0.036). A dose of glargine greater than >0.3 IU/day/kg was associated with a five times higher relative risk of incident cancer, compared with controls, even after adjusting for comorbidity score, other types of insulin administration, and metformin exposure (OR 5.43, 95%CI 2.18 to 13.53, P<0.001). No association was found between incident cancer and insulin doses for human insulin or other analogues. However, this finding could be due to insufficient sample size.

So what?
As the authors point out, in observational studies, different agents are prescribed to patients with different characteristics and those diversities cannot be entirely eliminated by statistical adjustments. Although this study took many confounding variables into account it is likely that some remain, and the study does not confirm that high doses of insulin glargine cause cancer. Nevertheless, it does suggest that dosages should be considered when the possible association between cancer and insulin and its analogues is assessed.

What does NICE say?

Type 1 diabetes

In CG15 (2004), NICE advises that:

1.9.3.8 Long-acting insulin analogues (insulin glargine) should be used when:

  • nocturnal hypoglycaemia is a problem on isophane (NPH) insulin 
  • morning hyperglycaemia on isophane (NPH) insulin results in difficult daytime blood glucose control
  • rapid-acting insulin analogues are used for meal-time blood glucose control.

Type 2 diabetes

In CG87, NICE advises:

1.7.2.4 Initiate insulin therapy from a choice of a number of insulin types and regimens.

  • Begin with human NPH insulin injected at bed-time or twice daily according to need.
  • Consider, as an alternative, using a long-acting insulin analogue (insulin detemir, insulin glargine) if:

− the person needs assistance from a carer or healthcare professional to inject insulin, and use of a long-acting insulin analogue (insulin detemir, insulin glargine) would reduce the frequency of injections from twice to once daily, or
− the person’s lifestyle is restricted by recurrent symptomatic hypoglycaemic episodes, or
− the person would otherwise need twice-daily NPH insulin injections in combination with oral glucose-lowering drugs, or
− the person cannot use the device to inject NPH insulin.

1.7.2.5 Consider switching to a long-acting insulin analogue (insulin detemir, insulin glargine) from NPH insulin in people:

  • who do not reach their target HbA1c because of significant hypoglycaemia, or
  • who experience significant hypoglycaemia on NPH insulin irrespective of the level of HbA1c reached, or
  • who cannot use the device needed to inject NPH insulin but who could administer their own insulin safely and accurately if a switch to a long-acting insulin analogue were made, or
  • who need help from a carer or healthcare professional to administer insulin injections and for whom switching to a long-acting insulin analogue would reduce the number of daily injections.

Study details:
Mannucci E, et al. Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients. Published online before print June 14, 2010, doi: 10.2337/dc10-0476

Design: Nested case-control study

Patients: Out of a consecutive series of 1,533 diabetic outpatients referred to the diabetes clinic at the University of Florence, Italy, and starting insulin therapy between January 1st 1998 and December 31st 2007, those free of previous malignancies were enrolled in the study. Case finding was performed on 1,340 patients (746 women and 594 men), mean age 63.1 years, median duration of diabetes 7.5 years, mean HbA1c 8.7% and mean BMI 27.9kg/m2.

Comparison: From within the cohort, those with cancer during follow-up were identified as cases and compared for treatments received with matched controls from the same cohort. For each case, up to five controls were chosen randomly from those members of the same cohort who were at risk for the same follow-up time as the case. Five-year age-classes, sex and BMI-classes (<18.5, 18.5 to 24.9, 25 to 29.9, >30 kg/m2) were considered as additional matching variables.

Outcomes and results: During a median follow-up of 75.9 months, 112 cases of incident cancer (incidence 1.9/100 persons/year) were compared with 370 matched controls. A significantly higher mean daily dose of glargine was observed in cases than in controls (0.24 vs. 0.16 IU/day/kg, P=0.036). Incident cancer was associated with a dose of glargine ≥0.3 IU/kg/day even after adjusting for Charlson comorbidity score, other types of insulin administration, and metformin exposure (OR 5.43, 95%CI 2.18 to 13.53, P<0.001). No association between incident cancer and insulin doses was found for human insulin or other analogues.

Sponsorship: Six of the authors have received consultancy fees and/or speaking fees and/or research grants from drug companies who manufacture insulin.

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A key message on intensive blood-pressure control in type 2 diabetes mellitus from ACCORD

Thursday, April 22nd, 2010
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20 April 2010

The ACCORD blood-pressure (BP) study conducted in patients with type 2 diabetes at high risk for cardiovascular (CV) disease concluded that intensive BP control to a target systolic blood-pressure of 120mm Hg, as compared with a target of 140mm Hg, did not reduce the rate of a composite outcome of fatal and nonfatal major CV events. There were significantly more serious adverse events attributed to antihypertensive treatment in the intensive-therapy group compared with the standard-therapy group; number needed to harm [NNH] 50 over 5 years.

Both the ACCORD BP and lipid trials add to ACCORD’s message on glycaemic control; over-intensification of treatment in type 2 diabetes mellitus provides limited or no overall benefit, and may increase the risk of adverse events.

Level of evidence: Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Action
Health professionals should continue to follow NICE guidance on the management of type 2 diabetes. The ACCORD BP trial suggests that targeting a systolic BP of less than 120mmHg, as compared with less than 140mmHg, does not reduce the rate of a composite of major CV events in patients with type 2 diabetes at high CV risk. NICE guidance recommends to reduce BP to below 140/80 mmHg (below 130/80 mmHg if there is kidney, eye or cerebrovascular damage). Health professionals may wish to consider the implications of the ACCORD BP trial, with respect to the risk and benefits of intensifying BP control, especially if aiming for BP targets below the standard target levels set by NICE.

What is the background to this?
As the NICE full guideline for diabetes notes, people with type 2 diabetes are at increased CV risk which is reduced by lowering BP. There is limited evidence from previous randomised trials to demonstrate whether or not reduction in BP below the recommended standard targets provides additional benefit. The ACCORD study evaluated the effect of intensive treatment of blood glucose on CV outcomes in 10,251 patients with type 2 diabetes who were at high risk for CV disease (see previous blog). From within the cohort of patients recruited to the ACCORD blood glucose study, patients were also recruited to two other trials to evaluate the effect of intensifying either systolic BP control (ACCORD BP trial) or lipid-modification therapy (ACCORD lipid trial) in people with type 2 diabetes.

What does this study claim
The ACCORD BP trial concluded that in people with type 2 diabetes at high risk of CV events, intensive BP control to a systolic blood-pressure target of less than 120mmHg, as compared with less than 140mmHg (standard therapy), did not reduce the rate of a composite outcome of fatal and non-fatal CV events significantly over a mean follow-up of 4.7 years. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio [HR] with intensive therapy, 0.88; 95% confidence interval [CI] 0.73 to 1.06; P=0.20). Statistically significant, small differences were seen in the rate of total stroke (0.32% per year in the intensive-therapy group vs. 0.53% per year in the standard-therapy group; HR 0.59; 95% CI 0.39 to 0.89; P=0.01) and in the rate of non-fatal stroke (0.30% per year in the intensive-therapy group vs. 0.47% per year in the standard-therapy group; HR 0.63; 95% CI 0.41 to 0.96; P=0.03). There were significantly more serious adverse events attributed to antihypertensive treatment in the intensive-therapy group (3.3%) compared with the standard-therapy group (1.3%) (P<0.001; number needed to harm [NNH] 50 over 5 years).

How does this relate to other studies?
The UKPDS and a post hoc subgroup analysis of the HOT trial showed reductions in CV events with antihypertensive therapy amongst patients with type 2 diabetes mellitus. The intensive treatment arms for both these trials achieved a mean systolic BP of 144mmHg, which is much higher than those for the ACCORD BP trial. The ADVANCE trial had no specific BP goals, and the mean systolic BP in the intensive group (135mmHg) was not as low as the mean systolic BP even in the ACCORD standard-therapy group. As there is limited evidence from randomised trials to support a strategy of lowering systolic BP below 135 to 140mmHg in patients with type 2 diabetes mellitus, the ACCORD BP trial investigated whether intensively targeting systolic BP to <120mmHg reduces major CV events.

So what?
Intensive antihypertensive therapy was not shown to significantly reduce the primary outcome or the rate of all-cause mortality, despite significant and sustained differences between the mean systolic BP of the intensive therapy group and the standard therapy group. Furthermore, no significant benefit of intensive BP control was seen with all of the secondary trial outcomes, with the exception of total and non-fatal stroke where there was a reduced rate with intensive antihypertensive therapy.

The trial showed signs of increased possible harm (including the rate of adverse events) associated with intensive BP control, compared with the standard therapy group. Both estimated glomerular filtration rate and macroalbuminuria were reduced in the intensive-therapy group, but the implications of these changes on CV and renal outcomes are uncertain. It is possible that the open-label design of the trial may have contributed as a potential source of bias in the reporting of adverse events.  As the trial focussed on evaluating the impact of specific BP targets, it remains unclear what contribution individual antihypertensive agents may have had on outcome measures and adverse events.

The observed primary outcome event rate was almost 50% lower than expected in the standard BP therapy group. This may have been due to the frequent use of statins and of inclusion criteria that directed participants with dyslipidaemia into the ACCORD lipid trial, potentially leaving lower CV risk participants in the BP trial.  Further limitations of the ACCORD BP trial include the possibility that 5 years is not long enough to see significant cardiac benefits from normalisation of systolic BP in patients with diabetes, especially if all other parameters (smoking status, glycaemic control, statins, aspirin etc.) are optimised.

NICE guidance on the management of type 2 diabetes recommends reducing BP to below 140/80 mmHg (below 130/80 mmHg if there is kidney, eye or cerebrovascular damage). The ACCORD BP trial concluded that there is no evidence that the strategy of intensive BP control, below NICE targets, reduces the rate of a composite of major CV events amongst patients with type 2 diabetes mellitus.

The ACCORD lipid trial concluded that the strategy of intensifying lipid modification therapy through combination use of fenofibrate and simvastatin (at a daily dose of 40mg or less) did not reduce rates of CV disease, as compared with simvastatin alone (see related blog ).

Study details
The Accord Study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. New Engl J Med 2010; published online March 14th (10.1056/NEJMoa1001286)

Design: Open-label, randomised controlled trial. Mean follow up 4.7 years.

Patients: Baseline characteristics were essentially similar between the two groups. The mean age of the participants was 62.2 years; 47.7% were women and 33.7% had CV disease at baseline. The mean BP of the participants at baseline was 139.2/76.0 mmHg.

Intervention and comparison: Of the 10,251 patients who were eligible for the ACCORD study, 4733 participants were enrolled in the ACCORD BP trial. Of these, 2362 were randomly assigned to intensive BP control and 2371 were assigned to standard therapy. Patients were randomised to intensive targeting of systolic BP to <120mmHg versus standard targeting of systolic BP control to <140mmHg. The primary outcome was a composite of major non-fatal myocardial infarction , stroke  or CV death.

Outcomes and results: After one year, the mean systolic BP was 119.3 mm Hg in the intensive-therapy group and 133.5 mm Hg in the standard-therapy group. The annual rate of the primary outcome was 1.87% in the intensive-therapy group and 2.09% in the standard-therapy group (hazard ratio with intensive therapy, 0.88; 95% CI 0.73 to 1.06; P=0.20). The annual rates of death from any cause were 1.28% and 1.19% in the two groups, respectively (HR 1.07; 95%CI 0.85 to 1.35; P=0.55). The annual rates of stroke, a pre-specified secondary outcome, were 0.32% and 0.53% in the two groups, respectively (HR 0.59; 95% CI, 0.39 to 0.89; P=0.01). Serious adverse events attributed to antihypertensive treatment occurred in 77 of the 2362 participants in the intensive-therapy group (3.3%) and 30 of the 2371 participants in the standard-therapy group (1.3%) (P<0.001).

Sponsorship: The studies were supported by grants from the National Heart, Lung, and Blood Institute and other components of the National Institutes of Health. Several pharmaceutical companies provided study medications, equipment, or supplies.

More information on in the management of type 2 diabetes can be found on the type 2 diabetes floor of NPCi.

You can find more information on management of hyperlipidaemia, and the rest of the evidence base for fibrates, on the lipids floor of NPCi.

Please comment on this blog in the NPCi discussion rooms, or using our feedback form.

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Fenofibrate does not reduce CV events in patients with type 2 diabetes when added to simvastatin

Thursday, April 22nd, 2010
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22 April 2010

The ACCORD lipid trial in patients with type 2 diabetes concluded that intensifying lipid modification therapy through combination use of fenofibrate and simvastatin (at a daily dose of 40mg or less) did not reduce the rate of fatal CV events, non-fatal myocardial infarction or stroke, as compared with simvastatin alone.

Both the ACCORD BP and lipid trials add to ACCORD’s message on glycaemic control; over-intensification of treatment in type 2 diabetes mellitus provides limited or no overall benefit, and may increase the risk of adverse events.

Level of evidence: Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Action
NICE guidance on the management of type 2 diabetes recommends that if the cardiovascular (CV) risk is high (as is usual in people with type 2 diabetes) consider adding a fibrate to statin therapy if triglyceride levels remain in the range 2.3 to 4.5mmol/litre despite statin therapy. Health professionals should continue to follow NICE guidance with respect to management of lipid levels in diabetes, but may wish to consider the implications of additional information now available from the ACCORD lipid study when discussing with patients the risks and benefits of adding a fibrate to statin therapy.

What is the background to this?
As the NICE full guideline for diabetes notes, people with type 2 diabetes are at increased CV risk which can be reduced by suitable lipid modification. The hypothesis tested by the ACCORD lipid trial was that in high-risk patients with type 2 diabetes, combination treatment with a fibrate (both to raise HDL cholesterol levels and to lower triglyceride levels) and a statin (to reduce LDL cholesterol levels) would reduce the rate of CV events, as compared with treatment with a statin alone. From within the cohort of patients recruited to the ACCORD blood glucose study, patients were also recruited to two other trials to evaluate the effect of intensifying either systolic blood pressure (BP) control (ACCORD BP trial – see related blog or lipid-modification therapy (ACCORD lipid trial), in people with type 2 diabetes.  

What does this study claim?
The ACCORD lipid trial found that combination therapy with fenofibrate and simvastatin (at a daily dose of 40mg or less) did not reduce rates of CV events, as compared with simvastatin alone. The annual rate of the primary outcome (major fatal or non-fatal cardiovascular event) was 2.2% in thefenofibrate group and 2.4% in the placebo group (hazard ratio [HR]0.92; 95% confidenceinterval [CI]0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome, including total mortality.

The study drug was discontinued by 66 patients (2.4%) in the fenofibrate group and 30 (1.1%) in the placebo group because of a decrease in the estimated GFR. At the last clinic visit, 440 patients (15.9%) in the fenofibrate group and 194 (7.0%) in the placebo group were receiving a reduced dose of either fibrate or placebo because of a decreased estimated GFR (P values not provided). There was a lower incidence of both microalbuminuria and macroalbuminuria in the fenofibrate group than in the placebo group. Despite this there was no significant between-group difference in the incidence of hemodialysis and end-stage renal disease (75 patients in the fenofibrate group vs. 77 in the placebo group).

How does this relate to other studies?
Previously the FIELD study suggested that fenofibrate did not significantly reduce the risk of the primary outcome of coronary events in patients with type 2 diabetes mellitus. As previous fibrate studies in diabetes, or in those without diabetes, did not evaluate the effectiveness of fibrates in patients who were also taking a statin, the ACCORD lipid trial was designed to examine this.

So what?
The trial investigated the effectiveness of fenofibrate in patients with type 2 diabetes mellitus who were also taking open-label simvastatin: assessed by giving patients masked fenofibrate or placebo. The expectation was that fenofibrate would increase plasma HDL cholesterol levels and reduce plasma triglyceride levels in patients already receiving simvastatin therapy and that this would result in additional CV benefits. However, the rate of the primary outcome (a composite of non fatal MI or stroke and all-cause CV mortality) did not differ significantly between the fenofibrate group and the placebo group.

The authors claim that there was a suggestion of heterogeneity according to baseline lipid levels found in the group of patients who had both a triglyceride level in the highest third (median triglyceride level 284 mg per decilitre [3.21 mmol per litre]) and an HDL cholesterol level in the lowest third (mean 29.5 mg per decilitre [0.76 mmol per litre]). Despite not reaching conventional levels of statistical significance (P=0.057), the point estimate from this subgroup is similar to those in post-hoc subgroup analyses performed in previous fibrate trials (Helsinki Heart Study, Bezafibrate Infarction Prevention, and FIELD). This supports the view that the addition of fenofibrate to a statin may benefit patients with type 2 diabetes who have substantial dyslipidaemia. This is consistent with NICE guidance on the management of type 2 diabetes that recommends that if the CV risk is high (as is usual in people with type 2 diabetes) consider adding a fibrate to statin therapy if triglyceride levels remain in the range 2.3 to 4.5mmol/litre despite statin therapy (plus appropriate dietary advice and adherence to that advice). The compromising of renal function with the combination, as seen in this study, would perhaps be a balancing factor in decision making, even though an increase in serious renal complications was not found.

For the entire ACCORD lipid cohort only sex had a significant interaction with treatment: men seemed to benefit from fenofibrate therapy, whereas there was a trend toward harm among women. This is in contrast to the results of the FIELD study, in which there was no significant interaction effect between treatment and sex on outcome.

The ACCORD lipid trial concluded that combination therapy with the use of fenofibrate and simvastatin (at a daily dose of 40mg or less) did not reduce rates of cardiovascular events, as compared with simvastatin alone. These results do not support the routine use of combination therapy with fenofibrate and simvastatin to reduce cardiovascular risk in the majority patients with type 2 diabetes.

Study details
The Accord Study Group. Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus. New Engl J Med 2010; published online March 14th (10.1056/NEJMoa1001282)  

Design: Randomised controlled trial.

Patients: Of the 10,251 patients with type 2 diabetes mellitus who were at high risk for cardiovascular disease who were enrolled in the ACCORD study, 5,518 participants were enrolled in the ACCORD lipid trial, with 2,765 assigned to receive fenofibrate plus simvastatin, and 2,753 assigned to receive placebo plus simvastatin. Baseline characteristics were similar between the two groups (all P>0.05). The mean age was 62 years, and 31% of the patients were female. Thirty-seven percent had a history of a CV event, and about 60% were taking a statin before enrollment.

Intervention and comparison: Patients were randomised to receive combination therapy with open-label simvastatin plus a fenofibrate or open-label simvastatin plus matching placebo. The primary outcome was the first occurrence of non-fatal myocardial infarction, non-fatal stroke, or death from CV causes. The mean follow-up was 4.7 years.

Outcomes and results: The annual rate of the primary outcome was 2.2% in the fenofibrate group and 2.4% in the placebo group (HR 0.92; 95% CI 0.79 to 1.08; P=0.32). There were also no significant differences between the two study groups with respect to any secondary outcome. Annual rates of death were 1.5% in the fenofibrate group and 1.6% in the placebo group (HR 0.91; 95% CI 0.75 to 1.10; P=0.33). Prespecified subgroup analyses suggested heterogeneity in treatment effect according to sex, with a benefit for men and possible harm for women (P=0.01 for interaction), and a possible interaction according to lipid subgroup, with a possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high density lipoprotein cholesterol (P=0.057 for interaction). However, the latter did not reach conventional levels of statistical significance.

Sponsorship: National Heart, Lung, and Blood Institute and other components of the National Institutes of Health. Several pharmaceutical companies provided study medications, equipment, or supplies.

More information on in the management of type 2 diabetes can be found on the type 2 diabetes floor of NPCi.

You can find more information on management of hyperlipidaemia, and the rest of the evidence base for fibrates, on the lipids floor of NPCi.

Please comment on this blog in the NPCi discussion rooms, or using our feedback form.

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Insulin use may increase mortality in type 2 diabetes

Thursday, April 15th, 2010
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15 April 2010

A large observational study found a statistically significant association between all-cause mortality and exposure to insulin in people with type 2 diabetes, with nearly a three times greater risk in the highest exposure group compared with never-users. This dose-response relationship was also seen with the secondary outcomes of cardiovascular and non-vascular mortality.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Action
NICE guidance on the management of type 2 diabetes recommends that patients should be involved in setting their individual glycated haemoglobin (HbA1c) target, which may be above the general target of 6.5% (48mmol/mol). NICE recommends adding a second oral drug where patients are unable to reach their agreed target by lifestyle modification or monotherapy with an oral hypoglycaemic agent (usually metformin). Insulin therapy is suggested by NICE as an option where the HbA1c does not fall below 7.5% (59mmol/mol), or does not reach an agreed higher target. Health professionals may wish to consider the implications of the present study, and others we have blogged, in their discussion with patients about risks and benefits of intensifying drug treatment, setting of individual HbA1c targets and use of insulin in type 2 diabetes mellitus.

What is the background to this?
The ACCORD, ADVANCE and VADT randomised controlled trials (RCTs) did not identify a consistent significant benefit of intensive glycaemic control in the treatment of type 2 diabetes with regard to cardiovascular (CV) outcomes and mortality. Indeed, the ACCORD study, which compared treatments that aimed to achieve HbA1c levels of less than 6.0% (42mmol/mol) with those of between 7.0% (53mmol/mol) and 7.9% (63mmol/mol) was stopped early because of an increased risk of death in the intensive treatment arm. It is unclear whether insulin use was associated with the increased mortality risk seen in the intensive treatment arm of the ACCORD study. (See Blog No.1021 on the post-hoc analysis of ACCORD).

This cohort study compared rates of all cause mortality in more than 12,000 newly treated people with type 2 diabetes exposed to various levels of insulin. Time at risk in patients who received an  average of fewer than three insulin prescriptions per year was classed as low exposure, 3 to 12 prescriptions per year (<1 vial/month) was classed as moderate exposure and 12 prescriptions or more per year  (> 1 vial/month) was classed as high exposure. Secondary outcomes were CV mortality and non-vascular-related mortality.

What does this study claim?
The study found a statistically significant dose-related association between all cause mortality and insulin exposure level. After adjusting for confounders, the risk of dying varied from about 75% higher in the lower exposure group to 179% higher in the  highest exposure group, compared to the non-exposed group (low exposure hazard ratio [HR] 1.75, 95%CI 1.24 to 2.47; moderate exposure HR 2.18, 95%CI 1.82 to 2.60; high exposure HR 2.79, 95%CI 2.36 to 3.30). A similar dose-response relationship was seen for the secondary outcomes: CV mortality and non-vascular mortality increased with increasing exposure to insulin.

So what?
Although, the study suggests that increasing levels of insulin exposure are associated with higher levels of mortality in patients with type 2 diabetes, the study has several limitations which mean that its findings should be interpreted with caution. Observational data such as these are subject to bias. Unlike an RCT, in ‘real life’ treatment plans are chosen, changed, or actively not chosen in the light of individual patients’ risk factors, preferences and tolerability or response to other drugs. Therefore, observed differences in outcomes may well be due to differences among the patients, not only the different treatments. Although adjustments were made for many potential confounders in this study, no adjustments could be made for clinical variables such as HbA1c, body mass index and smoking status. In addition, some variables were estimated using proxy markers and may not have been accurate. For example, number of insulin units per day prescribed was used as a marker for insulin dosage per day, and presence of micro- and macrovascular complications was considered as a marker for disease severity. It is possible that some residual bias or confounding could provide an alternate explanation for the results.

The authors of the paper make these points themselves in the paper. However, they also point out that the magnitude of the excess mortality with insulin is so great that according to their calculations this could, for example, only be explained by an imbalance in baseline HbA1c of 10% – a value which is improbable.

The findings of another recent large retrospective cohort study of patients with type 2 diabetes receiving intensive glucose control treatment suggested that the risk of all-cause mortality increases above and below an HbA1c level of about 7.5% (59mmol/mol). In that study, intensifying treatment with insulin was associated with a greater risk of these events than intensifying treatment with oral hypoglycaemic agents (see Blog No. 1017).

NICE guidelines recommend that further intensification of therapy, usually with insulin, should be considered for those patients who are unable to achieve an HbA1c of 7.5% on dual oral hypoglycaemic therapy. Importantly however, NICE also advises that patients should be involved in setting their individual target. Health professionals may wish to consider the implications of these two observational studies in their discussion with patients regarding the risks and benefits of further intensifying therapy, especially if insulin therapy is being considered.

Study details  
Gamble J –M, et al. Insulin use and increased risk of mortality in type 2 diabetes: a cohort study. Diabetes, obesity and metabolism 2010;12:47–53

Design: Population-based cohort study using administrative databases in Saskatchewan, Canada.

Patients: 12,272 new users of oral hypoglycaemic therapy between 1991–96, grouped according to cumulative insulin exposure based on total insulin dispensations per year: no exposure (reference group); low exposure (0 to <3); moderate exposure (3 to <12) and high exposure (12 or more).

Intervention and comparison: The relationship between insulin exposure was compared with all-cause mortality (primary outcome), CV-related mortality and non-vascular mortality (secondary outcomes) after adjusting for demographics, medications and co-morbidities.

Results: Average age was 65 years, 45% were female and mean follow up was 5.1 years. In total, 1,443 (12%) subjects started insulin, and 2,681 (22%) deaths occurred. After adjustment, a graded risk of mortality associated with increasing exposure to insulin was observed: low exposure adjusted HR 1.75, 95% CI 1.24 to 2.47; moderate exposure adjusted HR 2.18, 1.82 to 2.60; high exposure adjusted HR 2.79, 2.36 to 3.30; P=0.005 for trend. Analyses restricted to CV-related (P=0.042 for trend) and non-vascular (P=0.004 for trend) mortality showed a similar relationship. Adjusted HRs for CV-related mortality were 1.65 (95%CI 0.82 to 3.32), 1.71 (95%CI 1.17 to 2.50) and 2.51 (1.81 to 3.50) respectively. For non-vascular mortality they were 1.78 (95%CI 1.19 to 2.65), 2.34 (1.91 to 2.87) and 2.90 (2.39 to 3.52) respectively.

Sponsorship: Canadian Institute for Health Research (CIHR) Team Grant to the Alliance for Canadian Health Outcomes Research in Diabetes, sponsored by the CIHR Institute of Nutrition, Metabolism and Diabetes.

More information on the management of type 2 diabetes can be found on the appropriate floor on NPCi

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Categories:  Diabetes

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Update on glitazones and cardiovascular risks

Friday, March 19th, 2010
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19 March 2010

In a recent Science Advisory, the American Heart Association and the American College of Cardiology Foundation have summarised the currently available data on the cardiovascular risks of glitazones and provided practical recommendations for health professionals.

Action
In people with type 2 diabetes, priority should be given to reducing cardiovascular (CV) risk — lifestyle interventions (stopping smoking, losing weight, and taking more exercise as appropriate), controlling blood pressure, taking a statin, taking metformin.

In some patients, additional hypoglycaemic drugs may be considered to control blood glucose. However, NICE guidance on type 2 diabetes should be followed and individual targets for HbA1c should be agreed with each patient. These could be above that of 6.5% (48mmol/mol) set for people with type 2 diabetes in general and should take into account patient preferences and the balance of likely benefits and harms (such as hypoglycaemia) as well as the medicines management issues.

When considering prescribing a glitazone, health professionals should continue to follow MHRA advice published in October 2007 and December 2007. Neither pioglitazone▼ nor rosiglitazone should be used in people with heart failure or a history of heart failure. Rosiglitazone should be used in patients with previous or current ischaemic heart disease (IHD) only after a careful evaluation of the individual patient’s risk. Furthermore, neither glitazone should be commenced or continued in people at higher risk of fractures.

What does this Science Advisory say?
The Advisory says that “Thiazolidinediones [glitazones] should not be used with an expectation of benefit with respect to IHD events. Insufficient data exist to support the choice of pioglitazone over rosiglitazone. Thiazolidinediones increase the risk of heart failure and should not be initiated in patients with NYHA class III/IV CHF”

There has been only one prospective RCT specifically designed to assess the effect of rosiglitazone on CV outcomes — the RECORD study. However, due to study limitations the results relating to CV risks are inconclusive. Meta-analyses of RCTs have also reported inconsistent results. The Advisory concludes that an association between rosiglitazone and IHD has not yet been firmly established, although sufficient evidence has emerged to raise concerns about a potential adverse effect.

The majority of published studies on pioglitazone (including the PROactive study) do not suggest an increased risk of CV events. However, there are currently no prospective RCTs that have examined the risk of CV events associated with pioglitazone compared with rosiglitazone and observational studies have reached different conclusions. The Advisory also comments on the well established effects of glitazones in exacerbating heart failure.

The Advisory recommends that the essential components for prevention of CV events in patients with type 2 diabetes include smoking cessation, maintenance of optimal body weight, diet, physical activity, control of blood pressure and lipids (with statins as first-line therapy), and use of aspirin (see our blog which discusses recent data on the effectiveness of aspirin for primary prevention in patients with diabetes). These interventions are of proven benefit in reducing macrovascular disease and saving lives. There is however, a paucity of evidence that any hypoglycaemic drug reduces macrovascular risk, and there are questions about whether rosiglitazone or intensive glycaemic control may have adverse effects on risk for IHD. Of the available agents, metformin in obese patients with type 2 diabetes has provided the strongest evidence of CV disease benefit.

The Advisory concludes by saying that clinical trials focusing purely on glycaemic control as the primary outcome do not provide the quality of evidence required to make informed decisions regarding the efficacy and safety of glucose-lowering regimens with respect to both microvascular and macrovascular disease. More data are needed to clarify the effects of all existing and future glucose-lowering agents on CV events.

More information on the choice of hypoglycaemic drugs can be found on the type 2 diabetes floor of NPCi.

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Statins and risk of diabetes

Monday, March 1st, 2010
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01 March 2010

This meta-analysis found statin therapy was associated with a small increase in the absolute risk of developing diabetes. However, for people in whom statin therapy is indicated, this risk is outweighed by the benefit of statins in the reduction of cardiovascular events.

Level of evidence:
Level 1 (good quality patient-oriented evidence) according to the SORT criteria.

Action
Health professionals should continue to follow NICE guidance on lipid modification and offer statins to people with clinical evidence of cardiovascular disease (CVD), or a 20% or greater 10-year risk of developing this. The benefits of statin therapy continue to outweigh the risks, including any small increased risk there may be of developing diabetes. Health professionals should, however, be aware of the results of this meta-analysis so they can discuss them with new and existing patients in conjunction with a discussion around likely benefits and other possible harms. The NPCi patient decision aid on statins may help in these discussions.

What is the background to this?
This meta-analysis was conducted to explore whether there is any relationship between statin use and the development of diabetes, following conflicting reports from large, placebo-controlled, randomised controlled trials. Statin therapy is effective for the reduction of cardiovascular events and is generally recognised as being safe and well-tolerated. As we have previously blogged, the MHRA recently issued new advice and information on side effects of statins (such as sleep disturbance, memory loss, sexual disturbances, depression, and interstitial pneumopathy). Nevertheless, they also stated that the balance of risks and benefits of statins as a class remains positive, and that statins are one of the most important and widely used medicines in patients with lipid disorders and in the prevention of cardiovascular events.

What does this study claim?
Statin therapy was associated with a 9% increased risk for incident diabetes relative to those who hadn’t taken a statin (odds ratio [OR] 1.09; 95% confidence interval [CI] 1.02 to 1.17). Of the 91,140 patients included in 13 trials, 2,226 assigned statins and 2,052 assigned control treatment developed diabetes during a mean of four years. This represents one additional case of diabetes per 255 (95%CI 150 to 852) patients taking statins for four years. The risk of developing diabetes with statins was highest in trials with older participants, but baseline body-mass index and change in LDL-cholesterol concentrations did not seem to be important factors.

So what?
The results of this meta-analysis show that patients taking statins were at slightly increased risk of diabetes compared with those not taking statins, and this risk seemed higher in older patients. The results only show that statins were associated with an increased risk of diabetes, not that they caused this (although this is a possibility) and the association may be due to residual confounding factors. Also, we don’t know from this study if any increase risk of developing diabetes resulted in a detrimental effect on patient-oriented outcomes, i.e. did them developing diabetes prevent them living longer or better?

Whatever the cause, in absolute terms, the increased risk of diabetes is small, especially in relation to the reduction in cardiovascular events seen with statins. In this meta-analysis, one additional case of diabetes was seen per 255 patients taking statins for four years. The authors calculated that, using data from the Cholesterol Treatment Trialists (CTT) meta-analysis of statin trials in 71,370 non-diabetic patients, statins are associated with a reduction in major coronary events of 5.4 events per 255 patients treated for four years (this is compared with control therapy for a 1mmol/L reduction in LDL-cholesterol).

In view of the evidence for benefit with statins, the authors argue that the small excess risk of incident diabetes is favourably balanced by cardiovascular benefit. Therefore, these results should not change clinical decision making in patients for whom statins are indicated. NICE guidance on lipid modification states that statins should be offered to people with clinical evidence of CVD, or a 20% or greater 10-year risk of developing this; and this guidance remains appropriate. For patients at lower cardiovascular risk or in patient groups in which cardiovascular benefit has not been proven, the potentially raised risk of diabetes should be taken into account if statin therapy is considered.

The authors recommend that the development of diabetes should be specified as a secondary endpoint in future large statin trials. They also suggest that screening for diabetes might be useful in patients taking statins, particularly older patients, and this would seem to be sensible advice.

Study details 
Sattar N, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet. Early Online Publication, 17 February 2010, doi:10.1016/S0140-6736(09)61965-6

Design, patients, intervention and comparison
Meta-analysis of large placebo- and standard-care-controlled trials of statins with cardiovascular endpoints. Included only trials with more than 1000 patients, with identical follow-up in both groups and duration of more than one year. Trials in patients with diabetes, organ transplants or who needed haemodialysis were excluded.

Outcomes and results
13 statin trials with 91,140 patients were included. There was little heterogeneity between trials. During a mean follow-up of four years, 4,278 patients (2,226 assigned statins and 2,052 assigned control treatment) developed diabetes. There were 174 more cases of incident diabetes in the statin group, representing a 9% relative increased risk for incident diabetes (OR 1.09; 95% CI 1.02 to 1.17). In absolute terms, this is one additional case of diabetes per 255 (95%CI 150 to 852) patients taking statins for four years; or 12.23 cases per 1000 patient-years with statins and 11.25 cases per 1000 patient-years with control therapy. Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for residual variation in risk.

Sponsorship
None

More information on statins can be found on the cardiovascular disease – lipids floor of NPCi.

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Severe hypoglycaemia with intensive glucose-lowering therapy in type 2 diabetes: risk factors and mortality

Monday, February 8th, 2010
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8 February 2010

An epidemiological analysis [1] of data from the ACCORD study identified an association between symptomatic hypoglycaemia and mortality. However, this did not explain the increased mortality seen in the intensive glucose-lowering arm of the study compared with the standard treatment arm. Another analysis [2] of the ACCORD study identified factors that appear to put patients at increased risk of hypoglycaemia when receiving intensive glucose-lowering therapy.

Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.

Action
Health professionals should follow NICE guidance on the management of type 2 diabetes. Individual targets for HbA1c should be agreed with each patient, which could be greater than the general target of 6.5% (48mmol/mol). Highly intensive management to levels of less than 6.5% (48mmol/mol) should be avoided.

Severe hypoglycaemia carries an increased risk of mortality. When intensifying treatment for control of hyperglycaemia, clinicians need to be aware of the factors that put patients at increased risk of severe hypoglycaemia; these may include patients with higher HbA1c and those whose HbA1c levels do not respond promptly to treatment. Women, African Americans, people with lower education levels, older people, and those using insulin also appear to have a greater risk of severe hypoglycaemia.

What is the background to this?
Hypoglycaemia is a major risk of intensive glucose control. Although mild episodes generally are well tolerated, severe hypoglycaemia can cause serious injury, unconsciousness, seizures, coma, myocardial ischaemia, angina, residual neurological impairment, or death. We have also recently blogged about an association between lower HbA1c levels and an increased risk of car crashes (a relative risk increase of 26% for every 1% (11 mmol/mol) reduction.

The ACCORD study of patients with type 2 diabetes was stopped early when interim analysis detected greater mortality in the intensive glucose-lowering treatment arm compared with standard treatment. These post-hoc analyses were carried out to examine the relationship between increased incidences of severe hypoglycaemia and mortality, and to examine factors associated with the increased risk of hypoglycaemia seen in patients receiving intensive therapy in the ACCORD study.

What do the studies claim?
Symptomatic, severe hypoglycaemia was associated with an increased risk of death within the intensive (adjusted hazard ratio (HR) 1.41, 95%CI 1.03 to 1.93) and standard (adjusted HR 2.30, 95% CI 1.46 to 3.65) glucose-lowering treatment arms of the ACCORD study. However, symptomatic, severe hypoglycaemia did not appear to account for the difference in mortality between the two study arms up to the time when the ACCORD intensive treatment arm was discontinued. [1]

The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard treatment group. Statistically significant increased risks for hypoglycaemia were found among women, African-Americans (compared with non-Hispanic whites), those with less than a high school education (compared with college graduates), older patients, and those who used insulin at trial entry. Patients with poorer glycaemic control (i.e. higher baseline HbA1c) had a greater risk of hypoglycaemia than those with better control, irrespective of treatment group. A greater drop in HbA1c between baseline and four months was not associated with an increased risk for hypoglycaemia. The authors suggest that individuals started on intensive therapy who do not respond promptly with a fall in HbA1c may be at increased risk of severe hypoglycaemia than those that do. [2]

So what?
As we have blogged previously, the role of intensive glucose control is uncertain. In terms of cardiovascular outcomes, the addition of hypoglycaemic drugs to reduce HbA1c to levels significantly below that of standard treatments does not appear to offer any significant benefit in addition to that achievable by successful implementation of other interventions to reduce cardiovascular risk (including smoking cessation, exercise, losing weight, controlling blood pressure, taking statins, etc).

In contrast, intensive glucose lowering carries an increased risk of severe hypoglycaemia, as found in the intensive treatment arm of the ACCORD study. However, according to the first analysis [1], although severe hypoglycaemia may be a contributor, it does not appear to explain much of the increased risk of mortality seen in the two treatment arms of the ACCORD study.

The second analysis [2] suggests a number of risk factors for hypoglycaemia that may help clinicians identify those patients who may be susceptible to a greater risk of hypoglycaemia when intensifying glucose-lowering therapy. These include patients who do not respond promptly with a fall in HbA1c and those with poorer glycaemic control (i.e. a greater initial HbA1c). Patients receiving insulin, women, African-Americans, the less-well educated, the elderly and those with longer duration of diabetes were all identified as being at greater risk of hypoglycaemia. However, caution is needed when extrapolating the findings of these analyses beyond the patient populations and interventions studied in ACCORD.

Study details

[1] Bonds DE, et al. The association between symptomatic, severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. BMJ 2010;340:b4909

    Design: Retrospective epidemiological analysis of data from the ACCORD trial.

    Patients: Patients were eligible for the ACCORD study if they had type 2 diabetes, an HbA1c concentration of 7.5% (59mmol/mol) or more during screening, and were aged 40–79 years with established cardiovascular disease or 55–79 years with evidence of subclinical disease or two additional cardiovascular risk factors. 10,194 of the 10,251 participants enrolled in the ACCORD study who had at least one assessment for hypoglycaemia during regular follow-up for vital status were included in the analysis.

    Interventions: Intensive (HbA1c <6.0% [42mmol/mol]) or standard (HbA1c 7.0–7.9% [53–63mmol/mol]) glucose control.

    Outcomes: Symptomatic, severe hypoglycaemia, manifest as either blood glucose concentration of less than 2.8mmol/L (<50 mg/dL) or symptoms that resolved with treatment and that required either the assistance of another person or medical assistance, and all cause and cause specific mortality, including a specific assessment for involvement of hypoglycaemia.

    Results: Unadjusted annual mortality among patients in the intensive glucose control arm was 2.8% in those who had one or more episodes of hypoglycaemia requiring any assistance compared with 1.2% for those with no episodes (53 deaths per 1924 person years and 201 deaths per 16 315 person years, respectively; adjusted hazard ratio (HR) 1.41, 95%CI 1.03 to 1.93). A similar pattern was seen among participants in the standard glucose control arm (3.7% (21 deaths per 564 person years) v 1.0% (176 deaths per 17 297 person years); adjusted HR 2.30, 95% CI1.46 to 3.65). Among participants with at least one hypoglycaemic episode requiring any assistance, no significant difference in the risk of death was seen in those in the intensive arm compared with those in the standard arm (adjusted HR 0.74, 95%CI 0.46 to 1.23). A significantly lower risk was observed in the intensive arm compared with the standard arm in participants who had experienced at least one hypoglycaemic episode requiring medical assistance (adjusted HR 0.55, 95%CI 0.31 to 0.99).

    [2] Miller ME, et al. The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study. BMJ 2010;340:b5444

      Design: Post hoc epidemiological analysis of the ACCORD study.

      Patients and interventions: as above

      Outcomes: Severe hypoglycaemia was defined as episodes of “low blood glucose” requiring the assistance of another person and documentation of either a plasma glucose less than 2.8mmol/l (<50mg/dl) or symptoms that promptly resolved with oral carbohydrate, intravenous glucose, or glucagon.

      Results: The annual incidence of hypoglycaemia was 3.14% in the intensive treatment group and 1.03% in the standard treatment group. Significantly increased risks for hypoglycaemia were found among women (P=0.0300), African-Americans (P<0.0001 compared with non-Hispanic whites), those with less than a high school education (P<0.0500 compared with college graduates), older participants (P<0.0001 per 1 year increase), and those who used insulin at trial entry (P<0.0001). For every 1% unit decline in the HbA1c from baseline to 4 month visit, there was a 28% (95% CI19% to 37%) and 14% (95%CI 4% to 23%) reduced risk of hypoglycaemia requiring medical assistance in the standard and intensive groups, respectively. In both treatment groups, the risk of hypoglycaemia requiring medical assistance increased with each 1% unit increment in the average updated HbA1c (standard arm: HR 1.76, 95% CI 1.50 to 2.06; intensive arm: HR 1.15, 95% CI 1.02 to 1.21).

      Sponsorship:
      The studies were supported by grants from the National Heart, Lung, and Blood Institute and other components of the National Institutes of Health. Several pharmaceutical companies provided study medications, equipment, or supplies.

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