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Improving HbA1c targets in diabetes care: how low is too low?

Sara Da Costa
MBA BSc(Hons) DipN(Lond) FETC RGN
Nurse Consultant Diabetes
Western Sussex Hospitals Trust
Visiting Fellow University of Brighton

The landmark study of type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS), prompted a review of many aspects of diabetes care and management, and raised questions regarding what good control should look like.1

Subsequent research has continued this approach, with a focus on how low HbA1c should be to improve patient outcomes and reduce complications and cardiovascular risk. Two major studies - Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) - have contributed to this debate, and have raised concerns regarding how low is too low, given the excess mortality seen in the intensive treatment arm of ACCORD.2,3

While this outcome may or may not have been expected, it does highlight concerns and suggests that we should consider safer and better ways of reducing cardiovascular risk, rather than with an overzealous reduction of HbA1c alone. This article will consider this and implications for clinical practice, in the light of these two studies.

Hyperglycaemia and cardiovascular risk
The aim of both the ACCORD and ADVANCE studies was to determine the effect of lowering glucose to near-normal levels on cardiovascular risk. The UKPDS suggested a link between hyperglycaemia and cardiovascular risk, but there was less evidence that glucose lowering was associated with reduced risk. Indeed, the UKPDS showed that a reduction in HbA1c from 8 to 7% did not reduce cardiovascular events, although those patients on metformin had a lower risk. It is relevant to note specific differences regarding cardiovascular risk in the patients who were studied in the UKPDS and ACCORD and ADVANCE trials because these will affect study outcomes. In the UKPDS, patients were included at diagnosis and those with known cardiovascular disease were excluded; whereas in ACCORD, they had been diagnosed for at least 10 years, and were likely to have some cardiovascular disease.

In type 1 diabetes, the Diabetes Control and Complications Trial (DCCT) showed the benefits of reduction in blood glucose on microvascular rather than macrovascular complications; but the 10-year follow-up study (DCCT/Epidemiology of Diabetes Interventions and Complications (EDIC)) demonstrated the sustained benefits for patients who had improved their blood glucose control during the initial study on reduction in cardiovascular events as well.4 This prompted the notion of the "legacy effect", which means that early good control at diagnosis has a lasting effect. This may suggest an emerging difference between type 1 and longer duration of type
2 diabetes.

ACCORD and ADVANCE: study comparisons
While both studies compared intensive and standard glucose-lowering targets in type 2 diabetes, there were differences (as shown in Table 1).

[[Tab 1 diabetes]]

Interestingly, neither study appears to have emphasised lifestyle or dietary modification, which does not reflect current clinical practice. Education, either structured or ad hoc, is not mentioned either. One can only speculate what difference these factors could have made. It is worth noting here that the initial review into the increased deaths in both studies did not attribute them to any single treatment; although rosiglitazone did have a warning regarding cardiovascular risk it did not appear in this review to be a causal factor. Clearly, ongoing research will investigate this further.

Both studies compared intensive and standard glucose-lowering targets in type 2 diabetes, with the following similarities:

  • Large numbers of participants (10,000-11,000) with complete follow-up, median 3.5 years, which gives confidence in the sample size.
  • Treatments were used from a variety of classes, plus or minus insulin, which reflects current practice.
  • Patients selected were typical of patients we see in our clinical practice; a third had history of macrovascular disease, their duration of diabetes was eight to 10 years, and median HbA1c was 7.2-8.1%.

Other considerations are that non-glycaemic risk factors were not controlled in ADVANCE; only 50% were receiving aspirin or statins in either arm. ACCORD had higher use - 75% and 88% respectively. Few patients met the HbA1c goal of

ACCORD was stopped early as it was found there was an increased risk of death, despite near-normal blood glucose levels. There were several suggestions regarding the cause of the increased deaths, which included being precipitated by hypoglycaemia, or by increased weight gain (noted in the intensive treatment arm) and its acknowledged cardiovascular risk effect. Treatments that caused these side-effects, eg, rosiglitazone, insulin and sulphonylureas, were scrutinised, but no single treatment or combination of treatments were found to increase the risk when initially reviewed. However, ADVANCE, with its less tight control, had fewer hypos and fewer deaths. Perhaps there are lessons here regarding not using treatment that causes either hypos or weight gain when trying to aggressively lower blood glucose, or not trying to drive down blood glucose too quickly.

Other evidence regarding lowering blood glucose and cardiovascular risk
The Veterans Administration Trial (VADT) in the USA looked at levels of control in older veterans with long-standing diabetes (mean 7.5 years, HbA1c 9.5%, 80% with hypertension, 50% abnormal lipids, 40% prior cardiovascular events).5 The trial had an intensive group and comparator group, with each group achieving HbA1c of 6.9% and 8.4% respectively. Both blood pressure and lipids improved, and smoking was reduced. Tight control in the intensive group reduced nephropathy but this group also experienced increased hypoglycaemic episodes, comparable with ACCORD. Insulin was used in 90% of the intensive group and 74% in the comparator group; however, these outcomes were not statistically significant.

The UKPDS extension report (10-year follow-up study) reported the "legacy effect" - evidence of benefits of reduced complications for the originally intensively controlled group 10 years later.6 There was also a 15% reduction in the incidence of myocardial infarction in this tightly controlled group, which now reached statistical significance, and a 13% reduction in death from any cause.

These seem significant benefits, but clinicians should also consider the patient costs from such tight control on their quality of life, eg, increase in hypoglycaemia or weight, and ensure this is discussed when goal setting. This report for type 2 diabetes matches the outcomes of the EDIC study for type 1 diabetes.4

Influencing factors
In clinical practice we are inundated with targets, often with financial remuneration; but is that all we need to decide goals with our patients?

Table 2 demonstrates some of the targets and recommendations, but the concern is that the target can miss the patient if lifestyle and choice are not included in the discussion. We generally regard our patients as individuals, rather than adopt a "one size fits all" approach, although that is what the recommendations above seem to suggest we should. However, we have our clinical knowledge, experience, research which we may chose to implement, or not, and a range of treatments (some of which may not be available due to restricted prescribing) which continues to increase.

[[Tab 2 diabetes]]

Therefore, I believe, given this context there are several factors we can use with confidence in our practice. Neither study (ACCORD nor ADVANCE) undermines the importance of meeting current guidelines for care, which include dietary and exercise counselling, smoking cessation, blood pressure control and the use of statins, and helping patients achieve currently recommended goals. An HbA1c of 7% may be more appropriate unless the focus is on primary prevention of macrovascular disease, which may be more pertinent to focus on from diagnosis, and thereby harness the legacy effect. While trying to achieve good control from diagnosis, we should still be mindful of the patient's quality of life and check they are committed to these goals.

Control of cardiovascular risk factors in people with diabetes remains very important because we know the benefits of reducing blood pressure and cholesterol. There will be problems if we ignore this and become glucose-centric, which may be one of the risks of QOF with its reduction in HbA1c to

Conclusion
This article has focused on several studies that have established the effects of intensive glucose-lowering on cardiovascular risk. It would appear that there is a risk to patients who have longstanding diabetes and/or cardiovascular disease on reducing HbA1c too low, or too quickly. It would also appear that attempting good control from diagnosis is of benefit in both the short and long term, in reducing cardiovascular risk. However, slavish target achievement can affect our patients' quality of life, although in clinical practice we all understand the drivers for this.

So, at time of writing, we do not have a definitive level that is safe for all, but perhaps, as our patients are individuals, we never will have a singular target, but instead a safe range to guide our discussions with our patients. The need to optimise control as soon as possible after diagnosis does feel right, and is summed up well by the following quote by
Rory Holman: "Good glycaemic control should be the aim from the time diabetes is first diagnosed, with doses increased or therapies added sequentially, whenever there is a tendency for HbA1c levels to rise rather than allowing HbA1c levels to rise to unacceptable levels and then applying heroic 'rescue therapy'".6,7

References
1. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-53.
2. ACCORD study group. Effects of intensive glucose lowering in type 2 diabetes. New Engl J Med 2008;358:2545-59.
3. ADVANCE collaborative group (2008) Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. New Engl J Med 2008;358:2560-72.
4. Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993;329(14):977-86.
5. Duckworth W, Abraira C, Moritz T. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360(2):129-39.
6. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow up of intensive glucose control in type 2 diabetes (UKPDS 80). New Engl J Med 2008;359:1577-89.
7. Nathan DM, Buse JB, Davidson MB. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009;32(1):193-203.