Effects of intensive glucose lowering in patients with type 2 diabetes
Epidemiological studies have shown that increases in blood glucose levels are associated with an increased risk of cardiovascular disease (CVD). An association has been found between HbA1c levels and CVD at levels below the baseline level used in the diagnosis of diabetes. Thus, after adjustment for other risk factors, a 1% increase in the HbA1c levels is associated with an 18% increase in the risk of cardiovascular events, a 12-14% increase in the risk of death, and a 37% increase in the risk of retinopathy or renal failure.

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was specifically designed to determine whether a therapeutic strategy targeting normal HbA1c levels (i.e. below 6.0%) would reduce the rate of cardiovascular events as compared with a strategy targeting HbA1c levels of 7.0-7.9%. The study population consisted of middle-aged and elderly patients with type 2 diabetes mellitus, and either established CVD or additional cardiovascular risk factors. Interim analyses of the results in the different treatment arms led to the intensive glucose-lowering arm of the study being stopped 18 months earlier than scheduled. Using intensive glucose-lowering therapy for 3.5 years increased mortality and did not significantly reduce major cardiovascular events. Apparently, hypoglycaemia was not a contributory cause and data do not as yet allow us to look further into any role played by the antidiabetic agents used. At this point, it is important to note that in both glycaemic arms of the study, the overall mortality was lower compared to similar populations in other studies.

Following the release of the interim ACCORD findings, the investigators of the Action in Diabetes and Vascular Disease (ADVANCE) trial, which enrolled 11,140 patients with a mean age of 66 years, analysed their data to see if similar results could be found in those patients receiving intensive treatment to lower blood glucose. They found no evidence of an increased risk of death within the intensively treated groups. The major difference between the two trials was the glycaemia target. It could be speculated whether there should be a J-shaped curve for glucose lowering. Obviously, we will learn more when these data are analysed further (1,2).

In the meantime, it is interesting to note that a paper has recently been published reporting on the relationship between HbA1c levels and subsequent mortality in the participants of a New Zealand population-based screening programme. Measurements of HbA1c were obtained for 48,673 subjects. Excess mortality was evident at high HbA1c concentrations (of 7.0% or more). There was also a dose response with increasing levels of HbA1c in the participants without diabetes. This is the largest study conducted to date on HbA1c levels and the subsequent risk of mortality. It confirms previous findings that HbA1c levels are strongly associated with subsequent mortality in both men and women who have not been diagnosed with diabetes (3).

A different study explored the relationship between fasting blood glucose (FBG) levels among patients with diabetes and the risk of ischaemic stroke as well as other vascular events in a multiethnic prospective cohort. A total of 3,298 subjects were recruited and enrolled between 1993 and 2001. A strong relationship was found between elevated FBG levels among patients with diabetes and an increased risk of incident ischaemic stroke as well as other vascular events after adjustments for sociodemographic and vascular risk factors were made. The authors refer to the, at that time ongoing, ACCORD study which they suggest would ultimately provide conclusive evidence regarding the importance of glycaemic control in preventing macrovascular disease, including ischaemic stroke (4). I hope that in the near future we will be able to interpret the observations made in the ACCORD study.

Determinants of new-onset diabetes among hypertensive patients randomized in the ASCOT trial
New-onset diabetes (NOD) was a predefined tertiary end-point of the blood-pressure-lowering arm of the ASCOT study and, therefore, its database provides an excellent opportunity to evaluate baseline predictors for the development of NOD among a large hypertensive population. More than 14,000 patients with hypertension were considered to be free of diabetes. The analysis provided evidence that treating hypertensive patients with a regimen based on amlodipine and perindopril compared with a regimen based on atenolol and a thiazide diuretic significantly reduced the risk of NOD. The number needed to treat was 30 patients for 5 years to prevent 1 case of NOD. The authors advise against the use of beta-blockers and diuretics in combination, in preference to other combinations, such as calcium-channel blockers plus an ACE inhibitor, when treating non-diabetic hypertensive patients, except where compelling indications apply (5).

The ONTARGET, SANDS, and PERISCOPE randomized trials
Three more major randomized trials have recently been published: ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial), SANDS (Stop Atherosclerosis in Native Diabetics Study), and PERISCOPE (Pioglitazone Effect on Regression of Intravascular Sonographic Coronary Obstruction Prospective Evaluation).

The ONTARGET trial investigated telmisartan, ramipril, or both in patients at high risk of vascular events. A total of 25,620 patients had been randomized to the treatment groups. Among these patients, 38% had diabetes. They were treated with ramipril, telmisartan, or a combination of both. The major conclusion was that telmisartan was equivalent to ramipril in patients with high-risk vascular disease or diabetes, and was associated with less angio-oedema. The combination of the two drugs was associated with more adverse events without any increased benefit (6).

In SANDS, 548 men and women with type 2 diabetes had been randomized to an aggressive-treatment or a standard-treatment group. The study was undertaken to compare the progression of subclinical atherosclerotic disease, as evaluated by carotid ultrasound, in American Indians with type 2 diabetes. The targets were directed at lowering LDL cholesterol and systolic blood pressure. Reducing these parameters to lower targets resulted in regression of carotid intima-media thickness and greater decrease in left ventricular mass. Clinical events were lower than expected and did not differ significantly between groups. According to the authors, this suggests the possibility of an incremental cardiovascular benefit of achieving lower LDL cholesterol and blood pressure targets (7).

The PERISCOPE study compared the effect of pioglitazone with glimepiride on the progression of coronary atherosclerosis in patients with type 2 diabetes. It was a prospective, randomized, multicentre, double-blind clinical trial. The findings of the PERISCOPE study support the conclusion that treatment with the insulin-sensitizing thiazolidinedione pioglitazone compared with glimepiride can prevent the progression of atherosclerosis in patients with type 2 diabetes during 18 months of treatment. The authors find that these observations may have important implications for defining the optimal strategy for management of patients with type 2 diabetes and coronary atherosclerosis (8).

Strategies for screening and preventing type 2 diabetes in adults: cost-effectiveness analysis
Three active screening strategies were compared: A) a one-off screening for type 2 diabetes; B) screening for impaired glucose tolerance and type 2 diabetes, and intervening with lifestyle interventions in those with impaired glucose tolerance; and C) as for B, but with pharmacological interventions. These three active screening strategies were compared against a fourth strategy of no screening (current practice). The main conclusion was that a policy of a one-off screening for type 2 diabetes and impaired glucose tolerance, with appropriate intervention for those identified with impaired glucose tolerance, seems to be cost-effective in an “at risk” population. Further research is needed on the long-term clinical effects of early diagnosis (9).

Self-monitoring of blood glucose in patients with type 2 diabetes
Self-monitoring of blood glucose (SMBG) has been shown to be the largest, single component of management costs associated with implementing more intensive glycaemic control in the UK. In the next two studies, economic evaluations of SMBG were performed.

The first study was a randomized controlled trial of SMBG versus no monitoring. Patients with newly diagnosed type 2 diabetes aged < 70 years were recruited. Pre-designated primary end-points were differences between groups in HbA1c, psychological indices, and indices of hypoglycaemia. SMBG had no effect on glycaemic control, but was associated with higher scores on a depression subscale (10).

The second study reported from the diabetes glycaemic education and monitoring (DiGEM) trial, which was a randomized study of 453 patients with non-insulin-treated type 2 diabetes who had HbA1c levels of 6.2% or more and were self-monitoring not more than once a week. They were allocated to either standardized usual care, a blood glucose meter with advice for participants to contact their doctor for interpretation of results, or a blood glucose meter with training in self-interpretation and application of the results to diet, physical activity, and drug adherence (most intensive self-monitoring). After 12 months, the differences in HbA1c levels between the groups were not significant. The results indicate that self-monitoring in this group of patients is unlikely to have significant lifetime health benefits or to be cost-effective in addition to standardized usual care. It is possible that subgroups of patients exist for whom self-monitoring may be cost-effective (11).

Intensive insulin therapy and beta-cell function in type 2 diabetes
A total of 382 patients with newly diagnosed type 2 diabetes were enrolled in a study in which it was shown that early intensive insulin interventions have favourable outcomes with regard to recovery and maintenance of beta-cell function. The intervention prolonged glycaemic remission compared with treatment with oral hypoglycaemic agents. The findings support the initiation of early transient intensive insulin treatment in patients with newly diagnosed type 2 diabetes (12).

Hyperglycaemia and adverse pregnancy outcomes - a report from the HAPO Study Cooperative Research Group
Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) study was conducted to clarify the risks of adverse outcomes associated with various degrees of maternal glucose intolerance, less severe than that in overt diabetes mellitus. The pregnant women enrolled in the study had no diagnosis of diabetes during or prior to their current pregnancy. They required no medication and were not participating in another study that could interfere with the HAPO study. A strong, continuous association of maternal glucose levels below those diagnostic of diabetes with increased birth weight and increased cord-blood serum C-peptide levels was found. Secondary outcomes were premature delivery, shoulder dystocia or birth injury, need for intensive neonatal care, hyperbilirubinaemia, and pre-eclampsia. Positive associations between increasing plasma glucose levels and each of the 5 secondary outcomes examined were found. Thus, maternal hyperglycaemia, less severe than that used to define overt diabetes, is related to clinically important perinatal disorders or problems (13).

Metformin versus insulin for the treatment of gestational diabetes
In the next study, the results indicated that metformin alone or with supplemental insulin, is an effective and safe treatment option for women with gestational diabetes mellitus who meet the usual criteria for starting insulin, and that metformin is more acceptable to women with gestational diabetes than insulin (14).

Microalbuminuria and progression to macroalbuminuria in children
In adults with type 1 diabetes, microalbuminuria is an early marker of structural renal disease and a risk factor for the development of macroalbuminuria. The presence of macroalbuminuria is associated with the subsequent development of end-stage renal disease and increased coronary mortality. In childhood-onset type 1 diabetes, the risk for macroalbuminuria is similar to that observed in cohorts with adult-onset disease, but as it occurs in young-adult life, early intervention in normotensive adolescents might be needed to improve diagnosis (15).

Diabetic nephropathy and dialysis treatment
Two papers have been selected for this section. The first study discusses glycated albumin and HbA1c levels in diabetic subjects on haemodialysis. In many previous studies, it has been suggested that HbA1c should underestimate long-term glycaemic control in dialysis patients with diabetes. This seems to be the case, whereas glycated albumin seems to more accurately reflect glycaemic control in these patients. More studies on the association of glycated albumin with glycaemic control are needed (16).

The second study discusses clinical outcomes and peritoneal histology in patients starting peritoneal dialysis. Diabetes associated with uraemia seems to be more strongly related to the peritoneal changes than uraemia per se. Also hypoalbuminuria and peritoneal inflammatory infiltrates were markedly associated with technique failure and mortality in patients starting peritoneal dialysis treatment (17).

Serum adiponectin and progression of diabetic nephropathy in patients with type 1 diabetes
Adiponectin is a hormone that is secreted exclusively from adipocytes and has been shown to be higher in patients with renal disease than in healthy subjects. The next study aimed to elucidate whether adiponectin plays a role in the development and progression of diabetic nephropathy in patients with type 1 diabetes. This seemed to be the case because increased serum adiponectin was shown to predict the progression from macroalbuminuria to end-stage renal disease (18).

Endothelial dysfunction in patients with type 1 diabetes
A total of 199 patients with type 1 diabetes with diabetic nephropathy and 192 patients with persistent normoalbuminuria were followed prospectively. Two z scores, an inflammatory score and a score for endothelial dysfunction, were constructed. The data suggested that the high risk of CVD in type 1 diabetes may be explained, in part, by inflammatory activity; endothelial dysfunction was correlated after multivariate adjustments with the rate of decline in glomerular filtration rate. Even though these markers did not add prognostic value to the known cardiovascular risk factors, they do provide insights into the pathophysiological pathway of CVD (19).

Effectiveness of lifestyle intervention
Randomized controlled trials on lifestyle intervention in individuals with impaired glucose tolerance have conclusively demonstrated that progression to the manifestation of type 2 diabetes can be prevented or at least postponed. This was also shown in the post-intervention follow-up of the Finnish Diabetes Prevention Study (DPS). The aim of the DPS was to clarify whether and to what extent risk factors for type 2 diabetes, alongside other baseline characteristics of the participants, modified the effects of lifestyle intervention in reducing the incidence of diabetes, by using a simple risk-assessment tool (the Finnish Diabetes Risk Score - FINDRISC). The main observation was that intervention was most effective among those with higher baseline age or a high FINDRISC (20). More details on the FINDRISC can be found in the March 2003 issue of Diabetes Care.

References

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  2. ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358:2560-72.
  3. Brewer N, Wright CS, Travier N, Cunningham CW, Hornell J, Pearce N, et al. A New Zealand linkage study examining the associations between A1C concentration and mortality. Diabetes Care. 2008;31:1144-9.
  4. Boden-Albala B, Cammack S, Chong J, Wang C, Wright C, Rundek T, et al. Diabetes, fasting glucose levels, and risk of ischemic stroke and vascular events: findings from the Northern Manhattan Study (NOMAS). Diabetes Care. 2008;31:1132-7.
  5. Gupta AK, Dahlof B, Dobson J, Sever PS, Wedel H, Poulter NR; Anglo-Scandinavian Cardiac Outcomes Trial Investigators. Determinants of new-onset diabetes among 19,257 hypertensive patients randomized in the Anglo-Scandinavian Cardiac Outcomes Trial - Blood Pressure Lowering Arm and the relative influence of antihypertensive medication. Diabetes Care. 2008;31:982-8.
  6. ONTARGET Investigators; Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547-59.
  7. Howard BV, Roman MJ, Devereux RB, Fleg JL, Galloway JM, Henderson JA, et al. Effect of lower targets for blood pressure and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial. JAMA. 2008;299:1678-89.
  8. Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, et al.; PERISCOPE Investigators. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008;299:1561-73.
  9. Gillies CL, Lambert PC, Abrams KR, Sutton AJ, Cooper NJ, Hsu RT, et al. Different strategies for screening and prevention of type 2 diabetes in adults: cost effectiveness analysis. BMJ. 2008;336:1180-5.
  10. O'Kane MJ, Bunting B, Copeland M, Coates VE; ESMON study group. Efficacy of self monitoring of blood glucose in patients with newly diagnosed type 2 diabetes (ESMON study): randomised controlled trial. Br Med J. 2008;336:1174-7.
  11. Simon J, Gray A, Clarke P, Wade A, Neil A, Farmer A; Diabetes Glycaemic Education and Monitoring Trial Group. Cost effectiveness of self monitoring of blood glucose in patients with non-insulin treated type 2 diabetes: economic evaluation of data from the DiGEM trial. BMJ. 2008;336:1177-80.
  12. Weng J, Li Y, Xu W, Shi L, Zhang Q, Zhu D, et al. Effect of intensive insulin therapy on beta-cell function and glycaemic control in patients with newly diagnosed type 2 diabetes: a multicentre randomised parallel-group trial. Lancet. 2008;371:1753-60.
  13. HAPO Study Cooperative Research Group; Metzger BE, Lowe LP, Dyer AR, Trimble ER, Chaovarindr U, Coustan DR, et al. Hyperglycemia and adverse pregnancy outcomes. N Engl J Med. 2008;358:1991-2002.
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  16. Peacock TP, Shihabi ZK, Bleyer AJ, Dolbare EL, Byers JR, Knovich MA, et al. Comparison of glycated albumin and hemoglobin A(1c) levels in diabetic subjects on hemodialysis. Kidney Int. 2008;73:1062-8.
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