Achieving HbA1c targets and reducing risk of complications

The long-term management of type-2 diabetes is aimed at controlling the microvascular and macrovascular complications, thereby reducing morbidity and mortality.

This is achieved through patient education, lifestyle changes, retinal screening, glycaemic, BP and lipid control.

Several studies have emphasised the importance of glycaemic control. The UKPDS looked at patients newly diagnosed with type-2 diabetes and found a reduced risk of microvascular complications in the intensive glucose therapy group.¹

Clinical complications are significantly associated with hyperglycaemia. For each 1 per cent reduction in HbA1c, there is a relative risk reduction of 21 per cent for any diabetes-related endpoint, 21 per cent for diabetes-related deaths, 14 per cent for MI and 37 per cent for microvascular complications.²

The UKPDS 10-year post-trial follow-up found that the reduction in microvascular risk persisted.¹ So, early, intensive glucose therapy seems to offer long-lasting protection against microvascular disease.

Vascular outcomes
The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study looked at targeting normal HbA1c levels (<6 per cent) in patients with either established cardiovascular disease or additional cardiovascular risk factors. There were 257 deaths in the intensive therapy group compared with 203 in the standard therapy group.³

The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) collaborative group attempted to clarify the effects of intensive glucose control on vascular outcomes (target HbA1c 6.5 per cent). It found a reduced incidence of all events, but no significant reduction in major macrovascular events.⁴

Speculation about the negative findings in the ACCORD trial has led to an emerging consensus that it is perhaps not wise to attempt to achieve HbA1c <6.5 per cent in patients with known IHD.

Metformin
Metformin is the first-line therapy in most guidance, including the new NICE guidelines.5 Metformin improves insulin sensitivity by acting on peripheral tissues to increase glucose uptake, in addition to reducing hepatic gluconeogenesis. It can reduce HbA1c by up to 1 per cent and by up to 2 per cent in combination with other oral hypoglycaemics. Unlike other agents, metformin does not cause weight gain.

The UKPDS 34 study investigated the effects of intensive glucose control with metformin in overweight patients with diabetes and found risk reductions of 32 per cent for any diabetes-related endpoint, 42 per cent for diabetes-related death and 36 per cent for all-cause mortality.⁶

Poor compliance can arise from problems with tolerability, mainly GI side-effects.

Sulphonylureas
Sulphonylureas are insulin secretagogues that act on beta-cell potassium and calcium channels. They result in a 1-2 per cent reduction in HbA1c.

With long-term use, there is a progressive decrease in their efficacy as a result of a decline in the insulin-producing ability of beta cells. This is seen with other oral hypoglycaemics.⁷

Unlike metformin, the major side-effects are hypoglycaemia and weight gain; there has also been concern they may affect cardiac potassium channels, diminishing their protective response to cardiac ischaemia.⁷

UKPDS 33 looked at the effects of intensive blood glucose control with either sulphonylureas or insulin, compared with conventional treatment.

Intensive control led to relative risk reductions of 12 per cent for any diabetes-related endpoint, 10 per cent for any diabetes-related death and 6 per cent for all-cause mortality.⁸

In the intensive group, there were more hypoglycaemic episodes (1.4 per cent per year with glibenclamide) and a significantly higher weight gain over the 10-year period (1.7kg with glibenclamide). Although there was no significant reduction in macrovascular risk, none of the drugs had an adverse effect on cardiovascular outcome.

Meglitinides
Meglitinides such as repaglinide and nateglinide are also insulin secretagogues working on separate parts of the beta-cell receptor to sulphonylureas.

Repaglinide has a similar HbA1c efficacy to the sulphonylureas but there are no available data on its microvascular and macrovascular effects.

Thiazolidinediones
Thiazolidinediones activate the peroxisome proliferator-activated receptor gamma (PPAR-), thereby reducing insulin resistance. Rosiglitazone and pioglitazone reduce HbA1c by up to 1.5 per cent. Side-effects include fluid retention, increased risk of heart failure and an increased risk of fractures, particularly in postmenopausal women.

The PROactive study was a prospective randomised controlled trial looking at the effects of pioglitazone on macrovascular complications in diabetes and cardiovascular disease. The primary composite endpoint was non-significantly reduced, by 10 per cent, with pioglitazone compared with placebo.

However, the principal secondary endpoint, a composite of non-fatal MI and stroke was significantly reduced, by 16 per cent, with pioglitazone compared with placebo.⁹

Meta-analyses have suggested that rosiglitazone is associated with an increased risk of ischaemic events¹⁰ and current recommendations are that it should not be initiated in patients with known IHD.

No trials have demonstrated that thiazolidinediones reduce microvascular disease.

Alpha-glucosidase inhibitor
The alpha-glucosidase inhibitor acarbose inhibits digestive enzymes responsible for the hydrolysis of complex carbohydrates to absorbable mono-saccharides such as glucose. A reduction in HbA1c of up to 1.8 per cent has been reported.

Meta-analyses have shown that acarbose reduces the relative risk of cardiovascular events by 35 per cent and of MI by 64 per cent, irrespective of age or weight.¹¹ However, side-effects of flatulence, diarrhoea and abdominal pain occur in up to 73.2 per cent in some trials.¹¹

Incretins
Incretin hormones glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) are released from L- and K-cells in the GI tract postprandially and stimulate glucose-induced insulin secretion from the pancreas.

GLP-1 enhances insulin secretion, inhibits glucagon release and delays gastric emptying only under hyperglycaemic conditions.

Although patients with type-2 diabetes have low levels of circulating GLP-1, they can respond to it. GLP-1 and GIP are rapidly degraded by dipeptidyl peptidase-IV (DPP-IV). GLP-1 agonists and DPP-IV inhibitors potentiate the effects of GLP-1.

Exenatide, a GLP-1 agonist, is administered subcutaneously. It is indicated for adjunctive therapy where glycaemic control is inadequate with metformin, sulphonylureas or a combination of both. Clinical studies have shown that when added to these agents, exenatide can reduce HbA1c by 0.8-1.1 per cent.¹² It also promotes weight loss.

Hypoglycaemia is rare unless co-administered with a sulphonylurea. The most common side-effect is nausea.

DPP-IV inhibitors are administered orally. Sitagliptin monotherapy reduces HbA1c by 0.6-0.7 per cent, while vildagliptin lowers it by 0.9-1.4 per cent.¹² These reductions are improved when used in combination with metformin.

Weight reduction
Weight-reduction therapy is an emerging part of diabetes management. Two drugs are licensed for the long-term treatment of obesity: orlistat, a lipase inhibitor, and sibutramine, a monoamine reuptake inhibitor.

Insulin
Type-2 diabetes is a progressive illness and eventually pancreatic beta-cells can no longer produce insulin, despite all the above interventions. When this happens, exogenous insulin is required to preserve life as well as to achieve glycaemic control.

UKPDS confirmed the benefits of insulin in reducing microvascular complications.¹

Conclusion
Several studies have demonstrated the potential benefits of improving glycaemic control to achieve HbA1c targets in patients with type-2 diabetes.

In particular, the UKPDS has shown that these benefits persist up to 10 years later in those patients who receive intensive glucose-lowering therapy.

• Dr Devendra is consultant diabetologist and endocrinologist, Brent PCT & Central Middlesex Hospital, and senior lecturer at Imperial College, London

• 14 November 2008 is World Diabetes Day. For more information visit www.worlddiabetesday.org

References

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4. The ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type-2 diabetes. N Engl J Med 2008; 358(24): 2,560-72.

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9. Dormandy J A, Charbonnek B, Eckland D J, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVacsular Events): a randomised controlled trial. Lancet 2005; 366 (9,493): 1,279-89.

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