English: Illustration of the changes in blood glucose over time following a high and low GI carbohydrate. Designed and made Public Domain by Scott Dickinson (user: Studio34), Sydney, Australia. (Photo credit: Wikipedia)

Diabetes - type 2 - Evidence
Evidence on target blood glucose levels

There is good evidence from epidemiological and intervention studies that decreasing the HbA_1c level can reduce both the macrovascular and the microvascular complications of type 2 diabetes. There appears to be no threshold below which the risk is no longer reduced, nor a level above which the risk is no longer increased.
Two recent randomized controlled trials (RCTs) comparing intensive blood glucose lowering treatment (targeting an HbA_1c level below 6.0%) with standard treatment (targeting an HbA_1c level between 7.0% and 7.9%) failed to identify a significant improvement in macrovascular vascular outcomes with intensive therapy; one study demonstrated a significant increase in all-cause mortality with intensive therapy, and both studies demonstrated a significant increase in hypoglycaemia with intensive therapy.
In one long-term follow up study, despite an early loss of difference in glycaemic control between a conventional treatment group and an intensive treatment group, a continued reduction in microvascular risk and emergent risk reductions for myocardial infarction and death from any cause were observed during 10 years of post-trial follow-up.
Epidemiological studies have demonstrated a relationship between HbA_1c and vascular complications in people with type 2 diabetes:

The UK Prospective Diabetes Study 35 (n = 3867) suggested that the lower the HbA_1c level, the better the outcome [UK Prospective Diabetes Study Group et al, 2000]. For every percentage reduction in the HbA_1c level, there is a:

21% decrease in risk for any diabetes-related endpoint (95% CI 17 to 24, p < 0.0001).
21% decrease in risk for any diabetes-related death (95% CI 15 to 27, p < 0.0001).
14% decrease in risk for myocardial infarction (95% CI 8 to 21, p < 0.0001).
37% decrease in risk for microvascular complications (95% CI 33 to 41, p < 0.0001).

There was no indication of a threshold for any complication below which risk no longer decreased, nor a level above which risk no longer increased.

Two recent RCTs investigated the effect of intensive glucose control on vascular outcomes [Action to Control Cardiovascular Risk in Diabetes Study Group, 2008; ADVANCE Collaborative Group, 2008]:

The Action to Control Cardiovascular Risk in Diabetes (ACCORD) study investigated whether intensive therapy (target HbA_1c level below 6.0%) would reduce cardiovascular events compared with standard therapy (target HbA_1c level between 7.0% and 7.9%) in people with type 2 diabetes [Action to Control Cardiovascular Risk in Diabetes Study Group, 2008]:

People with type 2 diabetes and either established cardiovascular (CV) disease or additional CV risk factors (n = 10,251) were randomized to receive either intensive therapy targeting an HbA_1c level of less than 6.0% or standard therapy targeting a level of 7.0–7.9%.
The primary outcome was a composite of the first occurrence of nonfatal myocardial infarction (MI), nonfatal stroke, or death from CV causes.
Stable median HbA_1c levels of 6.4% (interquartile range 6.1 to 7.0) in the intensive therapy group and 7.5% (interquartile range 7.0 to 8.2) in the standard therapy group were achieved at 1 year and were maintained throughout follow up.
Intensive therapy was stopped after a mean of 3.5 years follow up because of a higher mortality rate in the intensive therapy group.
The incidence of nonfatal myocardial infarction (MI), nonfatal stroke, or death from CV causes did not differ between the two groups:

During follow up, the primary composite outcome occurred in 352 people (6.9%) in the intensive therapy group compared with 371 people (7.2%) in the standard therapy group (hazard ratio [HR] 0.90, 95% CI 0.78 to 1.04; p = 0.16).

However, all-cause mortality and death from CV causes increased in the intensive therapy group compared with the standard therapy group:

During follow up, death from any cause occurred in 257 people (5.0%) in the intensive therapy group compared with 203 people (4.0%) in the standard therapy group (HR 1.22, 95% CI 1.01 to 1.46; p = 0.04).
During follow up, death from CV causes occurred in 135 people (2.6%) in the intensive therapy group compared with 94 people (1.8%) in the standard therapy group (HR 1.35, 95% CI 1.04 to 1.76; p = 0.02).

Hypoglycaemia requiring assistance and weight gain of more than 10 kg were also more frequent in the intensive therapy group (p < 0.001).

The ADVANCE study was also designed to investigate the effects of intensive glucose control (using modified-release gliclazide plus other antidiabetic drugs as required to achieve an HbA_1c level of 6.5% or less) on vascular outcomes [ADVANCE Collaborative Group, 2008]:

People with type 2 diabetes and a history of major macrovascular or microvascular disease or at least one other risk factor for vascular disease (n = 11,140) were randomized to receive either intensive therapy (modified-release gliclazide with the addition of metformin, a glitazone, acarbose, or insulin as needed to attain an HbA_1c level of less than 6.0%) or standard therapy (HbA_1c targets defined on the basis of local guidelines).
The primary outcomes were a composite of macrovascular events (death from CV causes, nonfatal MI, or nonfatal stroke) and a composite of microvascular events (new or worsening nephropathy or retinopathy), considered both jointly and separately.
After a median of 5 years of follow up, the mean HbA_1c level was lower in the intensive glucose control group (6.5%) than in the standard glucose control group (7.3%).
The incidence of combined major macrovascular and microvascular events was reduced with intensive control (18%) compared with standard control (20%): HR 0.90, 95% CI 0.82 to 0.98; p = 0.01.
The incidence of major microvascular events was also reduced (9.4% compared to 10.9%, HR 0.86, 95% CI 0.77 to 0.97; p = 0.01), primarily because of a reduction in the incidence of nephropathy (4.1% compared to 5.2%, HR 0.79, 95% CI 0.66 to 0.93; p = 0.006), with no effect on retinopathy (p = 0.50).
The type of glucose control had no effect on major macrovascular events, death from CV causes, or death from any cause.
Severe hypoglycaemia, although uncommon, was more common in the intensive glucose control group (2.7%) than the standard glucose control group (1.5%): HR 1.8, 95% CI 1.42 to 2.40; p < 0.001.

A 10-year follow up of UK Prospective Diabetes Study (UKPDS 33) investigated whether intensive glucose-lowering treatment during the early stage of type 2 diabetes had a long-term effect on macrovascular outcomes [Holman et al, 2008].

In UKPDS 33, 4209 people with newly diagnosed type 2 diabetes were randomized to either conventional therapy (dietary restriction) or intensive therapy (either sulfonylurea or insulin or, in overweight patients, metformin). After the study, 3277 of the participants attended an annual review for 5 years, and completed a questionnaire for a further 5 years. No attempt was made to maintain their previously assigned study treatment.
Between-group differences in HbA_1c levels were lost after the first year of post-trail follow-up.
In the sulfonylurea–insulin group compared with the conventional treatment group, reductions in risk persisted at 10 years for any diabetes-related end point (risk ratio [RR] 0.91, 95% CI 0.93 to 0.99) and microvascular disease (RR 0.76, 95% CI 0.64 to 0.89). Reductions in risk for myocardial infarction (RR 0.85, 95% CI 0.74 to 0.97) and death from any cause (0.87, 95% CI 0.79 to 0.96) emerged over time, as more events occurred.
In the metformin group, reductions in risk persisted for any diabetes-related end point (RR 0.79, 95% CI 0.66 to 0.95), myocardial infarction (RR 0.67, 95% CI 0.51 to 0.89), and death from any cause (RR 0.73, 95% CI 0.59 to 0.89