Role Of Hyperglycemia In The Development Of Complications Evidence To Date

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Clinical evidence supporting glycemic control as a primary goal of management exists for both type 1 and type 2 diabetes (Table 1). The landmark study, the Diabetes Control and Complications Trial (DCCT), was reported in 1993. This trial evaluated a total of 1441 subjects with type 1 diabetes and included 726 subjects with no retinopathy at baseline (primary-prevention cohort) and 715 with mild retinopathy (secondary-intervention cohort). The subjects were randomly assigned to intensive treatment (administered either with an external insulin pump

Table 1 Clinical Evidence for Benefits of Glycemic Control

Study (subject type)

DCCT

Kumamoto

UKPDS

SDIS

(type 1)

(type 2)

(type 2)

(type 1)

Retinopathy

63%

69%

17-21%

63 vs. 33%b

Nephropathy

54%

70%

24-33%

26 vs. 7b

Neuropathy

60%

32 vs. 14b

Macrovascular Dx

41%a

16%a

HbAlcA

9-7%

9-7%

8-7%

9.5-7.2%

* Not statistically significant. b Compared with standard treatment.

or by three or more insulin injections) or to conventional therapy (one or two daily insulin injections). The subjects were followed for a mean of 6.5 years, and the appearance and progression of retinopathy and other complications were assessed regularly. The trial demonstrated conclusively that control of clinical hyperglycemia, as evidenced by a reduction in HbA,c, reduced retinopathy by 75%, nephropathy by 54%, and neuropathy by 60%. There was also a 41 % reduction in macrovascular disease, but this was not statistically significant because of the low number of events.

The Stockholm Diabetes Intervention Study (SDIS) also evaluated the benefit of glycemic control in type 1 subjects. In this trial, 43 subjects were randomized to intensified conventional treatment (ICT) and 48 subjects randomized to standard treatment (ST). Subjects were followed for 10 years while vascular complications, treatment side effects, well-being, and risk factors for complications were studied. HbA,c (normal range 3.9—5.7%) was reduced from 9.5 ± 1.4% (mean ± SD) in the ICT group and 9.4 ± 1.2% in the ST group to a mean (during 10 years) to 7.2 ± 0.6% and 8.3 ± 1.0%, respectively (p < 0.001). Serious retinopathy (63 vs. 33%; p = 0.003), nephropathy (26 vs. 7%; p = 0.012), and symptoms of neuropathy (32 vs. 14%; p — 0.041) were more common in the ST group after 10 years.

Several landmark studies have been reported for type 2 diabetic subjects. The Kumamoto Study examined whether intensive glycemic control could decrease the frequency and severity of diabetic complications. This prospective study of Japanese subjects with non-insulin-dependent diabetes (NIDDM) included 110 subjects with NIDDM who were randomly assigned to either the multiple insulin injection treatment (MIT) group or the conventional insulin injection treatment (CIT) group. Fifty-five subjects who showed no retinopathy and urinary albumin excretions <30 mg/24 hours at baseline were evaluated in the

t a primary prevention cohort, and the other 55 NTDDM subjects (who showed sim pie retinopathy and urinary albumin excretions <300 mg/24 hours) were evaluated in the secondary intervention cohort. The appearance and progression of retinopathy, nephropathy, and neuropathy were evaluated every 6 months over a 6-year period. A significant difference in glycemic control was demonstrated between groups as assessed by a 2.3% difference in HbAlc levels. The progression in retinopathy and nephropathy after 6 years was significantly less for the MIT group than for the CIT group, for both the primary and secondary intervention cohorts. In neurological tests, the MIT group showed significant improvement in the nerve conduction velocities, while the CIT group showed significant deterioration in the median nerve conduction velocities and vibration threshold. From this study, a HbAlc of <6.5% was indicated as the glycemic threshold to prevent the onset and progression of diabetic microangiopathy.

The United Kingdom Prospective Diabetes Study (UKPDS) was a multicenter, randomized, controlled trial in over 4000 type 2 diabetic subjects conducted between 1977 and 1997. Subjects were followed every 3 months for 3, 6, or 9 years. The study objectives were to determine whether intensive therapy of type 2 diabetic subjects reduces the risk for complications and to compare intensive pharmacological therapy with conventional therapy. Subjects were first placed on a low-fat, high-carbohydrate, high-fiber diet for 3 months and then randomized to diet alone, insulin, sulfonylurea, or metformin. Over 10 years, HbA,c was 7.0% (6.2-8.2) in the intensive group versus 7.9% (6.9-8.8) in the conventional group— an 11% reduction. There was no difference in HbAlc among agents in the intensive group. Compared with the conventional group, the risk in the intensive group was 12% lower (95% CI 1-21; p = 0.029) for any diabetes-related endpoint, 10% lower ( — 11 to 27; p = 0.34) for any diabetes-related death, and 6% lower (—10 to 20; p = 0.44) for all-cause mortality. Most of the risk reduction in the any-diabetes-related aggregate endpoint was due to a 25% risk reduction (7-40; p = 0.0099) in microvascular endpoints, including the need for retinal photocoagulation. There was no difference for any of the three aggregate endpoints between the three intensive agents (chlorpropamide, glibenclamide, or insulin).

In addition, 753 overweight subjects were included in a randomized controlled trial comparing conventional policy, primarily with diet alone (n = 411), with intensive blood glucose control policy with metformin, aiming for fasting plasma glucose <6 mmol/L (n = 342). A secondary analysis compared the 342 subjects allocated metformin with 951 overweight subjects allocated intensive blood glucose control with chlorpropamide (n = 265), glibenclamide (n = 277), or insulin (n = 409). Median HbAlc was 7.4% in the metformin group versus 8.0% in the conventional group. Subjects allocated metformin, compared with the conventional group, had risk reductions of 32% (95% CI 13-47; p = 0.002) for any diabetes-related endpoint, 42% for diabetes-related death (9-63; p = 0.017), and 35% for all-cause mortality (9-55; p = 0.011).

Table 2 Epidemiological Analysis of the UKPDS

Risk reduction relative to HbAlc (%)

Mortality

Mortality

All causes

14

17-21

Related to diabetes

21

24-33

Events

Any diabetes-related endpoint

21

32

Microvascular disease

37

56

Amputation/death PVD

43

65

Ml

14

21

CVA

12

18

CHF

16

24

Source: Stratton et al., 2000.

Source: Stratton et al., 2000.

Further analysis of the UKPDS suggests risk reduction for several endpoints; Table 2 demonstrates the risk reduction relative to specific decreases in HbA|C.

The findings of the cLinica] trials demonstrate conclusively that intensive therapy, by significantly improving clinical glycemia, reduces the risk of microvascular and neurological complications. It is also seen from these trials that exogenous insulin therapy did not increase the risk of complications, in particular, macrovascular disease. This concept is well demonstrated by the UKPDS results, in which insulin therapy appeared to control glycemia as well as the pharmacological therapies, but there appeared to be no difference in macrovascular events between those treated with insulin and those taking the other oral therapies. The UKPDS study aJso suggested that type 2 diabetes, the most common form of the disease, is indeed a progressive disease that will require additional therapies (i.e., combination oral therapies and/or addition of insulin) in order to control glycemia over time.

Finally, clinical trials to date have aiso provided the data required to suggest target levels for glycemic control, as assessed wid: the HbAlc. Current ADA guidelines suggest a target of <7%. However, in the epidemiologic data from the UKPDS, there appears to be no lower threshold for HbA,c levels for which complications are not reduced (Figure I). A number of smali cohort trials, preceding and during the large interventional trials, further corroborate the significance of HbA,c elevations greater than 6.5%. These findings are also consistent with a number of epidemiological studies implicating the association of hyperglycemia

with the development of diabetic complications. A more recent study also pointed to the observation that a lowered HbAlc may be favorable for cardiovascular events. This had been suggested by the EPIC-Norfolk Study, in which the relative risk for cardiovascular disease was much less, with recorded HbA,c levels of <5%. Based on the evidence, a Consensus Conference of the American College of Endocrinology was recently convened; this conference suggested that the primary target for obtaining glycemic control should be <6.5%.

mia and the duration of exposure of the protein to clinical hyperglycemia. Numerous techniques are used in laboratories to assess glycated hemoglobin levels. The "total glycated hemoglobin" is a measure of the percentage of glycation of all hemoglobin species and traditionally has been assessed with an affinity chromatography technique. The most common assay, however, HbAlc, has traditionally employed ion-exchange methodology and specifically measures the glycation of the major glycated hemoglobin species. It is important to recognize which test is offered in your clinic, because a measure of total glycated hemoglobin would be reported as a higher level than that of HbAlc. Because the hemoglobin in the red blood cell has a half-life of approximately 60-90 days, measurement of glycated hemoglobin gives an overall objective index of glycemic control for the preceding 2-3 months.

Recently there has been interest in measuring glycation of other proteins, primarily albumin, that have shorter circulating half-fives (days or weeks instead of months). This would offer the clinician an objective measure of more recent glycemic control. These tests, which are commercially available, are performed by obtaining a plasma or serum fructosamine level. Assessment of serum fruc-tosamine will provide an objective index over the past 1-2 weeks. These tests may be ideal in situations in which more frequent objective tests are needed, such as in pregnancy. Research also suggests that glucose may nonenzymatically attach to long-lived tissue protein, such as myelin in nerves and collagen in kidneys and arteries. It has been postulated that the glucose attached to these proteins may result in cross-linkage of proteins and lead to products referred to as advanced glycated end-products, or AGE proteins. The presence of these AGE proteins on long-lived tissue proteins has been postulated to alter protein structure and characteristics and therefore provide a mechanism by which hyperglycemia may contribute to the development of diabetic complications.

Clinical glycemia can be described as consisting of two components: 1) basal or fasting glucose levels, and 2) meal-related glycemic, or postprandial, elevations (Figure 2). The fasting glucose level is influenced by hepatic glucose production and hepatic sensitivity to insulin. Postprandial glucose levels are influenced by: 1) the preprandial glucose level, 2) meal-related insulin secretion, 3) the glucose load from the meal, and 4) peripheral tissue sensitivity to insulin. As demonstrated in Figure 2, the preprandial glucose is normally maintained in a narrow range. However, in subjects with diabetes, in which alterations occur in the factors controlling these parameters, both the fasting and postprandial levels are elevated. Thus, an elevated HbAlc level in diabetic states is reflective of contributions from the elevated fasting or preprandial glucose level and the postprandial glycemic rise. This concept is very important on clinical grounds, as it suggests that control of both fasting/preprandial and postprandial glucose levels is required to normalize the HbAlc level.

Traditionally, it has been the targeting of preprandial levels that has

"normal" and various levels of glycemic control. As demonstrated, profile A represents glucose levels for a nondiabetic individual with control of both pre-and postprandial excursions; one could suggest an approximate HbAlc of 5% for this individual based on the lowered glycemic profile. In contrast is a patient with uncontrolled hyperglycemia, as represented by profile D, with both elevated fasting and preprandial glucose levels, along with postprandial glycemic excursions. This profile may be representative of a patient with an HbA,c of approximately 10.5%. With improved control and improvement in both pre- and postprandial glucose levels, 24-hour glucose may be further improved, resulting in an HbAlc of approximately 7.8%, as suggested by profile C. This represents a very common clinical profile in that preprandial glucoses are controlled, yet the HbAlc is still not at target. This is a situation in which checking postprandial glycemia may be indicated, and adjusting therapy as needed to control these postprandial spikes. By improving postprandial hyperglycemia in the patient represented by profile C, a further reduction in HbA,c can be obtained, as outlined in the patient profile labeled B.

In summary, there is now definitive clinical evidence that hyperglycemia is related to the progression and development of diabetic complications. Although several mechanisms have been postulated, the precise mechanism(s) by whichl hyperglycemia contributes is not specifically known. Based on the clinical trialsj to date, we now have defined clinical goals for which to target levels of glycemic control. Further evolving concepts in the management of diabetes would suggest that understanding postprandial control may benefit our patients greatly by improving HbA,c and possibly by improving cardiovascular outcomes. However, the latter observation has not been clinically tested in prospective intervention trials.

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