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Handbook of Diabetes, 4th Ed., Excerpt #13: Control and Complications

Rudy Bilous, MD, FRCP
Richard Donnelly, MD, PHD, FRCP, FRACP



Much of the impact of chronic diabetes results from the development of tissue complications, mainly microvascular (retinopathy, nephropathy and neuropathy) and macrovascular disease (atherosclerosis). Microangiopathy is characterized by progressive occlusion of the capillary lumen with subsequent impaired tissue perfusion, increased vascular permeability and increased production of extracellular material by perivascular cells, resulting in basement membrane thickening. There is strong evidence that microvascular disease is related to the duration and severity of hyperglycemia in both type 1 and type 2 diabetes. A classic observational study by Pirart demonstrated this link in 4,400 type 1 and 2 patients followed for up to 25 years (Figure 14.1). As diabetes duration increased, the prevalence of retinopathy, nephropathy and neuropathy was greatest in those with the worst glycemic control and least in those with the best control….

Many other epidemiological studies have supported this relationship. In the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), the incidence and progression of retinopathy in subjects with type 1 (‘younger onset’) and type 2 (‘older onset’) diabetes were clearly related to glycemic status (Figure 14.2).


Convincing proof that good glycemic control could prevent complications in type 1 diabetes came with the Diabetes Control and Complications Trial (DCCT), which reported in 1993. This study is often regarded as a landmark in diabetes research: 1,441 patients in 29 centers in North America were allocated randomly to either ‘conventional’ therapy (one or two daily insulin injections, 3-monthly clinic visits, no insulin dosage adjustments according to self-monitored glucose data) or to ‘intensive’ therapy (three or more daily insulin injections or insulin pump therapy, monthly clinic visits and weekly telephone calls, frequent blood glucose self-monitoring with insulin dosage adjustment, and a diet and exercise program). Throughout the 9-year study, there was markedly better glycemic control in the intensively treated group. After a mean of 6.5 years follow-up, the intensive treatment arm had an HbA1c of 7.4% versus 9.1% (56 versus 76 mmol/mol) in the conventionally treated patients (Figure 14.3). However, less than 5% in the intensive arm had an average HbA1c consistently within the normal range.

Patients were divided into those who had no evidence of retinopathy at baseline (primary prevention) and those with mild to moderate retinopathy (secondary prevention). The study was powered for retinal and not renal or neurological endpoints.

However, the study showed clinically important reductions in retinopathy, nephropathy (as defined by urinary albumin excretion) and neuropathy in the intensively treated patients. Retinopathy was assessed by seven field fundus stereo-photographs and classified according to the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. A three-step change was regarded as significant (see Chapter 15).

In the primary prevention arm there was a 76% risk reduction (Figure 14.4), and a 54% risk reduction in the secondary prevention arm (63% risk reduction for both arms combined).

In type 2 diabetes, similar evidence came from the UKPDS which reported in 1998. This was a 20-year study recruiting over 5,000 patients with type 2 diabetes in 23 centers throughout the UK. In the main study, 3,867 patients with newly diagnosed type 2 diabetes were allocated randomly to ‘intensive’ therapy (sulphonylureas, [chlorpropamide or glibenclamide/glyburide] or to insulin) or to ‘conventional’ therapy, which was diet initially although tablets or insulin could be added later if patients became symptomatic or developed a fasting blood glucose above 15 mmol/L.

Over 10 years those in the intensive arm had an HbA1c of 7.0% versus 7.9% (53 versus 63 mmol/mol) in the conventionally treated patients. Intensive therapy was associated with a significant 25% reduction in microvascular disease endpoints (an aggregate of vitreous hemorrhage, laser photocoagulation, renal failure, defined as a serum creatinine > 250 u mol/L, or death from renal failure). At 12 years using the ETDRS scale, there was a 21% reduction in a two-step change in retinopathy level in the intensively treated patients (Figure 14.5).