The life expectancy of patients with untreated diabetes is 5 to 10 years shorter than that of normal individuals. Although premature cardiovascular disease is the most common cause of disability and death, microangiopathy caused by diabetes is also a cause. Diabetes is the most common cause of renal replacement therapy (renal dialysis) and the leading cause of blindness in people under 65 years of age. In addition, diabetes is the most common cause of nontraumatic amputation. The vast majority of these malignant events can be prevented, delayed, or minimized in terms of adverse outcomes given current medical conditions. The prevention, early diagnosis, and treatment of vascular complications of diabetes in adults is a matter of early prevention, early diagnosis, and early treatment.
The Dangers of Diabetic Complications
Diabetic complications are very common and impose a significant economic burden on individuals and society. Complications reduce the quality of life of patients, especially when microangiopathy and macroangiopathy are present at the same time. The Cost of Type 2 Diabetes in Europe Study (CODE-2), which pooled data from eight studies analyzing 7,000 patients with type 2 diabetes, showed that 72% of patients with type 2 diabetes had at least one complication, and 24% had both microangiopathy and macroangiopathy. Within 6 months, 13% of the patients were hospitalized, with an average of 23 days in the hospital. The estimated annual cost per patient was 2,834 euros (1,934 pounds or 3,585 dollars), with 55% of these costs spent on hospitalization and only 7% on insulin and oral hypoglycemic drugs.
Risk factors for complications
The risk factors for complications are varied. Renal disease is strongly influenced by genetic factors, but these are not yet known. The duration of diabetes, glycemic control, and hypertension are the most important risk factors for microangiopathy, while smoking, hypertension, dyslipidemia, and proteinuria are the most important risk factors for macroangiopathy.
Macrovascular lesions
Death from vascular disease can occur in all age groups; premenopausal women with diabetes lose protective factors against macroangiopathy. Young patients with type 1 diabetes are particularly common, while those with type 2 diabetes have a 2- to 5-fold higher risk of myocardial infarction and stroke than the general population.
Fundus lesions
The World Health Organization (WHO) estimates that blindness due to diabetic fundopathy accounts for 5% of blind people. Patients with a 20-year history of diabetes mellitus have varying degrees of fundus lesions, but only 20 to 50 percent of them result in impaired vision. However, in some centers, the cumulative incidence of visually impaired fundus lesions is decreasing.
Nephropathy
Nearly half of diabetic patients develop microalbuminuria, of which 1/3 progress to proteinuria, 1/3 remain in the microalbuminuria stage, and 1/3 reverse to normal. In some ethnic groups, microalbuminuria and proteinuria are more common. Once clinical proteinuria is present, progression to end-stage renal disease is inevitable. Between 20% and 50% of patients starting renal dialysis treatment are diabetic. In recent years, there has been a rapid increase in the number of diabetic patients requiring renal dialysis in Europe, mainly due to the increase in the number of patients with type 2 diabetes.
Neuropathy
Chronic peripheral neuropathy occurs in 30% to 50% of diabetic patients during their lifetime. 10% to 20% of patients have severe symptoms. Peripheral neuropathy can lead to foot ulcers and amputation of distal limbs. Penile erectile dysfunction can reach 50% in men over 50 years of age with diabetes (15% to 20% in non-diabetic men). Other neuropathies are rare, but have an important impact on quality of life and life expectancy.
Preventing complications
Blood glucose
The Diabetes Control and Complications Trial (DCCT) in patients with type 1 diabetes and the UK Prospective Study of Diabetes (UKPDS) in patients with type 2 diabetes showed that lower glycosylated hemoglobin levels were associated with a lower risk of microvascular complications. In the 8-year open follow-up study of the DCCT study population, glycosylated hemoglobin values were similar in the intensive and conventional groups. Despite this, patients who had previously been in the intensive group were less likely to have microvascular complications. Thus, good glycemic control over time may reduce the risk of complications over time, a phenomenon known as “metabolic memory”.
The association between glycemic control and cardiovascular disease is weak but important, and the UKPDS found that a 1% reduction in glycosylated hemoglobin reduced the risk of myocardial infarction by 14%. In the long-term follow-up of DCCT, the risk of cardiovascular events was reduced by 42% in the intensive group.
Blood pressure
In UKPDS, tight control of blood pressure (144/82 versus 154/87 mmHg) reduced microvascular events by 37%. A 10 mmHg decrease in systolic blood pressure reduced microvascular events by 13% and myocardial infarction by 11%. Other studies have also shown that lowering blood pressure in diabetic patients reduces risk by the same amount as in the non-diabetic population. Therefore, the absolute benefit of lowering blood pressure is greater in diabetic patients.
Effective blood pressure control is more important than the choice of medication at the time of initiation of blood pressure lowering. The ideal blood pressure control goal is <130/80 mm Hg, which is difficult to achieve and often requires a combination of at least three antihypertensive medications. Antihypertensive drugs should be chosen to lower blood pressure effectively once a day for 24 hours.
A Cochrane review suggests that angiotensin-converting enzyme inhibitors are the best drugs for preventing microalbuminuria and diabetic nephropathy. However, a recent meta-analysis did not support this conclusion.
Blood lipids
Two placebo-controlled trials have shown that treatment with statins reduces the risk of major cardiovascular events by 37% in patients with type 2 diabetes without clinical manifestations of cardiovascular disease. Therefore, patients over 40 years of age with diabetes mellitus should be treated with statins. Although younger patients have a relatively low risk of developing cardiovascular disease over 10 years, they are still at high risk over their lifetime. Statins should be used in high-risk groups.
The role of betablockers is unclear. In a recent large randomized controlled trial, fenofibrate did not reduce the risk of primary coronary events in type 2 diabetes. Although strong evidence is lacking, the addition of fibrates should be considered if triglycerides are >2.3 mmol/L after treatment with statins in the setting of glycemic and LDL cholesterol control.
Smoking
Patients must quit smoking to reduce the risk of cardiovascular disease and the possible risk of microvascular complications.
Aspirin
Although there are no studies on the use of aspirin for primary prevention of cardiovascular disease in patients with diabetes, low-dose aspirin is usually recommended, even in patients with diabetes without significant cardiovascular disease.
Detection and screening for complications
Early diagnosis of complications is essential to intervene promptly or to delay their progression to end-stage. Annual systemic screening of the entire body is the most valuable approach.
Large vessel disease
The inclusion criteria for screening subjects should be lowered, and those with angina or claudication should be screened for macrovascular disease. Routine exercise tolerance testing or post-load echocardiography is not recommended. 12-lead resting ECG provides useful baseline information but has low sensitivity and specificity.
Fundus disorders
Corrected visual acuity should be measured and retinopathy should be evaluated. Retinography is the best method, usually requiring dilated pupils and analysis by a medical professional, with attention to the sensitivity and specificity of the retinogram. A quality assurance system must be in place, and static or mobile cameras can be used in the community for screening, and retinal images can be read at local or remote centers.
Kidney disease
Urine albumin and plasma creatinine should be measured. Positive urine specimens should be repeated at least 2 times. Temporal trends in albumin excretion are important. Estimated glomerular filtration rate gives a better picture of glomerular filtration than blood creatinine. In the UK, automated assessments are now carried out by laboratories with computer networks. Table 2 shows the grading of nephropathy based on estimated glomerular filtration rate.
Neuropathy and peripheral arterial disease
Tests required for the 4 risk factors of the diabetic foot (deformity, neuropathy, ischemia, and infection). Penile erectile function should also be examined, but autonomic function tests are not routinely required.
Early treatment
Strict control of blood glucose and blood pressure reduces the risk of progression to vision loss and nephropathy in patients with existing diabetic retinopathy. The effect of blood glucose control on the progression of nephropathy is not well established. Control of blood pressure and lipids is particularly important.
Cardiovascular disease
The presence of symptoms in patients indicates the possibility of vascular disease, especially ischemic heart disease. In the secondary prevention of vascular disease, the absolute benefit of statin therapy is greater in patients with diabetes.
Retinopathy
Frequent retinal examinations should be performed and referral to ophthalmology should be made when vision loss occurs.
Renal disease
All patients should be given a long-acting, once-daily angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, titrated to the maximum recommended or tolerated dose. Other antihypertensive agents should be used in combination to achieve blood pressure control goals. The combination of an angiotensin-converting enzyme inhibitor and an angiotensin receptor blocker or the addition of an aldosterone antagonist may further reduce urinary protein and lower blood pressure in a short period of time. However, the long-term benefits are uncertain. Box 6 lists the indications for metastatic nephrology.
Neuropathy and peripheral arterial disease
Patients at high risk for foot ulcers or gangrene should be educated about foot care. The use of preventive foot care and specially designed shoes can reduce amputations by 30% to 50%. Patients with ulcers should be referred early to a specialized multidisciplinary comprehensive rehabilitation team for treatment.
Patients with penile erectile dysfunction should also be assisted and guided. Other causes of erectile dysfunction need to be ruled out (measurement of prolactin, follicle stimulating hormone, luteinizing hormone, testosterone and sex hormone synthesis globulin). Oral phosphodiesterase-5 inhibitors are effective in 60% of diabetic men. In addition, sublingual apomorphine, intraurethral drugs, intracavernosal drugs, vacuum devices, and penile prosthetics may be used.
The importance of multifactorial therapy
A small randomized controlled trial of patients with type 2 diabetes, microalbuminuria, and hypertension showed the importance of a sequential multifactorial approach to diabetes. The intensive treatment group received lifestyle advice under expert supervision and took aspirin, ACEI, and strict control of blood glucose, blood pressure, and lipids. After 8 years, the intensive group had a 40-60% reduction in the risk of microangiopathy and macroangiopathy.