Signs of nonproliferative retinopathy include microaneurysms, venous loops, retinal hemorrhages, hard exudates, and soft exudates. Proliferative retinopathy can include new vessels in the eyes or vitreous hemorrhage. The earliest sign of nephropathy is hypertension, which often coincides with the development of microalbuminuria. As nephropathy worsens, patients can develop edema, arrhythmias associated with hyperglycemia, or symptoms related to renal failure.

Signs and symptoms of neuropathy depend on the type of neuropathy that develops. Most commonly, patients develop symptomatic distal polyneuropathy. Signs include decreased or total loss of ankle jerk reflexes and vibratory sensation, with hyperalgesia and calf pain in some patients. These usually present in a "stocking and glove" distribution. Wasting of the small muscle of the hands and feet also can occur. Patients may present with focal neuropathies due to either mononeuritis or entrapment syndromes.

These produce focal neurologic deficits confined to a single nerve. A rare but severe form of diabetic neuropathy is diabetic amyotrophy, which begins with pain followed by severe weakness and spreads from unilateral to bilateral. It resolves spontaneously in 18 to 24 months. Patients with diabetes-associated CVD can present with stable or unstable angina pectoris, MI, or dysrhythmias; however, many patients have unrecognizable symptoms. Patients with cerebral vascular disease can present with a sudden onset of a focal neurologic deficit such as facial droop, hemiparesis, or isolated weakness of an arm or leg.

Dizziness, slurred speech, gait difficulties, and visual loss also can be the presenting symptoms. Peripheral vascular disease is recognized by exertional leg pain that can progress to pain at rest and ischemic ulcers.

Most cases are asymptomatic. Patients with diabetes should be screened regularly, at least every 6 months, for retinopathy, nephropathy, and neurology complications Table 1.

Those with uncontrolled diabetes should be examined more frequently. Dilated eye examinations by an ophthalmologist or optometrist should be performed within 5 years of onset in type 1 DM and at the time of diagnosis in type 2 DM, because the actual date of onset is hard to determine in type 2 DM.

Follow-up eye examinations should be performed annually in patients with no or minimal background retinopathy. More frequent follow-up examinations are needed in those who have more advanced retinopathy. Handheld ophthalmoscopy may be able to detect diabetic retinopathy, but it offers limited view of the retina and has difficulty detecting diabetic macular edema, a significant cause of vision loss in diabetes. Retinopathy is easier to detect with binocular vision.

In difficult cases, IV fluorescein angiography and confocal microscopy are used. Technology is available for screening with fundus photographs obtained in the practitioner's office and then read by an expert.

However, these do not show a complete view of the retina and do not include other aspects of the eye examination, such as eye pressure, and, thus, cannot replace yearly eye evaluations. The hallmark of early diabetic nephropathy is albumin excretion. Sensitive assays to detect very low levels of albumin, or microalbuminuria, have been available for many years.

The simplest screening measure is a spot urine test adjusted for the urine creatinine level. Timed overnight collections or hour collections also may be used. In general, microalbuminuria is defined as more than 30 mg albumin per gram of creatinine spot urine test or 30 to mg per 24 hours and more than mg gram of creatinine or 24 hours as albuminuria. Serum creatinine determinations should be performed at least annually in patients with albuminuria.

When estimated glomerular filtration rate eGFR values are declining, more specific measures of GFR most commonly, creatinine clearance should be used. Monofilament testing performed in the office is the easiest way to check for the insensate foot. The 5. Any loss of sensation is associated with an increased risk for ulcer formation. A patient who has had a foot ulcer is at increased risk for additional foot ulcers. Patients should be instructed to examine their feet daily. Patients who have difficulty examining their feet should seek assistance, especially if they have impaired vision.

The use of a mirror can help patients see the bottoms of their feet see the chapter, " Prevention and Treatment of Leg and Foot Ulcers in Diabetes Mellitus ".

Careful questioning about symptoms of ischemic coronary disease is still one of the most important ways to screen for CVD. Many patients with diabetes do not have typical exertional chest pain.

Consequently, clinicians must ask about reduced exercise tolerance, dyspnea, or exercise-induced nausea. Various studies have considered the issue of screening for CVD. The guidelines and individual recommendations are not entirely concordant.

Whereas nearly every group suggests stress tests for patients with symptoms of CVD or electrocardiographic changes suggesting ischemia, recommendations on screening for asymptomatic disease are less consistent. The American Diabetes Association ADA considers that candidates for cardiac stress testing should include those with a history of peripheral or carotid occlusive disease; those with a sedentary lifestyle who are older than 55 years and who plan to begin a vigorous exercise program; and those with two or more risk factors for CVD.

Screening for asymptomatic coronary artery disease with various stress tests in patients with T2D has not been clearly demonstrated to improve cardiac outcomes and is therefore not recommended. Screening is defined as the detection of disease in asymptomatic persons. Because screening tests are intended for widespread application, they should be rapid and inexpensive.

In addition, to be useful, the results of testing should lead to a change in management, and the results of testing should improve outcomes. Most consensus statements and guidelines on diabetes and CAD have suggested that noninvasive cardiac testing be performed in patients with diabetes and one additional criterion: peripheral arterial disease, cerebrovascular disease, rest changes on the electrocardiogram ECG , or the presence of two or more major CVD risk factors.

According to these guidelines, risk assessment begins with a medical history, including special attention to symptoms of atherosclerotic disease, such as angina, claudication, or erectile dysfunction.

Data from the ongoing DIAD study Detection of Ischemia in Asymptomatic Diabetics , [12] which is designed to determine risk factors associated with clinically silent myocardial disease using stress tests with cardiac imaging, has suggested that the presence of neuropathy may be one of the most important predictors of CVD risk. It is not yet clear how results from noninvasive testing can change risk management strategies in patients with diabetes, because diabetes is already considered a CVD risk equivalent.

Thus, noninvasive testing should be targeted as much as possible to identify patients who might have CVD that is amenable to surgical intervention. Whereas noninvasive screening in asymptomatic patients might detect disease amenable to percutaneous intervention or coronary artery bypass grafting, the cost effectiveness and effects on long-term outcomes are still uncertain. Careful attention to a patient's history of changes in exercise tolerance, atypical symptoms that suggest angina, or suggestive ECG abnormalities are reasons to consider stress testing.

In addition, dyslipidemia, obesity, hypertension, albuminuria, and a family history of CVD may be reasons to consider stress testing in patients who do not have clinical symptoms of CVD. In the absence of robust evidence, as noted by the AHA, practitioners need to make decisions about patients who might have silent myocardial disease.

The diagnosis of retinopathy is based on the findings of eye exams to determine if the patient has clinically significant macular edema, proliferative retinopathy, or severe nonproliferative retinopathy. The progressive changes in the retina that occur in patients with diabetes include the following:. The diagnosis of nephropathy is initially based on development of microalbuminuria. This is associated with a linear decline in GFR ranging from 0.

The diagnosis of neuropathy, defined by loss of ankle jerk reflexes, is based on finding focal individual root or diffuse entire limb involvement. Findings can be asymmetric mononeuritis multiplex or symmetric conforming to a distal-to-proximal gradient of involvement most common.

Electrodiagnostic studies can confirm peripheral nerve disease and define the pattern of disease. Autonomic neuropathy is diagnosed in patients with gastroparesis or orthostatic hypotension. The diagnosis of CVD can be confirmed by several diagnostic and imaging studies. A resting lead ECG is not sensitive enough to identify disease in patients with stable angina. Cardiovascular stress testing can be assessed with ECG assessment during exercise, dobutamine, dipyridamole, or adenosine.

Echocardiography can enhance the sensitivity of the test. Alternatively, nuclear stress testing with thallium or technetium 99m in association with dipyridamole or adenosine can be used. Significant CAD is identified by relative hypoperfusion in peak stress images. Coronary arteriography can confirm CAD.

The diagnosis of a stroke is based on a patient developing symptoms of focal neurologic deficit and can be confirmed by a CT scan or MRI. CT angiography can be used to identify the location of vascular occlusion and assess for salvageable brain tissue.

The diagnosis of peripheral arterial disease is diagnosed by determining the ankle brachial index ABI. This is the ratio of the Doppler-determined systolic ankle pressure over the systolic brachial pressure. An ABI less than 0. An ABI greater than 1. It is associated with increased risk of foot ulcers and CVD.

If revascularization is being considered, other tests including duplex ultrasonography, MR angiography, and CT angiography can be used to determine specific sites of surgical intervention. Appropriate management of the microvascular and macrovascular complications of diabetes requires practitioners to treat a comprehensive range of factors that focus on several areas including nutritional intake, control of blood glucose, lifestyle and activity, blood pressure, and lipids.

Guidelines for medical-nutrition therapy have been established by the ADA and are summarized in Table 2. There is clear evidence that excess saturated fat in the diet has a detrimental effect on lipid profiles; therefore, restriction of saturated fat is recommended.

Data supporting absolute restriction of carbohydrates are not robust, so the ADA guidelines allow flexibility in intake of carbohydrates. The ADA has published separate guidelines for the carbohydrate content and composition of the diet. The most important variable in prandial glycemic excursion is total carbohydrate intake. Consumption of low glycemic index foods results in lower prandial glucose excursion than consuming high glycemic index foods. In the context of a mixed meal, however, differences between low and high glycemic index foods are attenuated.

The amount and source of carbohydrates are important determinants of postprandial glucose levels. Restriction of alcohol and sodium is generally advised. Nutritional supplements are not necessary in patients who are consuming a well-balanced diet.

Many recommendations for weight management propose calorie restriction based on the degree of obesity along with 30 to 45 minutes of exercise 3 to 5 days a week. Exercise is an important component of any regimen for weight reduction and glycemic control. Other nutritional guidelines for patients with diabetes are generally consistent with the ADA guidelines.

Address individual nutritional needs, taking into consideration personal and cultural preferences and lifestyle while respecting the individual's wishes and willingness. Guidelines for exercise have not always been specific with regard to exact exercise prescriptions, especially regarding aerobic and resistance exercises. The commonly proposed recommendation is for minutes of moderate-intensity or 90 minutes of vigorous aerobic exercise per week to achieve benefits on glycemic control and reduce CVD risk.

Regular exercise is encouraged, but complications of diabetes need to be taken into account. For example, patients with loss of sensation in their feet should limit weight-bearing exercise. Because of the CVD risk in patients with diabetes, appropriate screening for CVD should be performed before patients engage in an exercise program. Benefits of exercise include weight control and improved glycemic control, often due to reduced insulin resistance.

Prevention is the optimal approach to managing the microvascular complications of diabetes. The two main approaches to preventing retinopathy and nephropathy are intensive glycemic control and aggressive control of hypertension. Intensive glycemic control has been the most effective approach to preventing neuropathic complications of diabetes. The Wisconsin Epidemiologic Study demonstrated that in patients with diabetes, higher baseline hemoglobin A1c HbA1c levels correlated with increased incidence of retinopathy, progression of retinopathy, and progression of proliferative retinopathy.

The Diabetes Control and Complications Trial [20] DCCT compared intensive insulin therapy insulin pump or multiple daily injections versus conventional therapy one or two injections per day in 1, patients with type 1 DM with mild to moderate retinopathy. After a mean of 6. In a 4-year follow-up after the study ended, [21] the reduced risks of progressive retinopathy proliferative retinopathy, macular edema, and need for laser therapy and nephropathy incidence of albuminuria persisted despite a narrowing of the HbA1c levels in the two groups.

The Kumamoto Trial, [22] which included patients with type 2 DM, showed that intensive therapy with multiple daily injections preprandial, regular, and bedtime intermediate acting insulin compared with once or twice daily insulin injections decreased HbA1c from 9. Patients using intensive treatment metformin; [23] sulphonylureas or insulin [24] versus conventional treatment had lower average HbA1c 7. These results further support the importance of intensive therapy in reducing the microvascular complications of diabetes.

Hypertension control has been shown to reduce the risk for both retinopathy and nephropathy. They were randomized to either captopril angiotensin-converting enzyme [ACE] inhibitor or atenolol beta blocker. Several studies have assessed the effects of hypertension control on nephropathy in patients with type 1 and type 2 DM have been performed assessing effects.

Many of these patients also experienced decreased albumin excretion rates. No studies in patients with type 1 DM have shown that starting ACE inhibitors when the albumin excretion rate is normal delays the development of microalbuminuria. Creatinine doubled in Several studies in patients with type 2 DM with microalbuminuria—with or without hypertension—have found that ACE inhibitors can delay progression to overt nephropathy, decrease the albumin excretion rate, and diminish the decline in GFR.

Another study demonstrated that in patients with type 2 DM who were normotensive and normoalbuminuric, treatment with enalapril attenuated the increase in the albumin excretion rate and decreased the likelihood of development of microalbuminuria a In other studies in patients with type 2 DM, there is a slowing of progression of microalbuminuria to overt nephropathy when angiotensin II-receptor blockers are administered.

Glucose, BP control. Self-administered glucose testing in patients with type 1 DM or in pregnant women with diabetes is recommended at least three times a day. The frequency of glucose monitoring for type 2 DM should be sufficient to facilitate achievement of the glucose goals. In hypertensive patients with microalbuminuria or albuminuria, therapy with ACE inhibitors or angiotensin II-receptor blockers should be strongly considered.

Patients with type 1 DM should have an initial dilated and comprehensive eye exam within 5 years of the onset of diabetes. Patients with type 2 DM should have an eye exam shortly after diagnosis. Patient with either type 1 or type 2 DM should have subsequent eye exams annually, performed by an ophthalmologist or optometrist knowledgeable and experienced in diagnosing retinopathy.

Visual loss in nonproliferative diabetic retinopathy occurs primarily through development of macular edema. When clinically significant macular edema is present, intraviteral anti vascular endothelial growth factor VGEF or focal laser photocoagulation are initial treatment options.

Once retinopathy is established, the best treatment to prevent blindness in those with high-risk and severe proliferative retinopathy is laser photocoagulation. If vitreous hemorrhage occurs and does not resolve, vitrectomy may restore vision. Early nephropathy is associated with microalbuminuria, hypertension, and, possibly, elevated creatinine. First-line therapy is directed toward controlling hypertension. Generally, ACE inhibitors are first-line agents. Patients who develop a severe cough, a common side effect of ACE inhibitors, can be switched to an angiotensin II-receptor blocker.

These agents have shown similar efficacy at decreasing microalbuminuria, lowering blood pressure, and preventing worsening renal function. Some calcium channel blockers diltiazem and verapamil have been shown to decrease microalbuminuria and may be added to the medications, if necessary. The Diabetes Control and Complications trial found some improvement in neuropathy with intensive diabetes control.

The most common neuropathy is bilateral distal polyneuropathy. Increasing doses of tricyclic antidepressants, gabapentin, phenytoin, carbamazepine, and benzodiazepines have been used with varying degrees of success. Several agents have shown promise for restoring the structural nerve damage that can cause neuropathy including laminin B2, immunoglobulin FI and FII, nerve growth factor, insulin, and neurotrophin Gastroparesis is treated with metoclopramide.

Patients with diabetes are at increased risk for the macrovascular complications of CVD. Compared with a nondiabetic population, patients with diabetes have a two- to four-fold increased risk of CVD, and more than half of patients with diabetes die from CVD complications. Table 3 lists the common CVD risk factors associated with diabetes and recommended therapeutic goals. Practitioners should note that not all patients with diabetes have an elevated risk of a cardiac event, so some discretion may be used with the guidelines.

The guidelines are generally consistent in recommending aggressive lipid-lowering management in diabetes. These guidelines are based on findings from lipid-lowering trials that included diabetic patients and were confirmed by subsequent trials. Post-hoc analyses of diabetic patients who were included in lipid-lowering trials have supported the notion that these patients have comparable relative reductions or perhaps greater absolute reductions in the risk for CVD events than their nondiabetic counterparts.

These data are summarized in the ACP guidelines. These guidelines are still recommended by the AACE. In patients with diabetes, large clinical trials have demonstrated favorable effects of BP control on reducing CVD risks. The beneficial effects could not be entirely attributed to BP reduction in these trials. Intervention trials have shown a somewhat modest relationship between glycemic control and CVD risk.

A patient with diabetes should be referred to an endocrinologist if targets for glycemic control cannot be achieved or if the patient is experiencing severe hypoglycemia. It is important to refer patients early in the disease stage to help them avoid long-term complications. Also, patients who develop complications should be referred to an endocrinologist to see if glycemic control can be improved or simply to treat the complications.

Aspirin should be used in combination with clopidogrel for up to 1 year in these patients following acute coronary syndrome. The watchword of the ADA is that diabetes is a serious disease associated with significant morbidity and mortality related to microvascular and macrovascular complications.

Careful screening for these complications provides clinicians with opportunities to reduce the risk for their development and progression. ADVANCE was a multi-national randomized trial testing the effect of intensive glucose control using a gliclazide-MR and routine blood pressure treatment using a fixed-dose combination of perindopril and indapamide on the risk of major microvascular and macrovascular events in 11, patients with type 2 diabetes and at least one other cardiovascular risk factor or pre-existing cardiovascular disease [ 7 , 8 , 9 ].

The design and characteristics of participants have been previously described [ 8 , 9 , 10 ]. Macrovascular disease was defined as the presence, at baseline, of myocardial infarction, stroke, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, hospital admission for unstable angina or transient ischaemic attack, lower-extremity amputation of at least one digit secondary to arterial insufficiency, or a peripheral revascularisation procedure.

Participants were categorized into four baseline groups: absence of both microvascular and macrovascular disease, presence of microvascular disease alone, presence of macrovascular disease alone, and presence of both microvascular and macrovascular disease. The primary outcomes were all-cause mortality, major macrovascular events MACE: a composite of nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death , and major clinical microvascular events a composite of end-stage renal disease ESRD , defined as requirement for renal-replacement therapy; death induced by renal disease; requirement for retinal photocoagulation; or diabetes-related blindness in either eye.

The secondary outcomes were cardiovascular death, fatal or nonfatal myocardial infarction, fatal or nonfatal stroke, ESRD or renal death, and requirement for retinal photocoagulation or blindness. Continuous variables were summarized as mean SD or, for those with a skewed distribution, median interquartile range.

Categorical variables were summarized as the number of patients with corresponding percentage. Characteristics of participants according to status of microvascular and macrovascular disease at baseline were compared using Chi squared, ANOVA, or Kruskal—Wallis tests. Cumulative incidence curves were used to plot survival outcome-free rates during follow-up, and compared using the log-rank test. Analyses were adjusted for randomized study allocations plus every potential confounding variable that was significantly different between microvascular and macrovascular disease at baseline: sex, age, region of origin Asia: Philippines, China, Malaysia, and India; established market economies: Australia, Canada, France, Germany, Ireland, Italy, Netherlands, New Zealand, United Kingdom; and Eastern Europe: Czech Republic, Estonia, Hungary, Lithuania, Poland, Russia, Slovakia , body mass index, duration of diabetes, HbA1c, systolic blood pressure, antihypertensive treatment, estimated glomerular filtration rate eGFR; computed by the Chronic Kidney Disease—Epidemiology Collaboration equation [ 11 ] and its square, urinary ACR, LDL- and HDL-cholesterol, and history of ever smoking basic model.

The proportional hazards assumption was checked using the Schoenfeld residuals method. We tested multiplicative interaction between baseline history of microvascular disease and macrovascular disease on the risk of each outcome by including these two individual variables and their product within Cox models. Since we assessed the additive value of microvascular disease including macroalbuminuria on the risk of all-cause mortality and MACE, urinary ACR was not included in the basic model in these analyses.

We also evaluated the individual and joint prognostic value of urinary ACR as a continuous variable and diabetic retinopathy, added to the basic model, on the discrimination of all-cause mortality and MACE.

We also evaluated the associations of microvascular and macrovascular disease at baseline on the risk of MACE and major clinical microvascular events after treating non-renal and non-cardiovascular death as a competing risk using the Fine and Gray method [ 13 ]. Statistical analyses were performed using SAS software, version 9. A P value less than 0.

Patients with microvascular disease alone at baseline had a longer duration of diabetes and higher HbA1c, systolic blood pressure, and ACR levels, whereas those with macrovascular disease alone were more frequently men, from established market economies, ever smokers, and treated with antihypertensive, lipid lowering and antiplatelet drugs Table 1. All-cause mortality, MACE, and major clinical microvascular events occurred in Their incidence rates were 2. The highest risks were observed in patients with both conditions at baseline 2.

Cumulative incidence of outcomes during follow-up according to status of microvascular and macrovascular disease at baseline. Black line absence of both macrovascular and microvascular disease. Blue line presence of microvascular disease alone. Green line presence of macrovascular disease alone. Red line presence of both microvascular and macrovascular disease. Comparable results were observed with secondary endpoints, except for the absence of association of baseline macrovascular disease with the risk of ESRD or renal death Table 2.

The addition of ACR 0. The addition of baseline microvascular disease to established cardiovascular risk factors improved the discrimination 0. Comparable associations were observed between baseline microvascular disease, including CKD or peripheral diabetic neuropathy, and the risk of outcomes, except for myocardial infarction or stroke Additional file 1 : Tables S2, S3.

Baseline microvascular or macrovascular disease remained significantly associated with MACE and major clinical microvascular events when we corrected for competing risk of non-renal and non-cardiovascular death Additional file 1 : Table S4. This study demonstrates the independent association of microvascular or macrovascular disease at baseline with excess risks of all-cause mortality, MACE, and major clinical microvascular events in patients with type 2 diabetes followed for a median duration of 9.

The presence of both conditions led to the highest risks. Baseline microvascular disease enhanced discrimination and classification of MACE, while baseline macrovascular disease modestly improved classification, but not discrimination, of major clinical microvascular events. Overall, the improvement in discrimination and classification of outcomes was quiet modest, but statistically significant.

Interestingly, urinary ACR and diabetic retinopathy yielded together the highest improvement of MACE supporting their additive value in the prediction of macrovascular disease. Our findings support previous studies showing that microvascular disease is an important predictor of future macrovascular disease and death [ 6 , 15 ].

ADVANCE participants with microvascular disease alone at baseline displayed similar hazard ratios for all-cause mortality or MACE, compared to those with macrovascular disease alone, suggesting that microvascular impairment plays an important role in the development of diabetic angiopathy.

A recent population-based cohort study has shown that retinal and skin microvascular abnormalities occurred early in prediabetes, were more severe in type 2 diabetes, and may contribute to the development of cardiovascular disease [ 16 ].

Other studies reported a high prevalence of coronary microvascular dysfunction in patients with type 2 diabetes free for known cardiovascular disease [ 17 , 18 ]. We evaluated, for the first time, the impact of macrovascular disease at baseline on the 9. Macrovascular disease at baseline was significantly associated with an elevated risk of the composite major microvascular endpoint, as well as retinal photocoagulation or blindness, but not ESRD or renal death.

Based on their poor prognosis, patients with chronic macrovascular disease at baseline may have died before experiencing ESRD during the follow-up. The impact of macrovasular disease on the risk of major clinical microvascular events seems to be weaker than the effect of microvascular disease on MACE risk, but there was no evidence of an interaction between the two conditions at baseline on the risk of any measured outcome.

Despite their common background, these conditions had independent effects, suggesting that different mechanisms may be involved in the impact of microvascular and macrovascular disease on future vascular events.

Hence there is a need to evaluate new predictors for both microvascular and macrovascular events. Several pathways may explain the relationship between microvascular and macrovascular disease in patients with diabetes. Diabetic microvascular complications are mainly caused by prolonged exposure to high glucose levels. Diabetes is also associated with accelerated atherosclerosis affecting large vessels [ 21 , 22 ].

Atherosclerosis is more prevalent in diabetic patients with microvascular disease compared to those without [ 21 , 22 ]. However, it is still unknown why intensive glucose control does not yield the same benefit on macrovascular events as observed for microvascular outcomes [ 23 ]. Chronic hyperglycaemia causes vascular damage through activation of major biochemical paths including polyol pathway flux, increased formation of advanced glycation end products AGEs , increased expression of AGEs receptor and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway [ 24 ].

Numerous lines of evidence suggest that these biochemical abnormalities may be activated by mitochondrial overproduction of reactive oxygen species ROS induced by hyperglycaemia [ 25 ]. The excess of ROS production with decreased in antioxidant capacity lead to oxidative stress, which plays an important role in the premature vascular morbidity and mortality in patients with diabetes [ 26 ].

Oxidative stress impairs endothelial function and endothelium-dependent vasodilation by inactivation of NO, and induces cell proliferation, hypertrophy, cardiac remodeling, apoptosis, and low-grade inflammation in endothelial and smooth cells of the vascular wall [ 27 , 28 , 29 , 30 ].

Moreover, oxidative stress is associated with many other accelerating conditions including insulin resistance, metabolic syndrome, hypertension, dyslipidaemia, and obesity, leading to both microvascular and macrovascular disease [ 25 , 31 ].

The depletion of circulating stem cells may also explain the association between microvascular and macrovascular disease. The reduced levels of circulating progenitor cells improve the prediction of both macrovascular and microvascular events [ 32 , 33 ].

The remodeling of bone marrow involves neurovascular changes and vascular abnormalities comparable to the known microangiopathy seen in the kidney and the retina [ 34 ]. The main strength of our study is the evaluation of the individual and the combined impact of microvascular and macrovascular disease at baseline on the risk of death and major microvascular and macrovascular outcomes in a large international cohort of patients with type 2 diabetes followed for a median duration of 9.

The main limitation is the absence of biochemical renal assessment during the ADVANCE-ON follow-up, which may underestimate the association between baseline macrovascular disease and kidney disease. Although comparable findings were observed when we evaluated the associations of microvascular disease at baseline, including the history of peripheral diabetic neuropathy, with the main outcomes.

The presence of microvascular or macrovascular disease at baseline is independently associated with increased risk of death, MACE, and major clinical microvascular events in people with type 2 diabetes followed for a median duration of 9.

These findings encourage consideration of prior microvascular disease including retinal status, in addition to traditional cardiovascular risk factors, in selecting participants for forthcoming clinical trials aiming to assess vascular endpoints in patients with type 2 diabetes.

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