ESC Guidelines on Diabetes, Pre-diabetes, and Cardiovascular Diseases Developed in Collaboration With the EASD

The Task Force on Diabetes, Pre-Diabetes, and Cardiovascular Diseases of the European Society of Cardiology (ESC) and Developed in Collaboration With the European Association for the Study of Diabetes (EASD)

Lars Rydén (ESC Chairperson) (Sweden); Peter J. Grant (EASD Chairperson) (UK); Stefan D. Anker (Germany); Christian Berne (Sweden); Francesco Cosentino (Italy); Nicolas Danchin (France); Christi Deaton (UK); Javier Escaned (Spain); Hans-Peter Hammes (Germany); Heikki Huikuri (Finland); Michel Marre (France); Nikolaus Marx (Germany); Linda Mellbin (Sweden); Jan Ostergren (Sweden); Carlo Patrono (Italy); Petar Seferovic (Serbia); Miguel Sousa Uva (Portugal); Marja-Riita Taskinen (Finland); Michal Tendera (Poland); Jaakko Tuomilehto (Finland); Paul Valensi (France); Jose Luis Zamorano (Spain); Jose Luis Zamorano (Chairperson) (Spain); Stephan Achenbach (Germany); Helmut Baumgartner (Germany); Jeroen J. Bax (Netherlands); Héctor Bueno (Spain); Veronica Dean (France); Christi Deaton (UK); Çetin Erol (Turkey); Robert Fagard (Belgium); Roberto Ferrari (Italy); David Hasdai (Israel); ArnoW. Hoes (Netherlands); Paulus Kirchhof (Germany UK); Juhani Knuuti (Finland); Philippe Kolh (Belgium); Patrizio Lancellotti (Belgium); Ales Linhart (Czech Republic); Petros Nihoyannopoulos (UK); Massimo F. Piepoli (Italy); Piotr Ponikowski (Poland); Per Anton Sirnes (Norway); Juan Luis Tamargo (Spain); Michal Tendera (Poland); Adam Torbicki (Poland); William Wijns (Belgium); Stephan Windecker (Switzerland); Guy De Backer (Review Coordinator) (Belgium); Per Anton Sirnes (CPG Review Coordinator) (Norway); Eduardo Alegria Ezquerra (Spain); Angelo Avogaro (Italy); Lina Badimon (Spain); Elena Baranova (Russia); Helmut Baumgartner (Germany); John Betteridge (UK); Antonio Ceriello (Spain); Robert Fagard (Belgium); Christian Funck-Brentano (France); Dietrich C. Gulba (Germany); David Hasdai (Israel); Arno W. Hoes (Netherlands); John K. Kjekshus (Norway); Juhani Knuuti (Finland); Philippe Kolh (Belgium); Eli Lev (Israel); Christian Mueller (Switzerland); Ludwig Neyses (Luxembourg); Peter M. Nilsson (Sweden); Joep Perk (Sweden); Piotr Ponikowski (Poland); Zeljko Reiner (Croatia); Naveed Sattar (UK); Volker Schächinger (Germany); André Scheen (Belgium);

Disclosures

Eur Heart J. 2013;34(39):3035-3087. 

In This Article

11. Microvascular Disease in the Eyes and Kidneys

Diabetes mellitus is an important risk factor for both renal and cardiovascular outcomes and renal impairment—in the form of elevated urinary albumin excretion and/or impaired GFR—is itself an independent predictor of cardiovascular outcomes.[161,504,505] Urinary albumin excretion and loss of glomerular filtration rate (GFR) are to some extent beneficially modifiable by interventions that lower blood glucose and blood pressure.

Retinopathy is the most frequent microvascular complication in DM. Although the incidence has declined slowly following the implementation of intensive treatment regimens, vision-threatening proliferative retinopathy affects 50% of people with T1DM and 29% with T2DM develop vision-threatening macular oedema.[506–508] Rapidly progressive retinopathy indicates increased cardiovascular risk and the combination of retinopathy and nephropathy predicts excess cardiovascular morbidity and mortality. In T2DM, advanced retinopathy more than doubles the risk of cardiovascular outcomes.[509]

11.1 Pathophysiology of Microvascular Disease

Renal neuropathic and ocular microvascular complications share some pathophysiological mechanisms that also affect the macrovascular endothelium. Chronic hyperglycaemia induces biochemical abnormalities causing protein glycation and overproduction of ROS, leading to vascular damage and responsive activation of tissue-specific growth/repair systems.[510] The phenotypic characteristics of microvascular damage in DM are progressive vascular occlusion and increased vascular permeability. In the retina, progressive vascular occlusion promotes aberrant responsive neovascularization, causing proliferative retinopathy as an advanced complication. At any stage of progressive vasoregression, increased vascular permeability causes retinal thickening, which is clinically significant when affecting the central macula.

In the kidney, endothelial dysfunction and increased vascular permeability are clinically represented by microalbuminuria, and vascular occlusion corresponds to a progressive decline in renal function as measured by GFR.

11.2 Treatment and Treatment Targets

Lifestyle Intervention: There are no trials proving that lifestyle interventions alone have an effect on the prevention of nephropathy, neuropathy or retinopathy.

Glycaemic Control: (see section 6.2.1) As primary intervention, strict glycaemic control prevents both microvascular and cardiovascular outcomes with a long-term beneficial effect, both in T1DMand T2DM.[151,152,154,155] In secondary prevention, strict glycaemic control prevents progression of renal impairment in both groups.[160,511]

Retinopathy: The recommended target for HbA1c in both T1DM and T2DM is <7% (<53 mmol/mol).[152,512–514] Beyond a certain level of retinal damage, euglycaemia no longer provides a benefit against progression of retinopathy. For T1DM, this level of damage is precisely defined (i.e. moderate non-proliferative diabetic retinopathy), while in T2DM the point of no return is unknown.[515] In T1DM, transient worsening of retinopathy due to euglycaemic re-entry (i.e. intensified insulin therapy after a prolonged period of insufficient glucose control) is outweighed by the long-term benefit of good glycaemic control.[515] In contrast, in T2DM, a similar deterioration is not a consistent feature of improved glycaemic control. Progressing retinopathy benefits from multifactorial treatment.[156] For further details, see Section 7.1.

Blood Pressure – Nephropathy: As a primary intervention, intensified blood pressure control using RAAS blockers prevents the onset of microalbuminuria in T2DM,[191,193] but not in T1DM.[516–518] As a secondary intervention, intensified blood pressure control using ACE-I to block the RAAS slowed progression of kidney disease in T1DM and reduced end-stage renal failure.[519,520] A concomitant reduction in cardiovascular events was not demonstrated in these young patients, although it should be expected, considering the renal effects of ACE-I. In T2DM, high doses of ramipril prevented both renal and cardiovascular events.[521] ARBs reduced progression from microalbuminuria to proteinuria and prevented renal events but not cardiovascular death.[522,523] The currently recommended blood pressure target is <140/85 mm Hg but in patients with hypertension and nephropathy with overt proteinuria an even lower SBP (<130 mm Hg) may be considered if tolerated by the patient (see even Section 6.3.3).[523]

Blood Pressure – Retinopathy: Blood pressure control has beneficial effects on the progression of retinopathy. The recommended threshold is <140/85 mm Hg[191,524] although other concomitant conditions, such as nephropathy, may require more intensive blood pressure control (systolic <130 mm Hg). Lowering blood pressure to this target does not adversely affect retinopathy. The DIabetic REtinopathy Candesartan Trials (DIRECT) studies investigated the effects of blood pressure-lowering with candesartan on the development and progression of retinopathy. There was a non-significant trend towards reduced progression of retinopathy, both in T1DM and T2DM.[524,525]

Lipid-lowering and Antiplatelet Therapy – Nephropathy: Interventions on blood lipids and platelet aggregation have not been documented as altering renal disease in DM. Fibrates and PPARα agonists may reduce kidney function.[526] In the FIELD study, fenofibrate reduced albuminuria and slowed estimated glomerular filtration rate (eGFR) loss over 5 years, despite initially and reversibly increasing plasma creatinine in T2DM.[527]

Recently, statin-plus-ezetimibe treatment provided cardiovascular protection in people with reduced kidney function including those with DM.[238]

Lipid-lowering and Antiplatelet Therapy – Retinopathy: There are no clear target levels of lipids (cholesterol, triglycerides) for the prevention or retardation of retinopathy. In T2DM, the FIELD study reported that fenofibrate was associated with a reduction in requirement for laser therapy, although this effect appeared to be independent of effects on lipid levels. The ACCORD trial tested the outcome of lipid lowering, using combined statins and fenofibrate, on progression of retinopathy. Progression was defined as a three-step increase of the retinopathy level on to the Early Treatment of Diabetic Retinopathy Study severity scale, assessed by fundus photography from baseline, to the four-year study endpoint or pre-specified treatment events (photocoagulation or vitrectomy). The OR for reduction in progression of retinopathy by lipid treatment was 0.60 (95% CI 0.42–0.86; P < 0.0056). After 4 years the rates of progression of retinopathy were 7.3% with intensive glycaemia treatment, against 10.4% with standard therapy (adjusted OR 0.67; 95% CI 0.51–0.87; P = 0.003).[513]

Patients with T2DM require antiplatelet agents for secondary prevention of CVD. There is no specific contra-indication against the use of aspirin or other antiplatelet agents, as they do not increase the incidence of intravitreal haemorrhages.[528] At doses given for secondary prevention of CVD, aspirin is unlikely to improve retinopathy outcome. Erythropoietin treatment in patients with diabetic kidney disease warrants close monitoring for retinopathy progression and for cardiovascular risk.[528,529]

Vision-threatening Retinopathy: Severe non-proliferative or proliferative retinopathy or any level of DM-related macular oedema should immediately be referred to an experienced ophthalmologist. Vision-threatening proliferative retinopathy and macular oedema are treated by laser photocoagulation.[528,530] In selected cases of severe non-proliferative DM-related retinopathy, laser photocoagulation may also be indicated. Selected cases of macular oedema with sub-foveal oedema and vision impairment <20/40 may benefit from intravitreal administration of ranibizumab, an inhibitor of vascular endothelial growth factor (VEGF). In four RCTs [Safety and Efficacy of Ranibizumab in Diabetic Macular Edema Study (RESOLVE), Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema (RESTORE), Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus (RIDE) and Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus (RISE)], one to two years of treatment with ranibizumab was more effective than sham or focal/grid laser therapy in improving best corrected visual acuity and reducing central retinal thickness in patients with visual impairment associated with diabetic macular oedema.[531–533]

11.3 Gaps in Knowledge

  • The balance between the benefit to microvascular risk associated with tightening of glycaemic control and the risk of adverse CV outcomes is not understood.

11.4 Recommendations for Management of Microvascular Disease in Diabetes

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