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The cardiovascular safety of dipeptidyl peptidase-4 inhibitors (gliptins) has been well studied. Favourable effects of these oral antidiabetic agents have been reported in meta-analyses of phase II-III randomised controlled trials. Three large prospective trials, which were specifically designed to investigate cardiovascular safety, showed non-inferiority of saxagliptin (SAVOR-TIMI 53), alogliptin (EXA-MINE) and sitagliptin (TECOS) versus placebo as far as major cardiovascular events are concerned, including mortality. The suspected increase in the rate of hospitalisation due to congestive heart failure reported in SAVOR-TIMI 53 was neither found in EXAMINE nor recently confirmed in TECOS. Direct comparative trials, evaluating not only safety but also efficacy, with other oral antidiabetic medications would be of major interest.

The strategy for the management ot type 2 diabetes, summarized by a group of European and American experts, has been updated early 2015. A patient-centered approach is recommended and the first drug choice is metformin combined with lifestyle improvement. After failure of metformin monotherapy, the selection of a second drug should be based on the efficacy, safety and cost of each pharmacological class. When compared to the position statement of 2012, the most important changes are the possible addition of a gliptin to a dual oral therapy or even to insulin, the commercialization of sodium-glucose cotransporters type 2 (SGLT2) inhibitors (gliflozins, to be used in dual or triple therapy, even in combination with insulin) and the possible combination of a glucagon-like peptide-I receptor agonist together with a basal insulin.

The diabetic kidney disease is the most frequent cause of end stage renal disease in Western countries. Its detection is obtained by simultaneously measuring urinary albumin excretion and estimating glomerular filtration rate through serum creatinine dosage. Many type 1 and type 2 diabetic patients can present decreased glomerular filtration rate before the occurrence of increased urinary albumin. While waiting for promising new pharmacological approaches currently evaluated in clinical trials, the best approach to stop the epidemic of diabetic nephropathy remains an early and individual multifactorial approach controlling the glucose level (without inducing hypoglycaemia), blood pressure (using a renin-angiotensin blocker), dyslipidaemia and over-weight.

Metformin is unanimously considered as the first-line glucose-lowering agent in type 2 diabetes. Theoretically, however, it cannot be prescribed in a large proportion of patients because of the presence of numerous contraindications corresponding to situations that may increase the risk of lactic acidosis. Recent data suggest that type 2 diabetes patients who are considered as being "at risk" because of the presence of cardiac disease still take benefit from metformin therapy, with a reduction of morbidity and mortality compared with other glucose-lowering agents. The present review analyzes the benefit-risk balance of metformin therapy in special populations, namely patients with stable coronary artery disease, acute coronary syndrome or myocardial infarction, or congestive heart failure.

Bariatric surgery becomes more and more important in the management of the obese patient with type 2 diabetes, especially in case of failure of medical approaches. Metabolic improvement results not only from weight loss and the subsequent reduction in insulin resistance, but also from modifications of digestive hormones (especially incretins) that contribute to promote insulin secretion. This new paradigm, moving from bariatric surgery to metabolic surgery, opens new perspectives. The present article briefly describes innovative surgical techniques focusing on endocrine and metabolic improvement rather than on weight loss, the preliminary results of metabolic surgery in patients with type 2 diabetes and a body mass index <35 kg/m2 and, finally, some data regarding the surgical management of obese patients with type I diabetes not well treated with classical medical means.

People with chronic kidney disease (CKD) of stages 3-4 (creatinine clearance <50 ml/min) represent 25-30% of type 2 diabetic patients, but the problem is often underrecognized or neglected in clinical practice. However, most of oral antidiabetic agents have limitations in case of renal impairment, either because they require a dose adjustment, or because they are contra-indicated for safety reasons. It is the case for metformin (risk of lactic acidosis) and for most sulfonylureas (risk of hypoglycaemia). New antidiabetic agents are better tolerated in case of CKD. However, the daily dose of dipeptidyl peptidase-4 inhibitors should be adjusted (except for linagliptin). Concerning new inhibitors of renal SGLT2 cotransporters, they have a reduced efficacy and their safety remains to be demonstrated in presence of CKD.

The blockade of the renin-angiotensin system (RAS) improves the prognosis of patients with complications related to diabetes, hypertension or, in general, atherosclerosis. Several observational studies have suggested the use of a dual blockade of the RAS to benefit from a better cardiorenal protection. However, recent randomized controlled studies failed to demonstrate that a dual blockade exert a better protection than single blockade, but showed a higher risk for renal complications and hyperkalemia. To decrease the residual risk, other opportunities may be recommended such as reinforcement of low salt diet, use of supraphysiological dose of a monotherapy inhibiting the RAS (perhaps prescribed at the evening) or addition of an aldosterone antagonist. However, all these approaches, as dual therapy, may also increase the risk of hypotension and renal insufficiency and thus require to be used under strict medical supervision.

Kidney plays a role in glucose homeostasis, not only by its capacity to produce glucose through local gluconeogenesis, but also, and even more important in presence of diabetes, by its capacity to excrete glucose in urine when hyperglycaemia exceeds tubular reabsorption threshold. Such reabsorption depends on sodium-glucose cotransporters-2 (SGLT2), which can be blocked by selective inhibitors. These pharmacological agents augment glucosuria and reduce hyperglycaemia independently of insulin. Some have already proven their efficacy to improve glucose control, in monotherapy or in combination, while promoting weight loss and without inducing hypoglycaemia. Dapagliflozin should be the first medication of this new pharmacological class to be commercialized for the management of type 2 diabetes.

It is now well accepted that a chronic, low-grade inflammation is observed in abdominal obesity, insulin resistance and type 2 diabetes mellitus, and that pro-inflammatory cytokines and oxidative stress play a role in the pathogenesis of type 2 diabetes. These new findings raise the question of whether antiinflammatory strategies may have a place in the prevention and treatment of type 2 diabetes. This review article describes the results obtained in studies on patients with metabolic syndrome or type 2 diabetes aiming to test the metabolic effect of anti-inflammatory (salicylates, antagonists of interleukine-1, antagonists of tumor necrosis factor-alpha) and anti-oxydants (succinobucol) drugs.

Various systemic pharmacological approaches have been evaluated to reduce the risk of restenosis and clinical complications after coronary angioplasty, with or without stent, a main objective in the high risk diabetic population. The aim of the present paper is to describe the effects of the main pharmacological classes on the risk of restenosis, the need for new revascularisation procedures and the incidence of major clinical events (MACE: death, myocardial infarction, revascularisation). We will analyse successively the role of antiplatelet agents, omega 3 fatty acids, statins, anti-inflammatory compounds, immunomodulators, anti-oxidants and inhibitors of the renin-angiotensin system. Whenever possible, we will focus our attention on the results obtained in the diabetic population.

The relationships between body weight and metabolic abnormalities are not so simple. Indeed, there are metabolically obese normal-weight (MONW) individuals, who are frequently not detected because of a falsely reassuring body weight, and, in contrast, metabolically healthy, but obese, people (MHO). The different topography and hormonal-metabolic and pro-inflammatory activities of various adipose depots seem to play a major role to explain this paradox. The present review paper aims at describing the main principles of management of MONW individuals, with the objective to reduce the higher risk of type 2 diabetes and cardiovascular disease, and to discuss both the advantages and uncertainties of a classical weight-reducing approach in MHO people.

The blockade of the renin-angiotensin-aldosterone system (RAAS) is helpful in the management of arterial hypertension, congestive heart failure, post-myocardial infarction and diabetic nephropathy. Such blockade can be obtained with an angiotensin converting enzyme inhibitor, a specific antagonist of angiotensin II AT1 receptors, an aldosterone receptor antagonist and/or a direct inhibitor of renin such as aliskiren. Various studies have demonstrated that a dual or even triple RAAS inhibition may offer a better cardiorenal protection, in refractory congestive heart failure and in nephropathy with proteinuria. However, in the ONTARGET study, the dual inhibition with ramipril plus telmisartan did not provide any additional benefit compared to ramipril alone in high-risk cardiovascular patients, but showed a worse tolerance profile.

Thiazolidinediones (TZDs) are used as insulin sensitizers in the treatment of type 2 diabetes, but are associated with an increased risk of congestive heart failure (CHF). The odds ratio of ICC was 1.43 (pioglitazone vs placebo) in diabetic patients with high cardiovascular risk in the PROactive trial while it averaged 1.22 (rosiglitazone vs metformin) and 2.20 (rosiglitazone vs metformin) in the ADOPT study. In the interim analysis of the ongoing RECORD trial, the odds ratio averaged 2.15 (rosiglitazone vs metformin or sulfonylureas). In four real life registries, the relative risk of CHF with TZDs varied between 1.06 and 1.76 (between 1.10 and 1.44 combined with insulin) as compared to a treatment without TZDs. Such higher CHF risk should be appreciated according to the potential benefits of glitazones in the management of type 2 diabetes.

Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted in response to a meal ingestion, which is rapidly degraded by a specific enzyme, dipeptidylpeptidase-4 (DPP-4). It enhances insulin secretion in a glucose-dependent manner, inhibits glucagon secretion, retards gastric emptying,... Two pharmacological approaches have been developed to increase the abnormally low GLP-1 levels in type 2 diabetic patients: either to subcutaneously inject an agent closed to GLP-1 (exenatide), which is partially resistant to the action of DPP-4, either to orally administer a selective DPP-4 inhibitor (sitagliptin,...). These new drugs offer improved blood glucose control of type 2 diabetic patients, without inducing hypoglycaemia and with favourable effects on body weight.

The prevention of type 2 diabetes and of cardiovascular diseases is a major public health objective. Obviously life-style changes play a major role in this strategy. The Finnish Prevention Study recently demonstrated that the remarkable diabetes prevention observed after a 4-year lifestyle intervention is maintained after a further 3-year period of follow-up without prolongation of the active intervention. Such a reminiscent effect may also be observed in the prevention of cardiovascular diseases with various pharmacological interventions: an ACE inhibitor (HOPE), a statin (4S), a fibrate (Helsinki Heart Study) or an intensive insulin therapy in type I diabetic patients (DCCT-EDIC). These intriguing results argue for a long-term memory of previous therapeutic interventions in cardiovascular prevention.

Diabetes mellitus markedly increases the risk of cardiovascular diseases, with an especially elevated relative risk among women. Aspirin prescription is mandatory in secondary prevention, even if the protection by aspirin appears less efficacious in diabetic than in non-diabetic patients. In primary prevention, available data are paradoxically rather scarce, but also suggest a less effective prevention when diabetes is present. Aspirin remains the first antiplatelet agent in the diabetic population in all international guidelines of cardiovascular prevention although a higher daily dose may be proposed in this subgroup of patients (160-300 mg rather than 75-100 mg).

The inhibition of cholesterol synthesis by a statin enhances intestinal absorption of both cholesterol and various phytosterols. The atherogenic role of phytosterols, well proven in hypersitosterolemia, is now suspected in patients with premature coronary artery disease. The cholestanol/cholesterol ratio can be used as a marker of intestinal cholesterol absorption. Individuals with elevated ratio ("high absorbers") have less favourable cholesterol-lowering response and cardiovascular protection with statin therapy as compared to individuals with low ratio ("high synthesizers"). They may benefit of an adjunct therapy with phytostanols or ezetimibe, both being capable to reduce plasma concentrations of cholesterol and of phytosterols.

Diabetes mellitus increases by 2.5 to 5 the relative risk of congestive heart failure. Besides the classical risk factors of congestive heart failure such as obesity, arterial hypertension and coronary artery disease that are frequently associated to type 2 diabetes, a diabetic cardiomyopathy plays also a role. This specific complication is related to metabolic factors and oxidative stress, leading to muscular cell apoptosis and fibrosis. The management of a diabetic patient with congestive heart failure has several specificities not only concerning the treatment of cardiac insufficiency but most importantly concerning antidiabetic therapy. The relationship between glitazones, peripheral oedema and risk of congestive heart failure is currently raising much interest and controversies.

Because of the increasing longevity of the population, a growing number of very old people are exposed to medications. Drug therapy in this population is difficult because of our lack of knowledge. The number of drugs administered is generally high and the prescription is often inappropriate. Changes in body composition, malnutrition and renal failure can cause drug accumulation and toxicity. However, hepatic metabolism via cytochrome P450 does not seem to be markedly influenced by oldness. Iatrogenic pathology is frequent in the elderly and may lead to hospitalisation and reduction in quality of life. Specific education of the medical care team should be promoted in order to tackle this important problem of public health.

RIO (Rimonabant In Obesity and related disorders) is a large phase 3 programme (>6600 patients) evaluating the efficacy and safety of rimonabant (5 or 20 mg/day), a CBI receptor antagonist of endocannabinoid system, in obese or overweight patients with or without comorbidities (RIO-Europe and RIO-North America), with untreated dyslipidaemia (RIO-Lipids) or with type 2 diabetes treated with metformin or sulfonylurea (RIO-Diabetes). Compared to placebo, rimonabant 20 mg/day consistently increases weight loss, reduces waist circumference, increases HDL cholesterol, lowers triglyceride levels, diminishes insulin resistance, and reduces the prevalence of metabolic syndrome. Almost half of the metabolic effects, including adiponectin increase, occur beyond weight loss, suggesting a direct peripheral effect of rimonabant.

Type 2 diabetes has a complex pathophysiology, combining a defect of insulin secretion by the pancreas, an increased glucose production by the liver and a reduced insulin-mediated glucose uptake by the skeletal muscle. Each of these abnormalities can be partially reversed by a specific drug, an agent promoting insulin secretion (sulphonylurea or glinide), metformin and a thiazolidinedione (glitazone), respectively. Therefore, a triple oral therapy, targeting simultaneously the three main metabolic abnormalities of type 2 diabetes, deserves special attention. Recent clinical trials have shown both the efficacy and safety of this triple oral therapy. However, its precise place remains to be better specified in the overall management of type 2 diabetes.