The action to control cardiovascular risk in diabetes (ACCORD) trial showed a neutral average treatment effect of intensive blood glucose and blood pressure (BP) controls in preventing major adverse cardiovascular events (MACE) in individuals with type 2 diabetes. Yet, treatment effects across patient subgroups have not been well understood. We aimed to identify patient subgroups that might benefit from intensive glucose or BP controls for preventing MACE.

As a post-hoc analysis of the ACCORD trial, we included 10 251 individuals with type 2 diabetes. We applied causal forest and causal tree models to identify participant characteristics that modify the efficacy of intensive glucose or BP controls from 68 candidate variables (demographics, comorbidities, medications and biomarkers) at the baseline. The exposure was (a) intensive versus standard glucose control [glycated haemoglobin (HbA1c) <6.0% vs. 7.0%-7.9%], and (b) intensive versus standard BP control (systolic BP <120 vs. <140 mmHg). The primary outcome was MACE.

Compared with standard glucose control, intensive one reduced MACE in those with baseline HbA1c <8.5% [relative risk (RR): 0.79, 95% confidence interval (CI): 0.67-0.93] and those with estimated glomerular filtration rate ≥106 ml/min/1.73 m2 (RR: 0.74, 95% CI: 0.55-0.99). Intensive BP control reduced MACE in those with normal high-density lipoprotein levels (women >55 mg/dl, men >45 mg/dl; RR: 0.51, 95% CI: 0.34-0.74). Risk reductions were not significant in other patient subgroups.

Our findings suggest heterogeneous treatment effects of intensive glucose and BP control and could provide biomarkers for future clinical trials to identify more precise HbA1c and BP treatment goals for individualized medicine.

To compare the effects of different selective sodium-glucose cotransporter-2 inhibitors (SGLT2i) on hemoglobin and hematocrit in patients with type 2 diabetes mellitus (T2DM) with a network meta-analysis (NMA).

Randomized controlled trials (RCTs) on SGLT2i for patients with T2DM were searched in PubMed, Embase, Cochrane Library, and Web of Science from inception of these databases to July 1, 2023. The risk of bias (RoB) tool was used to evaluate the quality of the included studies, and R software was adopted for data analysis.

Twenty-two articles were included, involving a total of 14,001 T2DM patients. SGLT2i included empagliflozin, dapagliflozin, and canagliflozin. The NMA results showed that compared with placebo, canagliflozin 100mg, canagliflozin 300mg, dapagliflozin 10mg, dapagliflozin 2mg, dapagliflozin 50mg, dapagliflozin 5mg, empagliflozin 25mg, and dapagliflozin 20mg increased hematocrit in patients with T2DM, while canagliflozin 100mg, canagliflozin 200mg, canagliflozin 300mg increased hemoglobin in patients with T2DM. In addition, the NMA results indicated that canagliflozin 100mg had the best effect on the improvement of hematocrit, and canagliflozin 200mg had the best effect on the improvement of hemoglobin.

Based on the existing studies, we concluded that SGLT2i could increase hematocrit and hemoglobin levels in patients with T2DM, and canagliflozin 100mg had the best effect on the improvement of hematocrit, while canagliflozin 200mg had the best effect on the improvement of hemoglobin.

https://www.crd.york.ac.uk/PROSPERO/#loginpage, identifier PROSPERO (CRD42023477103).

The current meta-analysis aims to assess the efficacy and safety of sodium glucose cotransporter 2 (SGLT2) inhibitors in individuals with diabetes and chronic kidney disease (CKD). The current meta-analysis was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A systematic search was conducted to identify all relevant studies related to the efficacy and safety of SGLT2 inhibitors in individuals with diabetes and CKD. The search was undertaken in PubMed, EMBASE, and Cochrane Library from January 2000 to September 2022. The primary efficacy outcome assessed in the current meta-analysis included major adverse cardiovascular events (MACE). Other efficacy outcomes included all-cause mortality and change in hemoglobin A1c (HbA1c) (%). Safety outcomes included serious adverse events, acute kidney injury, hypoglycemia, and hyperkalemia. In total 11 articles met the inclusion criteria and were included in the final analysis enrolling 27520 patients (14491 in the SGLT2 inhibitors and 13029 in the placebo group). The findings of this meta-analysis have shown that the risk of MACE and all-cause mortality was significantly lower in patients receiving SGLT2 inhibitors. Additionally, Hb1AC change was also significantly greater in SGLT2 inhibitors group. In relation to safety outcomes, serious adverse events, risk of acute kidney injury, and hyperkalemia were significantly lower in the SGLT2 inhibitors group. The SGLT2 inhibitors significantly decreased the risk of major cardiovascular events and all-cause mortality in patients with CKD and diabetes. Furthermore, SGLT2 inhibitor is also effective in reducing Hb1Ac levels in patients.

Diabetes is common in patients waitlisted for liver transplantation because of end-stage liver disease or hepatocellular cancer as well as in posttransplant phase (posttransplantation diabetes mellitus). In both conditions, the presence of diabetes severely affects disease burden and long-term clinical outcomes; careful monitoring and appropriate treatment are pivotal to reduce cardiovascular events and graft and recipients' death. We thoroughly reviewed the epidemiology of diabetes in the transplant setting and the different therapeutic options, from lifestyle intervention to antidiabetic drug use-including the most recent drug classes available-and to the inclusion of bariatric surgery in the treatment cascade. In waitlisted patients, the old paradigm that insulin should be the treatment of choice in the presence of severe liver dysfunction is no longer valid; novel antidiabetic agents may provide adequate glucose control without the risk of hypoglycemia, also offering cardiovascular protection. The same evidence applies to the posttransplant phase, where oral or injectable noninsulin agents should be considered to treat patients to target, limiting the impact of disease on daily living, without interaction with immunosuppressive regimens. The increasing prevalence of liver disease of metabolic origin (nonalcoholic fatty liver) among liver transplant candidates, also having a higher risk of noncirrhotic hepatocellular cancer, is likely to accelerate the acceptance of new drugs and invasive procedures, as suggested by international guidelines. Intensive lifestyle intervention programs remain however mandatory, both before and after transplantation. Achievement of adequate control is mandatory to increase candidacy, to prevent delisting, and to improve long-term outcomes.

Type 2 diabetes (T2D) is increasingly prevalent and associated with increased risk for cardiovascular and renal disease. After lifestyle modification, metformin is usually the first-line pharmacotherapy and sulfonylureas are traditionally added after metformin failure. However, with newer glucose lowering drugs that may have less risk of hypoglycemia or that may reduce cardiovascular and renal events, the position of sulfonylureas is being reevaluated.

In this article, the authors review relevant publications related to the use of sulfonylureas.

Sulfonylureas are potent glucose lowering drugs. The risk of hypoglycemia varies with different drugs within the class and can be minimized by using the safer drugs, possibly in lower doses. Cardiovascular events do not appear to be increased with some of the newer generation drugs. The durability of glycemic control also appears comparable to other newer agents. Sulfonylureas are the preferred treatment for some types of monogenic diabetes and selection of T2D patients who may have greater benefit from sulfonylureas based on certain phenotypes and genotypes is likely to be refined further by precision medicine. Sulfonylureas are inexpensive and readily available everywhere and they are still the most frequently used second-line treatment for T2D in many parts of the world.

Chronic kidney disease is a prevalent complication of type 2 diabetes mellitus (T2DM). Sodium-glucose cotransporter type 2 inhibitors (SGLT2is) have a unique mode of action targeting the kidney. As their glucose-lowering potency declines with the reduction in estimated glomerular filtration rate, their clinical use in patients with T2DM with chronic kidney disease has been submitted to restriction. However, recent observations demonstrated that SGLT2is reduce the progression of renal impairment in patients with mild-to-moderate chronic kidney disease, with or without albuminuria. Furthermore, SGLT2is reduce the incidence of cardiovascular events in patients with T2DM at high cardiovascular risk, independently of baseline estimated glomerular filtration rate. Thus, recent guidelines recommend the prescription of SGLT2is in patients with T2DM with mild-to-moderate chronic kidney disease defined by an estimated glomerular filtration rate between ≥ 30 and < 90 mL/min/1.73 m² and/or albuminuria. The present comprehensive review describes the pharmacokinetic/pharmacodynamic properties of SGLT2is commercialised worldwide and in Japan in patients with T2DM with mild, moderate and severe chronic kidney disease. Drug exposure increases when the estimated glomerular filtration rate declines but without a clear-cut relationship with the severity of chronic kidney disease and in a rather moderate amplitude that most often does not require a dose reduction in the presence of mild-to-moderate chronic kidney disease. The urinary glucose excretion steadily declines with the reduction in estimated glomerular filtration rate. This may explain a lower effect on glucose control, yet the positive effects on body weight and blood pressure still remain. The efficacy and safety of these SGLT2is are analysed among patients with stages 3a and 3b chronic kidney disease in placebo-controlled randomised clinical trials, with almost similar results in Asian and non-Asian individuals with T2DM. In summary, there is no reason not to prescribe SGLT2is in patients with T2DM with mild-to-moderate chronic kidney disease, especially if the aim is to benefit from cardiovascular and/or renal protection.

Diabetes mellitus (DM) is the leading cause of end-stage renal disease and 50% of dialysis patients are insulin-treated.

to search for unexplained hypoglycemia (HYPO).

identify a possible cause of HYPO due to altered insulin absorption.

insulin injected into subcutaneous lipo-hypertrophy (LH) nodules leads to unpredictable HYPOS.

looking for LH systematically and training patients to the best injection technique are new challenges for nephrologists to reduce HYPO and emergency hospitalization rates, thus sparing healthcare resources and improving the quality of life of insulin-treated dialysis patients.

Glucose-lowering therapy (GLT) should be individualized in older patients with type 2 diabetes (T2D) according to their health status and their life expectancy. This study aimed at assessing the inappropriateness of GLT prescribing and the one-year mortality rate in geriatric patients with T2D.

Retrospective cohort study of consecutive inpatients with T2D admitted to a geriatric ward of a Belgian university hospital. Inclusion criteria were age ≥ 75 years, T2D with GLT before admission, and HbA1c measurement during the hospital stay. Comorbidities and geriatric syndromes were collected. GLT agents were classified into hypoglycaemic and non-hypoglycaemic ones, and their dosages were expressed in daily defined dose (DDD). Health status (intermediate or poor) and GLT appropriateness (appropriate, overtreatment, undertreatment) were assessed according to the 2019 Endocrine Society guideline on diabetes treatment in older adults, in which GLT overtreatment requires the presence of hypoglycaemic therapy. One-year mortality was determined using the National Registry of vital status, and its associated factors were analysed using multivariable Cox' regression.

The 318 geriatric patients with T2D (median age 84 years; 46% female) were in intermediate (33%) or poor health (67%). These two groups reached similar low HbA1c values (median 6.9%) with similar GLT regimens. GLT overtreatment was frequent (57%) irrespectively of the geriatric features. One-year mortality rate was high (38.5%) and associated in multivariate analysis with poor health status (HR: 1.59, p = 0.033), malnutrition (HR: 1.67, p = 0.006) and GLT overtreatment (HR: 1.73, p = 0.023). Patients with GLT overtreatment had a higher mortality rate (44.5%).

GLT overtreatment was present in more than half of these geriatric patients. Many of them were in poor health status and died within one-year. Special attention should be paid to individualisation of the HbA1c goals in the geriatric patients with diabetes, and to GLT de-intensification in those being over-treated.

Diabetic kidney disease (DKD) is the major contributor to the mortality and the financial burden of diabetes, accounting for approximately 50% of the cases of end-stage renal disease (ESRD) in the developed world. Several studies have already demonstrated that achieving blood pressure targets in DKD with agents blocking the renin-angiotensin system confer superior renoprotection when compared to other agents. However, the effects on renal outcomes of antihyperglycaemic agents in these patients have not been reported or studied broadly until recent years. The intent of this article is to review the available data on safety, efficacy, impact on renal outcomes and pathophysiology implications of the most utilized antihyperglycaemic agents in DKD/ESRD.

Type 2 diabetes is the leading cause of impaired kidney function, albuminuria, and renal replacement therapy globally, thus placing a large burden on health-care systems. Current treatment strategies rely on intensive glucose lowering as well as strict blood pressure control through blockade of the renin-angiotensin-aldosterone system. Such approaches might slow decline in kidney function, but many patients progress to end-stage kidney failure despite optimal therapy. In recent clinical trials, new-generation glucose-lowering drug classes, the sodium-glucose co-transporter-2 inhibitors and agents that target the incretin pathway, have been shown to improve kidney outcomes in patients with type 2 diabetes. Other new approaches, which have been developed on the basis of an improved understanding of the mechanisms that contribute to kidney damage in the context of diabetes, include use of drugs that block endothelin receptors (eg, atrasentan) and non-steroidal mineralocorticoid receptors (eg, finerenone). In this Review, we provide an overview of recent clinical data relevant to these new therapeutic approaches for management of kidney disease in the context of type 2 diabetes.

Upregulation of chemokine CX3CL1 and its receptor CX3CR1 occurs in the diabetic human placenta. Metformin, an insulin-sensitizing biguanide, is used in the therapy of diabetic pregnancy. By preventing the activation of NF-κB, metformin exhibits anti-inflammatory properties. We examined the influence of hyperglycemia (25 mmol/L glucose; HG group; N = 36) on metformin-mediated effects on CX3CL1 and TNF-α production by placental lobules perfused extracorporeally. Additionally, CX3CR1 expression and contents of CX3CR1, TNF-α receptor 1 (TNFR1), and NF-κB proteins in the placental tissue were evaluated. Placentae perfused under normoglycemia (5 mmol/L glucose; NG group; N = 36) served as the control. Metformin (2.5 and 5.0 mg/L; subgroups B and C) lowered the production of CX3CL1 and TNF-α in a dose-dependent and time-dependent manner. Hyperglycemia did not weaken the strength of these metformin effects. Moreover, CX3CL1 levels after perfusion with 5.0 mg/L metformin were reduced by 33.28 and 33.83% (at 120 and 150 min, respectively) in the HG-C subgroup versus 24.98 and 23.66% in the NG-C subgroup, which indicated an augmentation of the metformin action over time in hyperglycemia. CX3CR1 expression was significantly higher in the HG-B and HG-C subgroups compared to that in the NG-B and NG-C subgroups. Increased CX3CR1 protein content in the placental lysates was observed in subgroups B and C. The two higher metformin concentrations significantly decreased the levels of NF-κBp65 protein content in both groups. However, the decrease was significantly stronger in hyperglycemia. TNFR1 upregulation in the HG group was not affected by metformin. Further studies on metformin therapy during pregnancy are needed, including safety issues.

Chronic kidney disease (CKD) represents a huge burden in patients with type 2 diabetes (T2DM). This review therefore has the aim of assessing the add-on value of new glucose-lowering agents compared or combined with inhibitors of the renin angiotensin aldosterone system (RAAS) on renal outcomes in T2DM patients.

This article first summarizes the results reported with RAAS inhibitors, mainstay of nephroprotection in T2DM with albuminuria. Second, it describes the positive results with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and, even more impressive, sodium-glucose cotransporter type 2 inhibitors (SGLT2is). Third, besides the potential of combined therapies, it briefly considers some new approaches currently in development.

RAAS inhibitors exert renoprotective effects beyond their blood pressure lowering effects while SGLT2is, and possibly GLP-1RAs, exert nephroprotection independently of their glucose-lowering activity. These effects were demonstrated not only on surrogate endpoints such as albuminuria and estimated glomerular filtration rate decline, but also on hard endpoints, including progression to end-stage renal disease requiring replacement therapy. The underlying mechanisms are different and potentially complementary on glomerular hemodynamics, arguing for combined therapies. Nevertheless, there is still room for new emerging drugs to tackle CKD in T2DM.

Diabetic kidney disease (DKD) represents an enormous burden in patients with type 2 diabetes mellitus (T2DM). Preclinical studies using most glucose-lowering agents have suggested renal-protective effects, but the proposed mechanisms of renoprotection have yet to be defined, and the promising results from experimental studies remain to be translated into human clinical findings to improve the prognosis of patients at risk of DKD. Also, it is important to distinguish effects on surrogate endpoints, such as decreases in albuminuria and estimated glomerular filtration rate (eGFR), and hard clinical endpoints, such as progression to end-stage renal disease (ESRD) and death from renal causes. Data regarding insulin therapy are surprisingly scarce, and it is nearly impossible to separate the effects of better glucose control from those of insulin per se, whereas favourable preclinical data with metformin, thiazolidinediones and dipeptidyl peptidase (DPP)-4 inhibitors are plentiful, and positive effects have been observed in clinical studies, at least for surrogate endpoints. The most favourable renal results have been reported with glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter type-2 inhibitors (SGLT2is). Significant reductions in both albuminuria and eGFR decline have been reported with these classes of glucose-lowering medications compared with placebo and other glucose-lowering agents. Moreover, in large prospective cardiovascular outcome trials using composite renal outcomes as secondary endpoints, both GLP-1RAs and SGLT2is added to standard care reduced renal outcomes combining persistent macro-albuminuria, doubling of serum creatinine, progression to ESRD and kidney-related death; however, to date, only SGLT2is have been clearly shown to reduce such hard clinical outcomes. Yet, as the renoprotective effects of SGLT2is and GLP-1RAs appear to be independent of glucose-lowering activity, the underlying mechanisms are still a matter of debate. For this reason, further studies with renal outcomes as primary endpoints are now awaited in T2DM patients at high risk of DKD, including trials evaluating the potential add-on benefits of combined GLP-1RA-SGLT2i therapies.

This analysis of real-world data aimed to (a) determine the proportion of Type II diabetes (T2DM) patients treated with metformin or dipeptidyl peptidase-4 inhibitors (DPP-4i) that require dose adjustment or therapy discontinuation due to chronic kidney disease (CKD), and (b) to assess the time required to dose adjustment from the time of worsening of CKD.

In this retrospective study, two study populations were defined in a large healthcare organization. In the cross-sectional analysis, the distribution of CKD stages and the appropriate dosage of metformin and DPP-4i in 2013 was examined according to renal function among T2DM patients. In the longitudinal analysis, a cohort was defined to assess the time elapsed from first indication worsening of CKD to dose adjustment, among patients treated with those medications during years 2006-2013.

Among patients treated with metformin or DPP-4i, one third of patients with CKD failed to adjust the dosage or to discontinue metformin or DPP-4i as indicated. Median time for dose adjustment or discontinuation was significantly longer for DPP-4i than for metformin (9.8 compared to 16.8 months for metformin and DPP-4i, respectively; p-value <.001).

This real-world data analysis showed that adjustment of dose or discontinuation of metformin or DPP-4i in patients with worsening CKD occurred less often in DPP-4i users than metformin users and took a longer time.

The sulfonylureas are effective oral glucose-lowering agents with a long history of clinical use. While all have the same general mechanism of action, their pharmacokinetic properties are influenced by factors such as dosage, rate of absorption, duration of action, route of elimination, tissue specificity, and binding affinity for pancreatic β-cell receptor. The result is a class of agents with similar HbA1c-lowering efficacy, but well-documented differences in terms of effects on hypoglycemia, and cardiovascular and renal safety. This review examines the differences between currently available sulfonylureas with a focus on how gliclazide modified release (MR) differs from other members of this class and from newer oral antihyperglycemic agents in the form of dipeptidyl peptidase-4 (DPP4) and sodium- glucose cotransporter 2 (SGLT2) inhibitors. The first part focuses on major outcome trials that have been conducted with the sulfonylureas and new oral agents. Consideration is then given to factors important for day-to-day prescribing including efficacy and durability, weight changes, hypoglycemia, renal effects and cost. Based on current evidence, third-generation sulfonylureas such as gliclazide MR possess many of the properties desired of a type 2 diabetes drug including high glucose-lowering efficacy, once-daily oral administration, few side effects other than mild hypoglycemia, and cardiovascular safety.

Post-transplantation diabetes mellitus (PTDM) may severely impact both short- and long-term outcomes of kidney transplant recipients in terms of graft and patient survival. However, PTDM often goes undiagnosed is underestimated or poorly managed. A diagnosis of PTDM should be delayed until the patient is on stable maintenance doses of immunosuppressive drugs, with stable kidney graft function and in the absence of acute infections. Risk factors for PTDM should be assessed during the pre-transplant evaluation period, in order to reduce the likelihood of developing diabetes. The oral glucose tolerance test is considered as the gold standard for diagnosing PTDM, whereas HbA1c is not reliable during the first months after transplantation. Glycaemic targets should be individualised, and comorbidities such as dyslipidaemia and hypertension should be treated with drugs that have the least possible impact on glucose metabolism, at doses that do not interact with immunosuppressants. While insulin is the preferred agent for treating inpatient hyperglycaemia in the immediate post-transplantation period, little evidence is available to guide therapeutic choices in the management of PTDM. Metformin and incretins may offer some advantage over other glucose-lowering agents, particularly with respect to risk of hypoglycaemia and weight gain. Tailoring immunosuppressive regimens may be of help, although maintenance of good kidney function should be prioritised over prevention/treatment of PTDM. The aim of this narrative review is to provide an overview of the available evidence on management and prevention of PTDM, with a focus on the available therapeutic options.

Diabetes is the leading cause of chronic kidney disease, and even in the absence of albuminuria, decreased renal function in type 2 diabetes mellitus (T2DM) patients increases the risk for major adverse cardiovascular events and death. The evidence derived from recent studies suggests that intensive glucose control not only reduces the risk for microalbuminuria and macroalbuminuria but may also decrease the rate of decline of glomerular filtration rate (GFR). Although insulin therapy is widely used in patients with T2DM and renal disease, metabolic control is particularly difficult to achieve and manage because of the limited therapeutic options and the frequent comorbidities seen in this population. Recent evidence suggests that dipeptidyl peptidase-4 (DPP-4) inhibitors may offer a better choice for improving glycemic control in T2DM patients with low GFR. This review will focus on vildagliptin, a DPP-4 inhibitor with a large body of evidence in patients with moderate to severe renal failure and a good clinical profile in terms of efficacy and safety. In particular, vildagliptin, with appropriate dose adjustment, provides clinically important reductions in glycated hemoglobin, without increasing weight and the risk of hypoglycemia even in patients with severe chronic kidney disease.

Dipeptidyl peptidase-4 inhibitors (DPP-4is) are increasingly being used in the management of type 2 diabetes (T2D). The present review summarizes the current knowledge of the effects of DPP-4is on renal outcomes by analyzing the experimental preclinical data, the effects of DPP-4is on urinary albumin-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFRs) from observational studies and clinical trials, and renal events (including kidney failure requiring renal replacement therapy) in recent large prospective cardiovascular outcome trials. Renal protection has been demonstrated in various animal models that have implicated different underlying mechanisms independent of glucose control, whereas prevention of new onset microalbuminuria and/or progression of albuminuria has been reported in some clinical studies, but with no significant effects on eGFR in most of them. The long-term clinical effects of DPP-4is on renal outcomes and the development of end-stage renal disease remain largely unknown and, thus, demand further investigations in prospective trials and long-term observational studies. In conclusion, despite promising results in animal models, data on surrogate biological markers of renal function and clinical renal outcomes remain rather scanty in patients with T2D, and mostly demonstrate the safety rather than true efficacy of DPP-4is.

Diabetes mellitus (DM) is one of the leading causes of chronic kidney disease (CKD) which eventually leads to insulin resistance and decreased insulin degradation. In patients with diabetic kidney disease (DKD), the overall insulin requirement declines which necessitates the reassessment for individualization, adjustment and titration of insulin doses depending on the severity of kidney disease.

To provide simple and easily implementable guidelines to primary care physicians on appropriate insulin dosing and titration of various insulin regimens in patients with DKD.

Each insulin regimen (basal, prandial, premix and basal-bolus) was presented and evaluated for dosing and titration based on data from approved medical literatures on chronic kidney disease. These evaluations were then factored into the national context based on the expert committee representatives' and key opinion leaders' clinical experience and common therapeutic practices followed in India.

Recommendations based on dosing and titration of insulins has been developed. Moreover, the consensus group also recommended the strategy for dose estimation of insulin, optimal glycaemic targets and self-monitoring in patients with DKD.

The consensus based recommendations will be a useful reference tool for health care practitioners to initiate, optimise and intensify insulin therapy in patients with DKD.

Diabetes is an important cause of end stage renal failure worldwide. As renal impairment progresses, managing hyperglycaemia can prove increasingly challenging, as many medications are contra-indicated in moderate to severe renal impairment. Whilst evidence for tight glycaemic control reducing progression to renal failure in patients with established renal disease is limited, poor glycaemic control is not desirable, and is likely to lead to progressive complications. Metformin is a first-line therapy in patients with Type 2 diabetes, as it appears to be effective in reducing diabetes related end points and mortality in overweight patients. Cessation of metformin in patients with progressive renal disease may not only lead to deterioration in glucose control, but also to loss of protection from cardiovascular disease in a cohort of patients at particularly high risk. We advocate the need for further study to determine the role of metformin in patients with severe renal disease (chronic kidney disease stage 4-5), as well as patients on dialysis, or pre-/peri-renal transplantation. We explore possible roles of metformin in these circumstances, and suggest potential key areas for further study.

The pace of anti-diabetic drug discovery is very slow in spite of increasing rate of prevalence of Type 2 Diabetes which remains a major public health concern. Though extensive research steps are taken in the past decade, yet craves for better new treatment strategies to overcome the current scenario. One such general finding is the evolution of gliptins which discriminately inhibits DPP4 (Dipeptidyl peptidase-4) enzyme. Although the mechanism of action of gliptin is highly target oriented and accurate, still its long-term use stands unknown. This step calls for a fast, flexible, and cost-effective strategies to meet the demands of producing arrays of high-content lead compounds with improved efficiency for better clinical success. The present review highlights the available gliptins in the market and also other naturally occurring DPP4 enzyme inhibitors. Along with describing the known inhibitors and their origin in this review, we attempted to identify a probable new lead compounds using advanced computational techniques. In this context, computational methods that integrate the knowledge of proteins and drug responses were utilized in prioritizing targets and designing drugs towards clinical trials with better efficacy. The compounds obtained as a result of virtual screening were compared with the commercially available gliptin in the market to have better efficiency in the identification and validation of the potential DPP4 inhibitors. The combinatorial computational methods used in the present study identified Compound 1: 25022354 as promising inhibitor.

Type 2 diabetes mellitus (T2DM) is a global epidemic that poses a major challenge to health-care systems. Improving metabolic control to approach normal glycaemia (where practical) greatly benefits long-term prognoses and justifies early, effective, sustained and safety-conscious intervention. Improvements in the understanding of the complex pathogenesis of T2DM have underpinned the development of glucose-lowering therapies with complementary mechanisms of action, which have expanded treatment options and facilitated individualized management strategies. Over the past decade, several new classes of glucose-lowering agents have been licensed, including glucagon-like peptide 1 receptor (GLP-1R) agonists, dipeptidyl peptidase 4 (DPP-4) inhibitors and sodium/glucose cotransporter 2 (SGLT2) inhibitors. These agents can be used individually or in combination with well-established treatments such as biguanides, sulfonylureas and thiazolidinediones. Although novel agents have potential advantages including low risk of hypoglycaemia and help with weight control, long-term safety has yet to be established. In this Review, we assess the pharmacokinetics, pharmacodynamics and safety profiles, including cardiovascular safety, of currently available therapies for management of hyperglycaemia in patients with T2DM within the context of disease pathogenesis and natural history. In addition, we briefly describe treatment algorithms for patients with T2DM and lessons from present therapies to inform the development of future therapies.

To achieve good metabolic control in diabetes and keep long term, a combination of changes in lifestyle and pharmacological treatment is necessary. Achieving near-normal glycated hemoglobin significantly, decreases risk of macrovascular and microvascular complications. At present there are different treatments, both oral and injectable, available for the treatment of type 2 diabetes mellitus (T2DM). Treatment algorithms designed to reduce the development or progression of the complications of diabetes emphasizes the need for good glycaemic control. The aim of this review is to perform an update on the benefits and limitations of different drugs, both current and future, for the treatment of T2DM. Initial intervention should focus on lifestyle changes. Moreover, changes in lifestyle have proven to be beneficial, but for many patients is a complication keep long term. Physicians should be familiar with the different types of existing drugs for the treatment of diabetes and select the most effective, safe and better tolerated by patients. Metformin remains the first choice of treatment for most patients. Other alternative or second-line treatment options should be individualized depending on the characteristics of each patient. This article reviews the treatments available for patients with T2DM, with an emphasis on agents introduced within the last decade.

Dipeptidyl peptidase-4 (DPP-4) inhibitors are widely used in the management of patients with type 2 diabetes mellitus (T2DM) and renal impairment (RI). A systematic literature review was performed to compare the efficacy and safety of DPP-4 inhibitors in patients with T2DM and RI.

We searched EMBASE, MEDLINE, and the Cochrane Central Register of Controlled Trials (cut-off, June 2015) to identify ≥12-week, randomized, placebo-controlled trials on DPP-4 inhibitors in ≥50 patients with T2DM and RI. Outcomes of interest included change in glycated hemoglobin (HbA1c), overall safety, and incidence of hypoglycemic events (HEs).

Seven trials of ≤52-54 weeks duration were retrieved, which included one study each on vildagliptin, saxagliptin, and sitagliptin, two on linagliptin, and the remaining two were extension studies of vildagliptin and saxagliptin. Majority of patients were on insulin at baseline (53-86%), except in the sitagliptin study, where approximately 11% received insulin during the placebo-controlled phase. After 52 weeks, vildagliptin and saxagliptin reduced HbA1c levels by 0.6-0.7% (baseline 7.8-8.4%) versus placebo in the overall population. HbA1c reductions were similar at weeks 12 and 52. In the 12-week, placebo-controlled phase, sitagliptin and linagliptin reduced mean HbA1c by approximately 0.4% (baseline 7.7-8.1%) versus placebo. Rates of HEs with DPP-4 inhibitors were not significantly different versus placebo in any study. Rates of adverse events (AEs) and changes involving renal function were similar in the active- and placebo-treated groups.

These results suggest that DPP-4 inhibitors have the potential to improve glycemic control in patients with RI without increasing the risk of HEs or overall AEs.

Novartis Pharma AG.

Type 2 diabetes (T2DM) is a common condition. Treatment of diabetes and related complications can be complex. In addition to lifestyle changes, medications play an important role in controlling patients' blood glucose levels and preventing complications. From an individual and societal standpoint, it is also an expensive disease. Medical spending attributed to diabetes per individual is significant. With appropriate therapy, patients can lead full, healthy lives with the disease, so making informed decisions regarding pharmacotherapy for T2DM is clearly of great importance.

We investigated the rate of severe hypoglycemic events and confounding factors in patients with type 2 diabetes treated with sulfonylurea at specialized diabetes centers, documented in the German/Austrian DPV-Wiss database.

Data from 29 485 sulfonylurea-treated patients were analyzed (median[IQR] age 70.8[62.2-77.8] years, diabetes duration 8.2[4.3-12.8] years). The primary objective was to estimate the event rate of severe hypoglycemia (requiring external help, causing unconsciousness/coma/convulsion and/or emergency hospitalization). Secondary objectives included exploration of confounding risk factors through group comparison and Poisson regression.

Severe hypoglycemic events were reported in 826(2.8%) of all patients during their most recent year of sulfonylurea treatment. Of these, n = 531(1.8%) had coma, n = 501(1.7%) were hospitalized at least once. The adjusted event rate of severe hypoglycemia [95%CI] was 3.9[3.7-4.2] events/100 patient-years (coma: 1.9[1.8-2.1]; hospitalization: 1.6[1.5-1.8]). Adjusted event rates by diabetes treatment were 6.7 (sulfonylurea + insulin), 4.9 (sulfonylurea + insulin + other OAD), 3.1 (sulfonylurea + other OAD) and 3.8 (sulfonylurea only). Patients with ≥1 severe event were older (p < 0.001) and had longer diabetes duration (p = 0.020) than patients without severe events. Participation in educational diabetes-programs and indirect measures of insulin-resistance (increased BMI, plasma-triglycerides) were associated with fewer events (all p < 0.001). Impaired renal function was common (n = 3113 eGFR; ≤30 mL/min) and associated with an increased rate of severe events (≤30 mL/min: 7.7; 30-60 mL/min: 4.8; >60 mL/min: 3.9).

These real-life data showed a rate of severe hypoglycemia of 3.9/100 patient-years in sulfonylurea-treated patients from specialized diabetes centers. Higher risk was associated with known risk factors including lack of diabetes education, older age and decreased eGFR but also with lower BMI and lower triglyceride levels, suggesting that sulfonylurea treatment in those patients should be considered with caution.

Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus. SGLT2 cotransporters are responsible for reabsorption of 90 % of the glucose filtered by the kidney. The glucuretic effect resulting from SGLT2 inhibition contributes to reduce hyperglycaemia and also assists weight loss and blood pressure reduction. Several SGLT2 inhibitors are already available in many countries (dapagliflozin, canagliflozin, empagliflozin) and in Japan (ipragliflozin, tofogliflozin). These SGLT2 inhibitors share similar pharmacokinetic characteristics with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites and a low renal elimination as a parent drug. Pharmacokinetic parameters are slightly altered in the case of chronic kidney disease (CKD). While no dose adjustment is required in the case of mild CKD, SGLT2 inhibitors may not be used or only at a lower daily dose in patients with moderate CKD. Furthermore, the pharmacodynamic response to SGLT2 inhibitors as assessed by urinary glucose excretion declines with increasing severity of renal impairment as assessed by a reduction in the estimated glomerular filtration rate. Nevertheless, the glucose-lowering efficacy and safety of SGLT2 inhibitors are almost comparable in patients with mild CKD as in patients with normal kidney function. In patients with moderate CKD, the efficacy tends to be dampened and safety concerns may occur. In patients with severe CKD, the use of SGLT2 inhibitors is contraindicated. Thus, prescribing information should be consulted regarding dosage adjustments or restrictions in the case of renal dysfunction for each SGLT2 inhibitor. The clinical impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy deserve attention because of preliminary favourable results in animal models.

Chronic kidney disease (CKD) is common in older adults, and its burden is expected to increase in older populations. Even if the knowledge on the approach to older patient with CKD is still evolving, current guidelines for pharmacological management of CKD does not include specific recommendations for older patients. Additionally, decision-making on renal replacement therapy (RRT) for older patients is far from being evidence-based, and despite the improvement in dialysis outcomes, RRT may cause more harm than benefit compared with conservative care when prognostic stratification is not carefully assessed. The use of comprehensive geriatric assessment tools could help clinicians in applying a more informed decision-making. Finally, physical exercise and rehabilitation interventions also represents a promising therapeutic strategy.

For drug dosing adaptation, the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend using estimated glomerular filtration rate (eGFR) by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, after 'de-indexation' by body surface area (BSA). In pharmacology, the Cockcroft-Gault (CG) equation is still recommended to adapt drug dosage. In the context of obesity, adjusted ideal body weight (AIBW) is sometimes preferred to actual body weight (ABW) for the CG equation. The aim of the present study was to compare the performance of the different GFR-estimating equations, non-indexed or de-indexed by BSA for the purpose of drug-dosage adaptation in obese patients.

We analysed data from patients with a body mass index (BMI) higher than 30 kg m(-2) who underwent a GFR measurement. eGFR was calculated using the CKD-EPI and Modification of Diet in Renal Disease (MDRD) equations, de-indexed by BSA, and the CG equation, using either ABW, AIBW or lean body weight (LBW) for the weight variable and compared with measured GFR, expressed in ml min(-1).

In our population of obese patients, use of the AIBW instead of the ABW in the CG equation, markedly improved the overall accuracy of this equation [57% for CGABW and 79% for CGAIBW (P < 0.05)]. For high BMI (over 40 kg m(-2)), the accuracy of the CG equations is no different when using LBW than when using AIBW. The MDRD and CKD-EPI equations de-indexed by the BSA also performed well, with an overall higher accuracy for the MDRD de-indexed equation [(80% and 76%, respectively (P < 0.05)].

The de-indexed MDRD equation appeared to be the most suitable for estimating the non-indexed GFR for the purpose of drug dosage adaptation in obese patients.

Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) offer a new opportunity for the management of type 2 diabetes mellitus. These agents reduce hyperglycemia by decreasing the renal glucose threshold and thereby increasing urinary glucose excretion. Subsequent reduction of glucotoxicity improves beta-cell sensitivity to glucose and tissue insulin sensitivity.

This article analyzes the efficacy and safety data of canagliflozin, dapagliflozin and empagliflozin in randomized controlled trials of 24 - 104 weeks duration, compared with placebo or an active comparator, in patients treated with diet/exercise, metformin, dual oral therapy or insulin.

SGLT2 inhibitors significantly and consistently reduce glycated hemoglobin, with a minimal risk of hypoglycemia. The improvement of glucose control is similar or slightly better compared with metformin, sulfonylureas or sitagliptin, with the add-on value of significant reductions in body weight and blood pressure. However, caution is recommended in fragile elderly patients and patients with chronic kidney disease. An increased risk of genital mycotic infections is observed, but urinary tract infections are rare. Concern about an unexpected risk of euglycemic ketoacidosis has been recently reported. A possible renal protection deserves further attention. A remarkable reduction in cardiovascular mortality was reported in EMPA-REG OUTCOME with empagliflozin.

Inhibitors of sodium-glucose co-transporter type 2 (SGLT2) are proposed as a novel approach for the management of type 2 diabetes mellitus (T2DM). Several compounds are already available in many countries (dapagliflozin, canagliflozin, empagliflozin and ipragliflozin) and some others are in a late phase of development. The available SGLT2 inhibitors share similar pharmacokinetic characteristics, with a rapid oral absorption, a long elimination half-life allowing once-daily administration, an extensive hepatic metabolism mainly via glucuronidation to inactive metabolites, the absence of clinically relevant drug-drug interactions and a low renal elimination as parent drug. SGLT2 co-transporters are responsible for reabsorption of most (90 %) of the glucose filtered by the kidneys. The pharmacological inhibition of SGLT2 co-transporters reduces hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. The amount of glucose excreted in the urine depends on both the level of hyperglycaemia and the glomerular filtration rate. Results of numerous placebo-controlled randomised clinical trials of 12-104 weeks duration have shown significant reductions in glycated haemoglobin (HbA1c), resulting in a significant increase in the proportion of patients reaching HbA1c targets, and a significant lowering of fasting plasma glucose when SGLT2 inhibitors were administered as monotherapy or in addition to other glucose-lowering therapies including insulin in patients with T2DM. In head-to-head trials of up to 2 years, SGLT2 inhibitors exerted similar glucose-lowering activity to metformin, sulphonylureas or sitagliptin. The durability of the glucose-lowering effect of SGLT2 inhibitors appears to be better; however, this remains to be more extensively investigated. The risk of hypoglycaemia was much lower with SGLT2 inhibitors than with sulphonylureas and was similarly low as that reported with metformin, pioglitazone or sitagliptin. Increased renal glucose elimination also assists weight loss and could help to reduce blood pressure. Both effects were very consistent across the trials and they represent some advantages for SGLT2 inhibitors when compared with other oral glucose-lowering agents. The pharmacodynamic response to SGLT2 inhibitors declines with increasing severity of renal impairment, and prescribing information for each SGLT2 inhibitor should be consulted regarding dosage adjustments or restrictions in moderate to severe renal dysfunction. Caution is also recommended in the elderly population because of a higher risk of renal impairment, orthostatic hypotension and dehydration, even if the absence of hypoglycaemia represents an obvious advantage in this population. The overall effect of SGLT2 inhibitors on the risk of cardiovascular disease is unknown and will be evaluated in several ongoing prospective placebo-controlled trials with cardiovascular outcomes. The impact of SGLT2 inhibitors on renal function and their potential to influence the course of diabetic nephropathy also deserve more attention. SGLT2 inhibitors are generally well-tolerated. The most frequently reported adverse events are female genital mycotic infections, while urinary tract infections are less commonly observed and generally benign. In conclusion, with their unique mechanism of action that is independent of insulin secretion and action, SGLT2 inhibitors are a useful addition to the therapeutic options available for the management of T2DM at any stage in the natural history of the disease. Although SGLT2 inhibitors have already been extensively investigated, further studies should even better delineate the best place of these new glucose-lowering agents in the already rich armamentarium for the management of T2DM.

The prevalence of chronic kidney disease (CKD) of stages 3-5 (glomerular filtration rate [GFR] <60 mL/min) is about 25-30 % in patients with type 2 diabetes mellitus (T2DM). While most oral antidiabetic agents have limitations in patients with CKD, incretin-based therapies are increasingly used for the management of T2DM. This review analyses (1) the influence of CKD on the pharmacokinetics of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists; and (2) the efficacy/safety profile of these agents in clinical practice when prescribed in patients with both T2DM and CKD. Most DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin) are predominantly excreted by the kidneys. Thereby, pharmacokinetic studies showed that total exposure to the drug is increased in proportion to the decline of GFR, leading to recommendations for appropriate dose reductions according to the severity of CKD. In these conditions, clinical studies reported a good efficacy and safety profile in patients with CKD. In contrast, linagliptin is eliminated by a predominantly hepatobiliary route. As a pharmacokinetic study showed only minimal influence of decreased GFR on total exposure, no dose adjustment of linagliptin is required in the case of CKD. The experience with GLP-1 receptor agonists in patients with CKD is more limited. Exenatide is eliminated by renal mechanisms and should not be given in patients with severe CKD. Liraglutide is not eliminated by the kidney, but it should be used with caution because of the limited experience in patients with CKD. Only limited pharmacokinetic data are also available for lixisenatide, exenatide long-acting release (LAR) and other once-weekly GLP-1 receptor agonists in current development. Several case reports of acute renal failure have been described with GLP-1 receptor agonists, probably triggered by dehydration resulting from gastrointestinal adverse events. However, increasing GLP-1 may also exert favourable renal effects that could contribute to reducing the risk of diabetic nephropathy. In conclusion, the already large reassuring experience with DPP-4 inhibitors in patients with CKD offers new opportunities to the clinician, whereas more caution is required with GLP-1 receptor agonists because of the limited experience in this population.

This article summarizes our current knowledge of the epidemiology, pathogenesis, and morbidity of hypoglycemia in patients with diabetic kidney disease and reviews therapeutic limitations in this situation.

Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type 2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarises the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and their hepatic safety was carefully analysed in large clinical trials. Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of HI, presumably without major clinical relevance. GLP-1 receptor agonists have a renal excretion rather than liver metabolism. Specific pharmacokinetic data in patients with HI are only available for liraglutide. No significant changes in liver enzymes were reported with DPP-4 inhibitors or GLP-1 receptor agonists, alone or in combination with various other glucose-lowering agents, in clinical trials up to 2 years in length. On the contrary, preliminary data suggested that incretin-based therapies may be beneficial in patients with CLD, more particularly in the presence of non-alcoholic fatty liver disease. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, because of a lack of clinical experience with incretin-based therapies in these vulnerable patients.

This study describes demographic characteristics, comorbidities, and hypoglycemia events in patients with type 2 diabetes mellitus (T2DM) identified using 2011 Medicare 5% Standard Analytical Files. Among 1,913,477 Medicare beneficiaries, 367,602 (19.2%) had T2DM. T2DM prevalence increased with age and was higher in blacks (26.4%) and Hispanics (25.5%) than in whites (18.0%); and in Medicare/Medicaid dual-eligible versus non-dual-eligible patients (28.0% vs 17.2%, respectively). Compared with whites, diagnosed hypertension and diabetic retinopathy were more common in blacks and Hispanics, and lipid metabolism disorders and atrial fibrillation were less common. Hypoglycemia requiring health care services was more common in blacks (4.7%) and Hispanics (3.6%) compared with whites (2.9%). T2DM, related comorbidities, and hypoglycemia are burdensome to the Medicare population. Differences in these endpoints were observed based on race/ethnicity, age, and dual-eligible status, highlighting the importance of demographic factors when determining T2DM management strategies.

The prevalence of type 2 diabetes mellitus (T2DM) among elderly people is increasing. Often associated with disabilities/comorbidities, T2DM lowers the chances of successful aging and is independently associated with frailty and an increased risk of hypoglycaemia, which can be further exacerbated by antihyperglycaemic treatment. From this perspective, the clinical management of T2DM in the elderly is challenging and requires individualization of optimum glycaemic targets depending on comorbidities, cognitive functioning and ability to recognize and self-manage the disease. The lack of solid evidence-based medicine supporting treatment guidelines for older people with diabetes further complicates the matter. Several classes of medicine for the treatment of T2DM are currently available and different drug combinations are often required to achieve individualized glycaemic goals. Many of these drugs, however, carry disadvantages such as the propensity to cause weight gain or hypoglycaemia. Dipeptidyl peptidase-4 (DPP-4) inhibitors, a recent addition to the pharmacological armamentarium, have become widely accepted in clinical practice because of their efficacy, low risk of hypoglycaemia, neutral effect on body weight, and apparently greater safety in patients with kidney failure. Although more information is needed to reach definitive conclusions, growing evidence suggests that DPP-4 inhibitors may become a valuable component in the pharmacological management of elderly people with T2DM. The present review aims to delineate the potential advantages of this pharmacological approach in the treatment of elderly people with T2DM.

Dipeptidyl peptidase-4 (DPP-4) inhibitors (gliptins) occupy a growing place in the armamentarium of drugs used for the management of hyperglycemia in type 2 diabetes, although some safety concerns have been raised in recent years.

An updated review providing an analysis of available safety data (meta-analyses, randomized controlled trials, observational cohort and case-control studies and pharmacovigilance reports) with five commercialized DPP-4 inhibitors (sitagliptin, vildagliptin, saxagliptin, alogliptin, linagliptin). A special focus is given to overall safety profile; pancreatic adverse events (AEs) (acute pancreatitis, pancreatic cancer); overall cardiovascular safety (myocardial infarction and stroke); congestive heart failure concern and finally, safety in special populations (elderly, renal impairment).

The good tolerance/safety profile of DPP-4 inhibitors has been largely confirmed, including in more fragile populations (elderly, renal impairment) with almost no increased risk of infection or gastrointestinal AEs, no weight gain and a minimal risk of hypoglycemia. Although an increased risk of acute pancreatitis and pancreatic cancer was suspected, the complete set of available data appears reassuring so far. Cardiovascular safety of DPP-4 inhibitors has been proven but an unexpected increased risk of heart failure has been reported which should be confirmed in ongoing trials and better understood. Further postmarketing surveillance is recommended.

When the maximal reabsorptive capacity for glucose is lowered by blockade of the activity of sodium-glucose cotransporter-2 (SGLT2), glucosuria occurs in proportion to the plasma glucose and glomerular filtration rate. Accordingly, the modest, 0.44%, hemoglobin A1c reduction found by Kohan et al. in diabetic patients with relatively good glycemic control and chronic kidney disease stage 3 treated with an SGLT2 inhibitor might have been anticipated. The 0.32% fall in hemoglobin A1c in the placebo group, however, seems less expected.

Inhibitors of sodium-glucose cotransporters type 2 (SGLT2) reduce hyperglycaemia by decreasing renal glucose threshold and thereby increasing urinary glucose excretion. They are proposed as a novel approach for the management of type 2 diabetes mellitus. They have proven their efficacy in reducing glycated haemoglobin, without inducing hypoglycaemia, as monotherapy or in combination with various other glucose-lowering agents, with the add-on value of promoting some weight loss and lowering arterial blood pressure. As they may be used concomitantly with many other drugs, we review the potential drug-drug interactions (DDIs) regarding the three leaders in the class (dapagliglozin, canagliflozin and empagliflozin). Most of the available studies were performed in healthy volunteers and have assessed the pharmacokinetic interferences with a single administration of the SGLT2 inhibitor. The exposure [assessed by peak plasma concentrations (Cmax) and area under the concentration-time curve (AUC)] to each SGLT2 inhibitor tested was not significantly influenced by the concomitant administration of other glucose-lowering agents or cardiovascular agents commonly used in patients with type 2 diabetes. Reciprocally, these medications did not influence the pharmacokinetic parameters of dapagliflozin, canagliflozin or empagliflozin. Some modest changes were not considered as clinically relevant. However, drugs that could specifically interfere with the metabolic pathways of SGLT2 inhibitors [rifampicin, inhibitors or inducers of uridine diphosphate-glucuronosyltransferase (UGT)] may result in significant changes in the exposure of SGLT2 inhibitors, as shown for dapagliflozin and canagliflozin. Potential DDIs in patients with type 2 diabetes receiving chronic treatment with an SGLT2 inhibitor deserve further attention, especially in individuals treated with several medications or in more fragile patients with hepatic and/or renal impairment.