Future perspectives of the pharmacological management of diabetic dyslipidemia

Introduction: Diabetic dyslipidemia is frequent among patients with type 2 diabetes mellitus (T2DM) and is characterized by an increase in triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and small-dense (atherogenic) particles, and by a decrease in low high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (Apo) A1 that are strongly related to insulin resistance. The increased flux of free fatty acids from adipose tissue to the liver aggravates hepatic insulin resistance and promotes all of aspects of the dyslipidemic state.

Areas covered: Statins are the first-line agents for treatment while other lipid-lowering drugs (ezetimibe, fibrate and proprotein convertase subtilisin/kexin type 9) or novel anti-diabetic agents (dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon like peptide-1 receptor agonist (GLP-1RA), sodium/glucose cotransporter 2 inhibitors (SGLT2is)) or nutraceuticals (berberine, omega 3 fatty acid, red yeast rice) can be used alone or in combination.

Expert commentary: In patients with T2DM, lipid abnormalities should be identified and treated as part of the overall diabetic treatment, in order to prevent cardiovascular disease. The choice of drugs to be used is mainly based on the lipid profile and on the characteristic lipoprotein abnormalities; the use of new drugs for the treatment of hyperglycemia and lipids alteration in these patients can improve diabetic dyslipidemia.     

An update on the safety and efficacy of oral antidiabetic drugs: DPP-4 inhibitors and SGLT-2 inhibitors

Introduction: Oral antidiabetic medications are important in many type 2 diabetes care plans

Areas covered: The article summarizes the cardiovascular and renal safety data for DPP-4 inhibitors and SGLT-2 inhibitors and specific safety data particular to each class.

Expert opinion: DPP-4 and SGLT-2 inhibitors provide unique anti-hyperglycemic mechanisms. The cardiovascular safety profiles of DPP-4 inhibitors are promising, but do not show the strong CV risk reduction of empagliflozin and canagliflozin. The heart failure signal associated with DPP-4 inhibitor use is unclear with differing agents, demonstrating increased risk or maybe even protective effects. The risk reduction in cardiovascular disease associated with SGLT-2 inhibitors has translated to recommendations to consider these therapies early in the treatment pathway. Both classes have potential safety concerns that necessitate appropriate patient selection and thorough education on potential side-effects. DPP-4 inhibitors are considered to have neutral or in some studies beneficial renoprotective effects. SGLT-2 inhibitor safety effects on the kidney are more complex. There are reports of acute kidney injury occurring soon after initiating SGLT-2 inhibitor therapy. However, there are large recent studies that have demonstrated the beneficial effect of SGLT-2 inhibitors in slowing the progression of established chronic kidney disease.     

Preventing and treating kidney disease in patients with type 2 diabetes

Introduction: 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.

Areas covered: 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.

Expert opinion: 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.     

Dipeptidyl peptidase IV inhibitors as a potential target for diabetes: patent review (2015-2018)

Introduction: Dipeptidyl peptidase 4 (DPP-4) belongs to the family of serine proteases and is involved in the degradation of GLP-1 and GIP hormones, which enhance the production and release of insulin. Targeting DPP-4 inhibitors is increasingly being considered as promising paradigms to treat type 2 diabetes mellitus and therefore DPP-4 inhibitors are being considered as promising antidiabetic drugs.

Areas covered: This review provides an overview of published patents describing natural and synthetic DPP-4 inhibitors from January 2015 to December 2018.

Expert opinion: A fair number of new synthetic and natural DPP-4 inhibitors have been reported in the last four years which describe the progress in the development of various heterocyclic scaffolds or heterocyclic hybrid compounds. As a result of this, many marketed DPP-4 inhibitors that have been approved by the appropriate governing bodies during the past decade, have been introduced as inhibitors. Molecular hybridization is an emerging idea in medicinal chemistry and therefore hybrid compounds of DPP-4 inhibitors with other DPP-4 inhibitors or with antidiabetic drugs should be formulated for a comprehensive evaluation. More detailed pharmacovigilance of DPP-4 inhibitors is required because this will address the pancreas-related adverse events as well as their impact on cardiovascular outcomes via long-term studies.     

Relationship of patient background with macro- and microvascular complications: a 2-year post-marketing surveillance of vildagliptin in nearly 20,000 Japanese diabetic patients

Background: Vildagliptin is indicated for type 2 diabetes mellitus (T2DM); however, the onset and exacerbation of diabetic complications in Japanese T2DM patients treated with vildagliptin is unknown.

Research design and methods: This 2-year post-marketing surveillance (PMS) assessed the real-world safety and efficacy of vildagliptin therapy in 19,218 Japanese T2DM patients. The relationship between the incidence of macro- and microvascular complications with patient characteristics and changes in glycemic control (HbA1c) were evaluated.

Results: The incidences of macro- and microvascular diseases were 1.14% and 3.09%, respectively. Patients with HbA1c ≥8.4% had a higher odds ratio (OR) for micro- and macrovascular disease (OR: 2.02 and 1.90) compared with patients with HbA1c <6.9%. Patient characteristics (OR, 95% CI) associated with macrovascular disease were age (1.04, 1.01–1.07) and a history of macrovascular disease (3.38, 1.98–5.75). Microvascular disease was associated with a final HbA1c level ≥7.0% (1.48, 1.11–1.98) and previous diabetic nephropathy (1.42, 1.05–1.93). The mean (SD) HbA1c decreased from 7.89% (1.46%) to 7.05% (0.99%) after 24 months.

Conclusions: Vildagliptin elicited no increases/exacerbations of diabetic complications; this PMS suggested that the incidence of diabetic complications tends to be low in subjects with good HbA1c control.     

Towards a better understanding of postprandial hyperglycemic episodes in people with diabetes: impact on daily functioning

Objective: Acute postprandial hyperglycemia (aPPHG) is often symptomatic and can be associated with behavioral changes such as impaired working memory and attention. However, there is little evidence of the impact of aPPHG on the daily lives of patients. The aim of this study was to explore the frequency and severity of aPPHG episodes and their impact on daily functioning in people with insulin-treated diabetes.

Methods: Adults (n?=?1200) with insulin-treated diabetes mellitus type 1 (T1DM) or 2 (T2DM), most of whom experienced aPPHG, were recruited to complete an online cross-sectional survey in the USA and UK. The survey captured self-reported severity and frequency of aPPHG episodes and included a newly developed questionnaire (aPPHG-Q) assessing the impact of aPPHG episodes on patients’ daily lives. Data was analyzed separately according to diabetes type and country. Regression analyses were used to assess the relationship between severity or frequency and scores on the aPPHG-Q.

Results: Between 70% and 86% of USA, and 87% and 88% of UK participants reported experiencing aPPHG episodes. Increasing frequency and severity of aPPHG episodes were associated with worse scores on the aPPHG-Q in patients with both T1DM and T2DM in both countries (p?<?.014) on all subscale scores (excluding the worry and concerns scores for T1DM in the UK), although the magnitude of the association was smaller for aPPHG frequency.

Conclusions: Increased severity and frequency of aPPHG episodes in patients with insulin-treated diabetes is associated with greater burden and experience of symptoms, and can negatively impact daily functioning.     

Comparison of persistence and adherence between fixed-dose combinations and two-pill combinations in Japanese patients with type 2 diabetes

Objective: To compare treatment patterns, persistence and adherence between fixed-dose combinations (FDCs) and two-pill combinations (TPCs) of oral antidiabetic drug (OAD) classes in Japanese patients with type 2 diabetes mellitus (T2DM) using administrative claims databases (Japan Medical Data Center [JMDC] and Medical Data Vision [MDV]).

Methods: This was a retrospective, longitudinal cohort analysis conducted between 2011 and 2015, in patients with T2DM receiving OADs as FDC or TPC. Outcomes included prescribing patterns, treatment persistence and adherence.

Results: Data from 3474 and 3066 patients receiving FDCs, and 4325 and 5192 patients receiving TPCs from the JMDC and MDV databases, respectively, was extracted. The most common OAD combination received by over half of all patients was dipeptidyl peptidase-4 inhibitor (DPP-4i) + thiazolidinediones (TZDs) (64.1% [JMDC] and 70.5% [MDV]). Overall, 12-month persistence rates were higher in patients receiving FDCs compared with TPCs (70.4 vs. 66.2% [JMDC], 75.6 vs. 55.7% [MDV]). In the JMDC population receiving FDCs or TPCs, persistence rates were highest with DPP-4i schedules (67.5–83.5%). Median time to discontinuation was significantly longer with biguanide?+?TZD, and DPP-4i?+?TZD FDC schedules (p < .05) than TPC; adherence rates were ≥80% across all antidiabetic drug classes in both database populations.

Conclusions: Persistence with and adherence to OADs in Japanese patients with T2DM were greater with FDCs than with TPCs, which may suggest increased patient satisfaction due to reduced treatment burden. Further studies are warranted to investigate the impact of adherence and persistence of FDCs of OADs on glycemic control.     

Pharmacologic treatment options for type 1 diabetes: what’s new?

Introduction: The expanding variety of insulins, including biosynthetic human insulin and rapid and long-acting insulin analogs, have dramatically transformed the management of type 1 diabetes (T1D) over the past 25 years. Moreover, increasing interest in the use of novel drugs developed for the treatment of type 2 diabetes (T2D) as adjunctive therapies for T1D remains a work in progress.

Areas Covered: We reviewed articles published up to December 2018 in PubMed and ClinicalTrials.gov for recent developments in the pharmacologic treatment of T1D, including inhaled insulin, ultrafast and ultralong-acting insulins and adjunctive therapies including pramlintide, metformin, GLP-1 receptor agonists, DPP-4 inhibitors, SGLT-2, and SGLT1/2 inhibitors.

Expert Opinion: With the creation of ultrafast-acting insulin analogs and very prolonged duration of action of basal insulins, it is possible to more closely mimic physiologic insulin secretion. Adjunctive therapies, likewise, may also overcome some of the abnormal physiology that is a hallmark of T1D. Therefore, individualized consideration of the efficacy of these agents must be measured alongside the potential adverse effects when choosing an adjunctive therapy.     

An evaluation of the efficacy and safety of Tofogliflozin for the treatment of type II diabetes

Introduction: Accumulating data from recent studies has altered the gold standard of care for diabetes treatment. In patients with type 2 diabetes (T2D) and established cardiovascular disease (CVD) or those at high risk for CVD, subsequently to lifestyle changes and metformin therapy, the administration of an SGLT-2 inhibitor with established benefits for cardiovascular outcome (CVOT) should be considered.

Areas covered: Tofogliflozin is the most selective SGLT-2 inhibitor and has been approved for the treatment of T2D in Japan. This review summarizes the available data on Tofogliflozin as compared to other SGLT-2 inhibitors, and primarily the three SGLT-2 inhibitors with published CVOT: Empagliflozin, Canagliflozin and Dapagliflozin.

Expert opinion: Tofogliflozin’s higher selectivity profile increases the positive effects on cardiovascular (CV) outcomes and death and reduces side effects. However, the clinical data on Tofogliflozin from both clinical and real-world studies remain sparse and much less abundant than the other main 3 SGLT-2 inhibitors, thus calling for caution and underscoring the need for further research.     

Managing chronic kidney disease in diabetes patients with the latest chemical therapies

Introduction: During the years, while treatment strategy for diabetes mellitus has improved, the incidence of diabetes worldwide increases continuously. Chronic kidney disease (CKD) is one of the major diabetic microvascular complications, and a primary cause leading to end-stage renal disease (ESRD). The progression to ESRD, affected by hyperglycemia and hypertension, is characterized by microalbuminuria and macroalbuminuria. With advances in understanding the pathogenesis of CKD in diabetic patients, many novel therapeutic targets have been proposed, and the corresponding agents are being developed continually to prevent the progression of CKD.

Areas covered: This review focuses on those tested in phase III clinical trials for the treatment of CKD in diabetic patients, including renin-angiotensin system blockers, aldosterone antagonists, calcium channel blockers, TGF-β inhibitors, protein kinase C inhibitors, advanced glycation end products inhibitors, GLP-1 analogues, DPP-4 inhibitors, SGLT2 inhibitors, endothelin receptor antagonists, and so on.

Expert commentary: The ideal control of glucose and blood pressure and healthy lifestyle are prerequisite for diabetic patients, despite the progression of CKD is inevitable. Over the last few years, several agents have been developed to delay and even reverse progression of CKD in diabetic patients.     

Advances in pharmacological treatment of type 1 diabetes during pregnancy

Introduction: In women with type 1 diabetes mellitus (T1DM), pregnancy is associated with a potential risk of maternal, foetal and neonatal outcomes. Stringent metabolic control is required to improve these outcomes.

Areas covered: In this review, the authors summarise the current evidence from studies on the pharmacological therapy and on monitoring of T1DM during pregnancy. The authors also discuss the use of new technologies to improve therapeutic management and patient compliance.

Expert opinion: Pre-conception counselling is essential in T1DM to minimise pregnancy risks. Pregnancy in T1DM is always considered a high-risk pregnancy. During pregnancy, the target haemoglobin A1C (HbA_1c) is near-normal at <6%, without excessive hypoglycaemia. Strict control of pre- and post-prandial glucose is also required. Human soluble insulin, neutral protamine Hagedorn and the quick-acting insulin analogues aspart and lispro are widely used. Insulin is administered either as a basal-bolus regimen or by continuous subcutaneous insulin infusion. Careful and strict glucose monitoring is also needed during labour and delivery, including caesarean section. Moreover, the control of retinopathy, hypertension, nephropathy, hyper- and hypothyroidism is required. Post-partum, insulin requirements decrease, and less stringent glycaemic control is pursued, to avoid hypoglycaemias. Finally, breastfeeding is recommended and should be encouraged.     

Safety evaluation of trelagliptin in the treatment of Japanese type 2 diabetes mellitus patients

Introduction: Trelagliptin is a novel, long-acting dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM) in japan. The safety and efficacy of trelagliptin has been evaluated in three published clinical trials to date: one phase II and two phase III studies. As trelagliptin only requires dosing once per week, this new agent has the potential to improve compliance and subsequently, glycaemic control, in patients with T2DM.

Areas covered: This article reviews the available safety data for trelagliptin from published clinical trials, and evaluates the published safety profile relative to competitor once-daily and once-weekly DPP-4 inhibitors.

Expert opinion: Clinical trial data to date suggest that trelagliptin is a safe and efficacious medication with a similar safety profile to once-daily DPP-4 inhibitors, and to the once-weekly DPP-4 inhibitor, omarigliptin. Trelagliptin is well tolerated when given alone, and in combination with other anti-diabetic medications. An advantage of trelagliptin over existing once-daily DPP-4 inhibitors is the decrease of dosing frequency, rather than once-daily. No specific, serious adverse events have been reported for trelagliptin in published clinical trials, making it an attractive alternative to other DPP-4 inhibitors.     

CTLA4 antagonists in phase I and phase II clinical trials,current status and future perspectives for cancer therapy

Introduction: In cancer, the immune response to tumor antigens is often suppressed by inhibitors and ligands. Checkpoint blockade, considered one of the most promising frontiers for anti-cancer therapy, aims to stimulate the immune anti-cancer response. Agents such as cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) inhibitors offer prolonged survival with manageable side effects.

Areas covered: We summarize the recent clinical successes of CTLA-4 inhibitors and place a strong emphasis on those in early phase clinical trials, often in combination with other immune check-point inhibitors, i.e., programmed cell death protein 1 (PD-1) and BRAF/mitogen-activated protein kinase inhibitors.

Expert opinion: Recent phase I and phase II clinical trials confirm the efficacy of anti-CTLA-4 therapy for treatment of cancers such as renal cell carcinoma. These studies also indicated increased efficacy with combined immune checkpoint blockade with PD-1 or Ras/Raf/mitogen-activated protein kinase/ERK kinase (MEK)/extracellular-signal-regulated kinase (ERK) inhibitors. Researchers must search for new immune targets that may enable more effective and safe immune checkpoint blockade and cancer therapy. This goal may be achieved by next-generation combination therapies to overcome immune checkpoint therapy resistance.     

SGLT2 inhibitors for the treatment of diabetes: a patent review (2013-2018)

Introduction: The sodium-glucose co-transporter 2 (SGLT2) is ascribed to target renal tubular glucose re-absorption, and its inhibition has been proved to induce glucosuria which improves the glycemic index. Accordingly, SGLT2 inhibitors have found to be the promising class of antidiabetic agents for the management of type 2 diabetes mellitus. A large number of SGLT2 inhibitors have developed through structural modification and investigated for their ability to selectivity inhibit SGLT2 transporters with better bioavailability.

Areas covered: This review comprises a summary of patent applications (2013–2018) of SGLT2 inhibitors with focus on chemical structural advancement and therapeutic potentials in the management of diabetes and related disorders.

Expert opinion: SGLT2 inhibitors exert multiple metabolic benefits, including reduced glycated hemoglobin (HbA1c), improved glycemic control (fasting and postprandial), reduced body weight, reduced systolic and diastolic blood pressure and improved HDL cholesterol. Due to the virtue of no interference with insulin action and secretion, their efficacy remains the same even in presence of progressive β cell failure in type 2 diabetes. Additionally, few members of this class have been reported to exhibit cardioprotective, renoprotective, and anticancer activity. However, more study on the long-term outcomes in patients taking SGLT2 inhibitors is warranted.     

Dapagliflozin and cardiovascular outcomes: anything else to DECLARE?

Introduction: Individuals with type 2 diabetes mellitus (T2DM) have increased cardiovascular risk with regulatory agencies requiring cardiovascular outcome trials (CVOTs) for the approval of new antidiabetic drugs.

Areas covered: In this paper, the authors critically discuss the background, trial design, results and implications of a recent CVOT [NCT01730534; DECLARE-TIMI 58 study], which demonstrated that dapagliflozin was non-inferior to placebo in terms of major adverse cardiovascular events, and superior for the occurrence of hospitalization for heart failure (HF) and composite renal endpoints, thus confirming the cardiovascular benefit of sodium-glucose co-transporter-2 (SGLT2) inhibitors. No statistically-significant effects were found for amputations, fractures, and stroke (debated safety issues having emerged in previous CVOTs).

Expert opinion: DECLARE-TIMI 58 is the longest (4.2 years of follow up), largest (>17,000 participants) and most inclusive (only 41% of individuals with established atherosclerotic cardiovascular disease) CVOT raising the debate towards SGLT2 inhibitor therapy in primary prevention and the potential use of these drugs also in patients with HF without T2DM and other subpopulations.     

Impact of cigarette smoking on kidney inflammation and fibrosis in diabetic rats

Background: Cigarette smoking is a very common habit worldwide contributing to risk of kidney dysfunction and diabetes (DM). However, the mechanisms are unclear.

Aim: The goal of the present study was to assess the effects of cigarette smoking on kidney oxidative stress, inflammation, and remodeling in streptozotocin (STZ) rat model of diabetes.

Methods: Rats were randomized into control (intraperitoneal (i.p.) citrate buffer injection and exposure to fresh air), cigarette smoking (1?h daily for 6?d/week, citrate buffer), DM (single dose STZ 35?mg/kg i.p. and exposure to fresh air), and DM?+?smoking groups for a period of 4?weeks. Kidney biomarkers of inflammation, oxidative stress, and remodeling were measured.

Results: A significant increase in kidney to body weight ratio was observed in diabetic groups. Diabetes but not smoking increased blood urea nitrogen levels without changes in creatinine levels. Kidney levels of thiobarbituric acid substances, nitrite, endothelin-1, and C-reactive protein were increased significantly in the DM?+?smoking groups. Smoking induced GSH expression and activity of superoxide dismutase. A significant increase in kidney fibrosis was observed in the DM?+?smoking group coupled with a similar increase in transforming growth factor beta. Protein levels of matrix metalloproteinase-2, (MMP-2), mitogen-activated protein kinases, and c-Jun N terminal kinase were elevated in Smoking and DM?+?smoking groups.

Conclusion: Cigarette smoke might promote risk of kidney dysfunction in DM by augmentation of renal inflammation, oxidant radicals and fibrosis. The kidney promotes compensatory increase in MMP-2 in response to smoking probably to prevent pro-fibrotic factors induced-fibrosis.     

Understanding the cardiovascular risk with non-insulin antidiabetic drugs

Introduction: Diabetes mellitus is a major public health problem with significant macro- and microvascular complications. Achievement of glucose control is associated with a substantial reduction of microvascular events, while the effects of antidiabetic drugs in macro-vascular complications are less clear. This review summarizes and critically discusses the cardiovascular effects of non-insulin antidiabetic agents.

Areas covered: A selective literature search of Pubmed was performed regarding the efficacy and safety of non-insulin antidiabetic agents in randomized controlled clinical trials and relevant meta-analyses. Data are presented for all major classes of antidiabetic drugs: metformin, sulfonylureas, thiazolidinediones, DPP-4 inhibitors, GLP-1 analogues, and SGLT-2 inhibitors. Efficacy and safety were focused on the cardiovascular system.

Expert opinion: Disparities in cardiovascular safety and efficacy between antidiabetic drugs exist. Metformin remains the first-choice drug with proven cardiovascular benefits. The cardiovascular profile of sulfonylureas is yet unclarified, while thiazolidinediones seem to be effective in secondary stroke prevention but heart failure concerns limit their use. The cardiovascular safety of DPP-4 inhibitors has been demonstrated, without however significant morbidity and mortality benefits. SGLT-2 inhibitors and GLP-1 analogues offer significant cardiovascular benefits and are recommended for patients with overt cardiovascular disease.     

Selective COX-2 inhibitors as anticancer agents: a patent review (2014-2018)

Introduction: COX-2 is a key enzyme in the process of prostaglandins (PGs) synthesis. The products of this enzyme could play a major role as the mediators of the inflammatory response and some other medical states such as cancer. The design and synthesis of novel selective COX-2 inhibitors have always been attractive to researchers. This review discusses the structures of novel COX-2 inhibitors synthesized during the last five years and describes their efficacy as anticancer agents.

Areas covered: It is well established that COX-2 is overexpressed in many different cancers and treatment with selective COX-2 inhibitors could relieve their symptoms and limit their adverse sequences.

Expert opinion: The diversity of selective COX-2 inhibitors is mainly related to the types of scaffolds. Monocyclic, bicyclic, tricyclic, and acyclic scaffolds with different pharmacological effects and toxicological profiles could be found in the family of selective COX-2 inhibitors. The great interest of the researchers in this field is due to the importance of selective COX-2 inhibitors as a relatively safe and effective set of compounds which could present different properties such as antirheumatic, anti-inflammatory, antiplatelet, anti-Alzheimer’s disease, anti-Parkinson’s disease, and anticancer.     

Dose adjustment of metformin and dipeptidyl-peptidase IV inhibitors in diabetic patients with renal dysfunction

Objectives: 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.

Methods: 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.

Results: 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).

Conclusions: 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.     

Cardiovascular safety of therapies for type 2 diabetes

Introduction: Dipeptidyl peptidase-4 (DPP4) inhibitors, glucagon-like peptide-1 (GLP-1) analogs and sodium-glucose cotransporter 2 (SGLT2) inhibitors are relatively new therapies for the treatment of type 2 diabetes mellitus. Given the high prevalence of cardiovascular complications in patients with type 2 diabetes and recent concerns questioning CV safety of newer antidiabetic medications, cardiovascular safety of these medications requires evaluation.

Areas covered: Cardiovascular effects of these drug classes from preclinical and clinical data as well as non-cardiovascular safety issues are delineated from literature searches covering the last decade and up to June 2016. Major clinical trials assessing the cardiovascular safety of GLP-1 agonists (ELIXA and LEADER), DPP-4 inhibitors (SAVOR-TIMI 53, EXAMINE, and TECOS) and SGLT2 inhibitors (EMPA-REG OUTCOME) are reviewed and interpreted.

Expert opinion: Based on review of the present evidence, these 3 classes of antihyperglycemic therapies have acceptably safe CV safety profiles for patients with type 2 diabetes. The latest evidence from LEADER and EMPA-REG OUTCOME trials indicate that liraglutide and empagliflozin have cardiovascular benefits that may prove to be of clinical importance in the management of type 2 DM.