Effects Of Glucose-lowering Agents Research Articles

Characterization of the SGLT2 interaction network and its regulation by SGLT2 inhibitors: a bioinformatic analysis

Abstract Background SGLT2 (Solute Carrier Family 5 Member 2, SLC5A2) is a promising target of a new class of drugs primarily established as kidney-targeting, effective glucose-lowering agents used in diabetes mellitus (DM) patients. Rising evidence indicates that besides renal effects, SGLT2 inhibitors (SGLT2i) have also a systemic impact via indirectly targeting the heart, endothelial cells, liver, adipose tissue. Our hypothesis states that the pleiotropic effects of SGLT2i are associated with its binding force, location of their targets in the SGLT2 networks, target involvement in signaling pathways, and their tissue-specific expression. Methods Thus to investigate differences in SGLT2i impact on human organisms, we re-created the SGLT2 interaction network incorporating its inhibitors and analyzed its tissue-specific expression using publicly available datasets. We analyzed it in the context of the so-called key terms (Autophagy, Oxidative stress, Aging, Senescence, Inflammation, AMPK pathways, mTOR pathways) which seems to be crucial to elucidate SGLT2 role in a variety of clinical manifestations. Results Our analysis focused on selected organs using the TISSUES database identified in the following order: kidney, liver, adipose tissue, blood, heart, muscle, intestine, brain, and artery showed the highest expression confidence of SGLT2 and its network components. Drug repurposing analysis of known SGLT2i pointed out the influence of SGLT1 regulators on the heart and intestine tissue. Additionally, Dapagliflozin seems to also have a stronger impact on brain tissue through the regulation of SGLT3 and SLC5A11. Shortest paths analysis identified interaction SIRT1-SGLT2 among the top five interactions across six from seven analyzed networks associated with the key terms. Other top first-level SGLT2 interactors associated with key terms were ADIPOQ, INS, GLUT4, ACE, and GLUT1, but also less recognized ILK, ADCY7. Among interactors not associated with key-terms, but which appeared in multiple shortest-paths analyzes were GPT, COG2 and MGAM. Enrichment analysis of SGLT2 network components showed the highest overrepresentation of hypertensive disease, DM related diseases for both levels of SGLT2 interactors. Additionally, for the extended SGLT2 network, we observed enrichment in obesity (including SGLT1) and cancer-related terms. Conclusion This study provides comprehensive and ranked information regarding the SGLT2 interaction network in the context of tissue expression and might be helpful to predict the clinical effects of the most commonly used SGLT2i. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Agencja badań medycznych - grant number 2019/ABM/01/00037Medical University of Warsaw - grant number 1M9/2/M/MG/N/21

Characterization of the SGLT2 Interaction Network and Its Regulation by SGLT2 Inhibitors: A Bioinformatic Analysis

Background: Sodium–glucose cotransporter 2 (SGLT2), also known as solute carrier family 5 member 2 (SLC5A2), is a promising target for a new class of drugs primarily established as kidney-targeting, effective glucose-lowering agents used in diabetes mellitus (DM) patients. Increasing evidence indicates that besides renal effects, SGLT2 inhibitors (SGLT2i) have also a systemic impact via indirectly targeting the heart and other tissues. Our hypothesis states that the pleiotropic effects of SGLT2i are associated with their binding force, location of targets in the SGLT2 networks, targets involvement in signaling pathways, and their tissue-specific expression. Methods: Thus, to investigate differences in SGLT2i impact on human organisms, we re-created the SGLT2 interaction network incorporating its inhibitors and metformin and analyzed its tissue-specific expression using publicly available datasets. We analyzed it in the context of the so-called key terms ( autophagy, oxidative stress, aging, senescence, inflammation, AMPK pathways, and mTOR pathways) which seem to be crucial to elucidating the SGLT2 role in a variety of clinical manifestations. Results: Analysis of SGLT2 and its network components’ expression confidence identified selected organs in the following order: kidney, liver, adipose tissue, blood, heart, muscle, intestine, brain, and artery according to the TISSUES database. Drug repurposing analysis of known SGLT2i pointed out the influence of SGLT1 regulators on the heart and intestine tissue. Additionally, dapagliflozin seems to also have a stronger impact on brain tissue through the regulation of SGLT3 and SLC5A11. The shortest path analysis identified interaction SIRT1-SGLT2 among the top five interactions across six from seven analyzed networks associated with the key terms. Other top first-level SGLT2 interactors associated with key terms were not only ADIPOQ, INS, GLUT4, ACE, and GLUT1 but also less recognized ILK and ADCY7. Among other interactors which appeared in multiple shortest-path analyses were GPT, COG2, and MGAM. Enrichment analysis of SGLT2 network components showed the highest overrepresentation of hypertensive disease, DM-related diseases for both levels of SGLT2 interactors. Additionally, for the extended SGLT2 network, we observed enrichment in obesity (including SGLT1), cancer-related terms, neuroactive ligand–receptor interaction, and neutrophil-mediated immunity. Conclusion: This study provides comprehensive and ranked information about the SGLT2 interaction network in the context of tissue expression and can help to predict the clinical effects of the SGLT2i.

182-OR: Clinical Effects of SGLT2 Inhibitors in HNF1A-Diabetes (MODY3) : A Case Series

Mutations in hepatocyte nuclear factor 1-alpha (HNF1A) cause HNF1A-diabetes (or maturity-onset diabetes of the young type 3 (MODY3)) . Treatment of HNF1A-diabetes is primarily based on sulphonylureas (SU) and secondarily insulins, glucagon-like peptide 1 receptor agonists (GLP1-RA) and dipeptidyl peptidase-4 inhibitors (DPP4i) . Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are effective glucose-lowering agents, cause body weight loss and protect from chronic kidney disease, heart failure and major adverse cardiovascular events. The utility of SGLT2i in patients with HNF1A-diabetes is unknown. Here, we describe a case series of five patients with HNF1A-diabetes treated with SGLT2i. Patient characteristics (median [range]) : age: 52 [35; 68] years; men/women: n=4/1; diabetes duration: 23 [9; 55] years; age at diabetes onset: 18 [13; 44] years; HbA1c: 6.9 [6.0; 7.4]% (52 [42; 57] mmol/mol) ; body weight: 92.3 [65.5; 95.1] kg; BMI: 25.6 [23.8; 29.4] kg/m2. At baseline, patients were treated with SU (n=5) , insulin (n=3; total daily dose: 15 [6; 25] IE divided into 1-4 injections/day) , DPP-4i (n=3) , GLP1-RA (n=2) , metformin (n=1) . All patients were started on empagliflozin mg QD. Follow-up was 1.5 [0.7; 1.8] years (total 6.2 patient years) . After three to six months of SGLT2i therapy, HbA1c was 6.1 [5.5; 7.5]% (43 [37; 59] mmol/mol) and had decreased in four patients (HbA1c change: -0.5 [-1.3; 0.7]% (-5 [-14; 8] mmol/mol)) , while body weight had decreased in all patients (change: -3.4 [-5.9; -1.5] kg) . During SGLT2i treatment, insulin was fully ceased in two patients and insulin dose was reduced from 15 IE/day to 3 IE/day in one patient. No serious adverse events were reported. Our data suggest that SGLT2i is safe, have glucose-lowering effects and is well-tolerated in HNF1A-diabetes, but randomized controlled trials are needed. Disclosure H.Maagensen: None. S.Haedersdal: None. J.Krogh: None. T.Hansen: None. F.K.Knop: Advisory Panel; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi, ShouTi, Zucara Therapeutics, Consultant; AstraZeneca, Eli Lilly and Company, Novo Nordisk, Pharmacosmos A/S, Sanofi, ShouTi, Zealand Pharma A/S, Zucara Therapeutics, Research Support; AstraZeneca, Novo Nordisk, Sanofi, Zealand Pharma A/S, Speaker's Bureau; AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk, Sanofi, Stock/Shareholder; Antag Therapeutics. T.Vilsbøll: Consultant; AstraZeneca, Bristol-Myers Squibb Company, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Merck Sharp & Dohme Corp., Mundipharma, Novo Nordisk, Sun Pharmaceutical Industries Ltd.

Type 2 Diabetes Patients With Serum ALT Greater Than AST: The Clinical Characteristics and Effects of Glucose Lowering Agents

Type 2 Diabetes Patients With Serum ALT Greater Than AST: The Clinical Characteristics and Effects of Glucose Lowering Agents

The Effects of Glucose Lowering Agents on the Secondary Prevention of Coronary Artery Disease in Patients with Type 2 Diabetes.

BackgroundPatients with diabetes have a higher risk of requiring repeated percutaneous coronary intervention (PCI) than non-diabetic patients. We aimed to evaluate and compare the effects of anti-diabetic drugs on the secondary prevention of myocardial infarction among type 2 diabetes mellitus patients.MethodsWe analyzed the general health check-up dataset and claims data of the Korean National Health Insurance Service of 199,714 participants (age ≥30 years) who underwent PCIs between 2010 and 2013. Those who underwent additional PCI within 1 year of their first PCI (n=3,325) and those who died within 1 year (n=1,312) were excluded. Patients were classified according to their prescription records for glucose-lowering agents. The primary endpoint was the incidence rate of coronary revascularization.ResultsA total of 35,348 patients were included in the study. Metformin significantly decreased the risk of requiring repeat PCI in all patients (adjusted hazard ratio [aHR], 0.77). In obese patients with body mass index (BMI) ≥25 kg/m2, patients treated with thiazolidinedione (TZD) exhibited a decreased risk of requiring repeat revascularization than those who were not treated with TZD (aHR, 0.77; 95% confidence interval, 0.63 to 0.95). Patients treated with metformin showed a decreased risk of requiring revascularization regardless of their BMI. Insulin, meglitinide, and alpha-glucosidase inhibitor were associated with increased risk of repeated PCI.ConclusionThe risk of requiring repeat revascularization was lower in diabetic patients treated with metformin and in obese patients treated with TZD. These results suggest that physicians should choose appropriate glucose-lowering agents for the secondary prevention of coronary artery disease.

Platelet Effects of Anti-diabetic Therapies: New Perspectives in the Management of Patients with Diabetes and Cardiovascular Disease

In type 2 diabetes, anti-thrombotic management is challenging, and current anti-platelet agents have demonstrated reduced efficacy. Old and new anti-diabetic drugs exhibited—besides lowering blood glucose levels—direct and indirect effects on platelet function and on thrombotic milieu, eventually conditioning cardiovascular outcomes. The present review summarizes existing evidence on the effects of glucose-lowering agents on platelet properties, addressing pre-clinical and clinical research, as well as drug–drug interactions with anti-platelet agents. We aimed at expanding clinicians’ understanding by highlighting new opportunities for an optimal management of patients with diabetes and cardiovascular disease. We suggest how an improvement of the thrombotic risk in this large population of patients may be achieved by a careful and tailored combination of anti-diabetic and anti-platelet therapies.

Insulin Signaling in Arthritis.

Inflammatory arthritis is burdened by an increased risk of metabolic disorders. Cytokines and other mediators in inflammatory diseases lead to insulin resistance, diabetes and hyperlipidemia. Accumulating evidence in the field of immunometabolism suggests that the cause-effect relationship between arthritis and metabolic abnormalities might be bidirectional. Indeed, the immune response can be modulated by various factors such as environmental agents, bacterial products and hormones. Insulin is produced by pancreatic cells and regulates glucose, fat metabolism and cell growth. The action of insulin is mediated through the insulin receptor (IR), localized on the cellular membrane of hepatocytes, myocytes and adipocytes but also on the surface of T cells, macrophages, and dendritic cells. In murine models, the absence of IR in T-cells coincided with reduced cytokine production, proliferation, and migration. In macrophages, defective insulin signaling resulted in enhanced glycolysis affecting the responses to pathogens. In this review, we focalize on the bidirectional cause-effect relationship between impaired insulin signaling and arthritis analyzing how insulin signaling may be involved in the aberrant immune response implicated in arthritis and how inflammatory mediators affect insulin signaling. Finally, the effect of glucose-lowering agents on arthritis was summarized.

An up-to-date evaluation of sotagliflozin for the treatment of type 1 diabetes

ABSTRACT Introduction The majority of patients with type 1 diabetes mellitus (T1DM) do not achieve glycemic targets. In addition, treatment with insulin is associated with increased risk for hypoglycemia and weight gain. Accordingly, there is an unmet need for new safe and effective glucose-lowering agents in this population. Sotagliflozin, a dual inhibitor of sodium-glucose co-transporters 1 and 2, has been recently approved for use in patients with T1DM. Areas covered The authors review the major trials that have evaluated the safety and efficacy of sotagliflozin and provide their expert opinion. Expert opinion Even though sotagliflozin reduces HbA1 c levels and does not appear to increase the risk for hypoglycemia in most patients, the substantially increased risk for diabetic ketoacidosis limits the use of this agent to a carefully selected subgroup of patients with T1DM. Based on the existing evidence, sotagliflozin should be considered only in patients who have failed to achieve adequate glycemic control despite optimal insulin therapy, are at low risk for diabetic ketoacidosis, have been adequately trained to recognize this complication and are able to be in close contact with their physician.

Role of Gliclazide MR in the Management of Type 2 Diabetes: Report of a Symposium on Real-World Evidence and New Perspectives.

In patients with type 2 diabetes mellitus (T2DM) who require additional glucose-lowering on top of first-line metformin monotherapy, sulfonylureas are the most common choice for second-line therapy followed by dipeptidyl peptidase inhibitors (DPP-4i). This article summarises presentations at a symposium entitled “Real-World Evidence and New Perspectives with Gliclazide MR” held at the International Diabetes Federation Congress in Busan, South Korea on 4 December 2019. Although guideline recommendations vary between countries, the guidelines with the highest quality ratings include sulfonylureas as one of the preferred choices as second-line therapy for T2DM. Data from randomised controlled trials (RCTs) have consistently demonstrated that sulfonylureas are effective glucose-lowering agents and that the risk of severe hypoglycaemia with these agents is low. In addition, both RCTs and real-world observational studies have shown no increased risk of mortality or cardiovascular disease with the use of newer-generation sulfonylureas compared with other classes of glucose-lowering treatments. However, differences between sulfonylureas do exist, with gliclazide being associated with a significantly lower risk of mortality or cardiovascular mortality compared with glibenclamide, as well as the lowest incidence of severe hypoglycaemia compared with other agents in this class. Recent real-world studies into the effectiveness and safety of gliclazide appear to confirm these findings, and publication of new data from these studies in patients with T2DM in the UK, and in Muslim patients who are fasting during Ramadan, are awaited with interest. Another study being undertaken with gliclazide is a pan-India study in patients with maturity-onset diabetes of the young (MODY) subtypes 1, 3 and 12. Patients with these MODY subtypes respond particularly well to sulfonylurea treatment, and sulfonylureas are the first-line agents of choice in these patients. These new and ongoing studies will add to the cumulative data on the efficacy and safety of certain sulfonylureas in patients with diabetes.

Effects of glucose-lowering agents on cardiorespiratory fitness.

Exercise therapy is essential for the management of type 2 diabetes (T2D). However, patients with T2D show lower physical activity and reduced cardiorespiratory fitness than healthy individuals. It would be ideal for clinicians to co-prescribe glucose-lowering agents that improve cardiorespiratory fitness or exercise capacity in conjunction with exercise therapy. Metformin does not improve cardiorespiratory fitness and may attenuate any beneficial effect of exercise in patients with T2D. In contrast, thiazolidinediones appear to improve cardiorespiratory fitness in patients with T2D. Although evidence is limited, sodium–glucose cotransporter 2 (SGLT2) inhibitors may improve cardiorespiratory fitness in patients with heart failure, and the effect of glucagon-like peptide-1 (GLP-1) receptor agonists on cardiorespiratory fitness is controversial. Recent clinical trials have shown that both SGLT2 inhibitors and GLP-1 receptor agonists exert a favorable effect on cardiovascular disease. It becomes more important to choose drugs that have beneficial effects on the cardiovascular system beyond glucose-lowering effects. Further studies are warranted to determine an ideal glucose-lowering agent combined with exercise therapy for the treatment of T2D.

The Relationship between Frequently Used Glucose-Lowering Agents and Gut Microbiota in Type 2 Diabetes Mellitus.

Metabolic diseases, especially diabetes mellitus, have become global health issues. The etiology of diabetes mellitus can be attributed to genetic and/or environmental factors. Current evidence suggests the association of gut microbiota with metabolic diseases. However, the effects of glucose-lowering agents on gut microbiota are poorly understood. Several studies revealed that these agents affect the composition and diversity of gut microbiota and consequently improve glucose metabolism and energy balance. Possible underlying mechanisms include affecting gene expression, lowering levels of inflammatory cytokines, and regulating the production of short-chain fatty acids. In addition, gut microbiota may alleviate adverse effects caused by glucose-lowering agents, and this can be especially beneficial in diabetic patients who experience severe gastrointestinal side effects and have to discontinue these agents. In conclusion, gut microbiota may provide a novel viewpoint for the treatment of patients with diabetes mellitus.

Glucose lowering effect of montbretin A in Zucker Diabetic Fatty rats.

Diabetes is an increasingly prevalent disease state with a global impact. It is important that effective and cost-efficient methods be developed to treat this disease state. Zucker diabetic fatty rats, an animal model of type 2 diabetes, were treated with montbretin A (MbA), a selective human pancreatic α-amylase inhibitor, isolated from the corms of the Crocosmia crocosmiiflora plant that may have potential as a glucose-lowering agent. The study purpose was to determine if MbA was an orally effective treatment for diabetes. The effect of MbA was compared to a current clinical treatment modality, acarbose that is associated with gastrointestinal side effects known to affect patient compliance. MbA and acarbose were administered daily in the drinking water. Body weight and fluid intake were measured daily to calculate dose consumption. Plasma glucose levels were determined twice weekly in both the fed and fasted state. At termination samples were collected to assess increased risk of secondary complications related to diabetes and oxidative stress. There was no effect of either MbA or acarbose treatment on insulin levels. Plasma glucose levels were significantly lower following MbA treatment in the ZT group which persisted throughout the study period (day 49: 12.1±1.2mM). However, while there was an initial decrease in plasma glucose levels in the acarbose-treated fatty group, this effect was not sustained (day 49: 20.6±1.3mM) through to termination. MbA improved the oxidative status of the fatty diabetic animals as well as attenuated markers for increased risk of cardiovascular complications associated with diabetes. This study demonstrated that, at a lower dose as compared to acarbose (10mg/kg/day), chronic oral administration of MbA (7.5mg/kg/day) was an effective glucose-lowering agent in the treatment of type 2 diabetes.

Incretin-based drugs and adverse pancreatic events: almost a decade later and uncertainty remains.

Over the past few years, substantial clinical data have been presented showing that incretin-based therapies are effective glucose-lowering agents. Specifically, glucagon-like peptide 1 receptor agonists demonstrate an efficacy comparable to insulin treatment with minimal hypoglycemia and have favorable effects on body weight. Thus, many of the unmet clinical needs noted from prior therapies are addressed by these agents. However, even after many years of use, many continue to raise concerns about the long-term safety of these agents and, in particular, the concern with pancreatitis. This clearly remains a complicated topic. Thus, in this issue of Diabetes Care, we continue to update our readers on this very important issue by presenting two studies evaluating incretin-based medications and risk of pancreatitis. Both have undergone significant revisions based on peer review that provided significant clarification of the data. We applaud both author groups for being extremely responsive in providing the additional data and revisions requested by the editorial team. As such, because of the critical peer review, we feel both articles achieve the high level we require for Diabetes Care and are pleased to now present them to our readers. In keeping with our aim to comprehensively evaluate this topic, we asked for additional commentaries to be prepared. In the narrative outlined below, Dr. Laurent Azoulay provides a commentary about the remaining uncertainty in this area and also discusses the results from a nationwide population-based case-control study. In the narrative preceding Dr. Azoulay's contribution, Prof. Edwin A.M. Gale provides a commentary on the report that focuses on clinical trials of liraglutide in the treatment of diabetes. From the journal's perspective, both of the articles on pancreatitis and incretin-based therapies reported in this issue have been well vetted, and we feel both of the commentaries are insightful.

Smoke or fire? Acute pancreatitis and the liraglutide trials.

Over the past few years, substantial clinical data have been presented showing that incretin-based therapies are effective glucose-lowering agents. Specifically, glucagon-like peptide 1 receptor agonists demonstrate an efficacy comparable to insulin treatment with minimal hypoglycemia and have favorable effects on body weight. Thus, many of the unmet clinical needs noted from prior therapies are addressed by these agents. However, even after many years of use, many continue to raise concerns about the long-term safety of these agents and, in particular, the concern with pancreatitis. This clearly remains a complicated topic. Thus, in this issue of Diabetes Care, we continue to update our readers on this very important issue by presenting two studies evaluating incretin-based medications and risk of pancreatitis. Both have undergone significant revisions based on peer review that provided significant clarification of the data. We applaud both author groups for being extremely responsive in providing the additional data and revisions requested by the editorial team. As such, because of the critical peer review, we feel both articles achieve the high level we require for Diabetes Care and are pleased to now present them to our readers. In keeping with our aim to comprehensively evaluate this topic, we asked for additional commentaries to be prepared. In the narrative outlined below, Prof. Edwin A.M. Gale provides a commentary on the report that focuses on clinical trials of liraglutide in the treatment of diabetes. In the narrative that follows Prof. Gale's contribution, Dr. Laurent Azoulay provides a commentary about the remaining uncertainty in this area and also discusses the results from a nationwide population-based case-control study. From the journal's perspective, both of the articles on pancreatitis and incretin-based therapies reported in this issue have been well vetted, and we feel both of the commentaries are insightful.

Effects of glucose-lowering agents on vascular outcomes in type 2 diabetes: A critical reappraisal

Type 2 diabetes mellitus (T2DM) is strongly associated with cardiovascular complications, especially coronary artery disease. Numerous epidemiological studies have shown a close relationship between major cardiovascular events and glycaemia, and several pathophysiological mechanisms have been described that explain how hyperglycaemia induces vascular damage. However, randomized controlled trials investigating either an intensive glucose-lowering strategy vs standard care or the addition of a new glucose-lowering agent vs a placebo have largely failed to demonstrate any clinical benefits in terms of cardiovascular morbidity or mortality. This lack of evidence has led some people to contest the clinical efficacy of lowering blood glucose in patients with T2DM, despite its positive effects on microvascular complications. This article analyzes the various reasons that might explain such discrepancies. There are still strong arguments in favour of targeting hyperglycaemia while avoiding other counterproductive effects, such as hypoglycaemia and weight gain, and of integrating the glucose-lowering approach within a global multi-risk strategy to reduce the burden of cardiovascular disease in T2DM.

A Critical Analysis of the Clinical Use of Incretin-Based Therapies

There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns reported regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to a potential risk for the increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider the use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative following the contribution by Dr. Butler and colleagues, Dr. Nauck provides a defense of incretin-based therapies and that the benefits clearly outweigh any concern of risk.—William T. Cefalu, MD Editor In Chief, Diabetes Care

A Critical Analysis of the Clinical Use of Incretin-Based Therapies

There is no question that incretin-based glucose-lowering medications have proven to be effective glucose-lowering agents. Glucagon-like peptide 1 (GLP-1) receptor agonists demonstrate an efficacy comparable to insulin treatment and appear to do so with significant effects to promote weight loss with minimal hypoglycemia. In addition, there are significant data with dipeptidyl peptidase 4 (DPP-4) inhibitors showing efficacy comparable to sulfonylureas but with weight neutral effects and reduced risk for hypoglycemia. However, over the recent past there have been concerns regarding the long-term consequences of using such therapies, and the issues raised are in regard to the potential of both classes to promote acute pancreatitis, to initiate histological changes suggesting chronic pancreatitis including associated preneoplastic lesions, and potentially, in the long run, pancreatic cancer. Other issues relate to an increase in thyroid cancer. There are clearly conflicting data that have been presented in preclinical studies and in epidemiologic studies. To provide an understanding of both sides of the argument, we provide a discussion of this topic as part of this two-part point-counterpoint narrative. In the point narrative preceding the counterpoint narrative below, Dr. Butler and colleagues provide their opinion and review of the data to date and that we need to reconsider use of incretin-based therapies because of the growing concern of potential risk and based on a clearer understanding of the mechanism of action. In the counterpoint narrative provided below, Dr. Nauck provides a defense of incretin-based therapies and that benefits clearly outweigh any concern of risk.—William T. Cefalu, MD Editor in Chief, Diabetes Care

Cardiovascular outcomes associated with a new once-weekly GLP-1 receptor agonist vs. traditional therapies for type 2 diabetes: a simulation analysis

The effect of glucose-lowering agents on diabetes-related complications including cardiovascular (CV) events is of major importance. In the absence of a long-term study, we simulated such a trial using a mathematical model where subjects were given exenatide once-weekly (EQW), which has been shown to improve glycaemic control and reduce weight, systolic blood pressure (SBP) and lipids in patients with type 2 diabetes mellitus (T2DM). Using the Archimedes Model, we followed a simulated population derived from individuals with T2DM in NHANES who were drug-naïve or on oral agents only. We modelled the effects of four treatment strategies including standard care (SC, maintaining levels of control seen in NHANES), intensive glycaemic control (IGC, target HbA1c < 7% with conventional antidiabetic agents) and two versions of EQW added to SC: one with glycaemic and weight reduction only (EQW-1) and one with additional improvements in SBP and lipids (EQW-2). EQW strategies were derived from 52-week clinical trial data. Endpoints included macrovascular and microvascular outcomes. Simulated EQW treatment resulted in earlier benefit and 2-3 times greater relative reductions in major adverse CV events than IGC when compared to SC (6% relative reduction by year 20 for IGC vs. 12 and 17% for the EQW strategies). For microvascular complications, EQW showed comparable benefit to IGC for neuropathy but significantly greater impact on renal complications. This analysis shows that the novel drug EQW has the potential to greatly reduce CV events through its combined effects on glycaemia, weight and other CV risk factors.

What to add in with metformin in type 2 diabetes?

This review considers the therapeutic choices currently faced by people with type 2 diabetes and those caring for them when glucose levels initially controlled with lifestyle management and metformin start to rise. While sulphonylureas are familiar agents and cheaper than other alternatives, they cause hypoglycaemia and modest weight gain, and robust outcome data are still lacking. Dipeptidyl peptidase 4 inhibitors ('gliptins') have an attractive pharmacological and adverse effect profile, but their effects on the cardiovascular system are also uncertain. Thiazolidinediones ('glitazones') are effective glucose-lowering agents, but cause weight gain and increase the risk of fracture, while the cardiovascular benefits hoped for in association with 'insulin-sensitization' have not been as expected. Glucagon-like peptide-1 agonists will not be acceptable as initial second-line agents for many people as they are injectable rather than oral. Well-powered 'head-to-head' clinical trials of adequate duration are therefore required to allow evidence-based decisions on second-line therapy.

Diabetes and the Bone

This article discusses both the linkages between glucose and bone metabolism that are actively being researched, as well as the effects of glucose-lowering agents on bones.