Publications by authors named "Clifford J Bailey"

95 Publications

Flash Continuous Glucose Monitoring: A Summary Review of Recent Real-World Evidence.

Clin Diabetes 2021 Jan;39(1):64-71

Emory University School of Medicine, Atlanta, GA.

Optimizing glycemic control remains a shared challenge for clinicians and their patients with diabetes. Flash continuous glucose monitoring (CGM) provides immediate information about an individual's current and projected glucose level, allowing users to respond promptly to mitigate or prevent pending hypoglycemia or hyperglycemia. Large randomized controlled trials (RCTs) have demonstrated the glycemic benefits of flash CGM use in both type 1 and type 2 diabetes. However, whereas RCTs are mostly focused on the efficacy of this technology in defined circumstances, real-world studies can assess its effectiveness in wider clinical settings. This review assesses the most recent real-world studies demonstrating the effectiveness of flash CGM use to improve clinical outcomes and health care resource utilization in populations with diabetes.
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http://dx.doi.org/10.2337/cd20-0076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839606PMC
January 2021

Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease.

N Engl J Med 2021 01 16;384(2):129-139. Epub 2020 Nov 16.

From Brigham and Women's Hospital Heart and Vascular Center and Harvard Medical School, Boston (D.L.B., C.P.C., B.M.S.); Colorado Prevention Center Clinical Research and Department of Medicine, Division of Cardiovascular Medicine, University of Colorado Anschutz Medical Campus, Aurora (M.S.); the State University of New York Downstate School of Public Health, Brooklyn (M.S.); the University of Michigan, Ann Arbor (B.P.); Li Ka Shing Knowledge Institute and the Division of Endocrinology and Metabolism, St. Michael's Hospital, and the Departments of Medicine and Nutritional Sciences, University of Toronto (L.A.L.), and the Division of Nephrology (D.Z.I.C.) and the Cardiovascular Division, Department of Medicine, Women's College Hospital and Peter Munk Cardiac Centre (J.A.U.), University Health Network, University of Toronto - all in Toronto; the University of Texas Southwestern Medical Center and Parkland Health and Hospital System, Dallas (D.K.M.), and Lexicon Pharmaceuticals, The Woodlands (P.L.) - both in Texas; Vanderbilt University Medical Center, Nashville (J.B.L., J.P.D.); the Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health and Science University, Portland (M.C.R.); the Section of Endocrinology, Yale School of Medicine, New Haven, CT (S.E.I.); Saint Luke's Mid America Heart Institute, University of Missouri-Kansas City, Kansas City (M.N.K.); the School of Life and Health Sciences, Aston University, Birmingham (C.J.B.), and the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London (K.K.R.) - both in the United Kingdom; the Department of Medicine, Estudios Clínicos Latinoamérica, Instituto Cardiovascular de Rosario, Rosario, Argentina (R.D.); Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC (R.D.L.); and Université de Paris, French Alliance for Cardiovascular Trials, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, INSERM Unité 1148, Paris (P.G.S.).

Background: The efficacy and safety of sodium-glucose cotransporter 2 inhibitors such as sotagliflozin in preventing cardiovascular events in patients with diabetes with chronic kidney disease with or without albuminuria have not been well studied.

Methods: We conducted a multicenter, double-blind trial in which patients with type 2 diabetes mellitus (glycated hemoglobin level, ≥7%), chronic kidney disease (estimated glomerular filtration rate, 25 to 60 ml per minute per 1.73 m of body-surface area), and risks for cardiovascular disease were randomly assigned in a 1:1 ratio to receive sotagliflozin or placebo. The primary end point was changed during the trial to the composite of the total number of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure. The trial ended early owing to loss of funding.

Results: Of 19,188 patients screened, 10,584 were enrolled, with 5292 assigned to the sotagliflozin group and 5292 assigned to the placebo group, and followed for a median of 16 months. The rate of primary end-point events was 5.6 events per 100 patient-years in the sotagliflozin group and 7.5 events per 100 patient-years in the placebo group (hazard ratio, 0.74; 95% confidence interval [CI], 0.63 to 0.88; P<0.001). The rate of deaths from cardiovascular causes per 100 patient-years was 2.2 with sotagliflozin and 2.4 with placebo (hazard ratio, 0.90; 95% CI, 0.73 to 1.12; P = 0.35). For the original coprimary end point of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, the hazard ratio was 0.84 (95% CI, 0.72 to 0.99); for the original coprimary end point of the first occurrence of death from cardiovascular causes or hospitalization for heart failure, the hazard ratio was 0.77 (95% CI, 0.66 to 0.91). Diarrhea, genital mycotic infections, volume depletion, and diabetic ketoacidosis were more common with sotagliflozin than with placebo.

Conclusions: In patients with diabetes and chronic kidney disease, with or without albuminuria, sotagliflozin resulted in a lower risk of the composite of deaths from cardiovascular causes, hospitalizations for heart failure, and urgent visits for heart failure than placebo but was associated with adverse events. (Funded by Sanofi and Lexicon Pharmaceuticals; SCORED ClinicalTrials.gov number, NCT03315143.).
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http://dx.doi.org/10.1056/NEJMoa2030186DOI Listing
January 2021

Metformin in women with type 2 diabetes in pregnancy.

Lancet Diabetes Endocrinol 2020 10;8(10):802-803

School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(20)30308-9DOI Listing
October 2020

Choosing GLP-1 receptor agonists or SGLT-2 inhibitors by cardiorenal risk.

Lancet Diabetes Endocrinol 2020 02 13;8(2):97-99. Epub 2019 Dec 13.

School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK. Electronic address:

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http://dx.doi.org/10.1016/S2213-8587(19)30414-0DOI Listing
February 2020

GIP analogues and the treatment of obesity-diabetes.

Peptides 2020 03 19;125:170202. Epub 2019 Nov 19.

School of Life and Health Sciences, Aston University, B4 7ET, Birmingham, UK. Electronic address:

The potential application of glucose-dependent insulinotropic polypeptide (gastric inhibitory polypeptide, GIP) in the management of obesity and type 2 diabetes has been controversial. Initial interest in the therapeutic use of GIP was dampened by evidence that its insulinotropic activity was reduced in type 2 diabetes and by reports that it increased glucagon secretion and adipose deposition in non-diabetic individuals. Also, attention was diverted away from GIP by the successful development of glucagon-like peptide-1 (GLP-1) receptor agonists, and a therapeutic strategy for GIP became uncertain when evidence emerged that both inhibition and enhancement of GIP action could prevent or reverse obese non-insulin dependent forms of diabetes in rodents. Species differences in GIP receptor responsiveness complicated the extrapolation of evidence from rodents to humans, but initial clinical studies are investigating the effect of a GIP antagonist in non-diabetic individuals. A therapeutic role for GIP agonists was reconsidered when clinical studies noted that the insulinotropic effect of GIP was increased if near-normal glycaemia was re-established, and GIP was found to have little effect on glucagon secretion or adipose deposition in obese type 2 diabetes patients. This encouraged the development of designer peptides that act as GIP receptor agonists, including chimeric peptides that mimic the incretin partnership of GIP with GLP-1, where the two agents exert complementary and often additive effects to improve glycaemic control and facilitate weight loss. Polyagonist peptides that exert agonism at GIP, GLP-1 and glucagon receptors are also under investigation as potential treatments for obese type 2 diabetes.
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http://dx.doi.org/10.1016/j.peptides.2019.170202DOI Listing
March 2020

Reports of Lactic Acidosis Attributed to Metformin, 2015-2018.

Diabetes Care 2020 01 9;43(1):244-246. Epub 2019 Oct 9.

Yale School of Medicine, New Haven, CT.

Objective: In 2016, the U.S. Food and Drug Administration (FDA) revised metformin's label to permit use in patients with mild-moderate chronic kidney disease. We sought to determine whether this change was associated with increased reports of metformin-associated lactic acidosis (MALA) to the FDA's Adverse Event Reporting System (FAERS).

Research Design And Methods: Publicly available FAERS reports were analyzed.

Results: MALA reports increased from 521 in 2015 to 1,939 in 2018. After restriction to U.S. reports, absolute and relative increase in MALA reports was less, from 111 to 243. The proportionate reporting ratio (PRR), a measure adjusted for rates of other adverse event reports, was stable.

Conclusions: The increased reports deserve attention, but the PRR's stability and FAERS's known limitations, including lack of a denominator or control group, do not permit the conclusion that U.S. MALA rates have increased. Further study with more robust data sources is needed.
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http://dx.doi.org/10.2337/dc19-0923DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011199PMC
January 2020

Durability of glycaemic control with dapagliflozin, an SGLT2 inhibitor, compared with saxagliptin, a DPP4 inhibitor, in patients with inadequately controlled type 2 diabetes.

Diabetes Obes Metab 2019 11 26;21(11):2564-2569. Epub 2019 Aug 26.

AstraZeneca, R&D Bio Pharmaceuticals, Late CVRM, Gaithersburg, Maryland.

Dapagliflozin is associated with greater reductions in HbA1c and weight than saxagliptin in management of type 2 diabetes mellitus (T2DM). The present post hoc analyses compared the durability of these effects over short- and long-term follow-up in patients with T2DM who were inadequately controlled with metformin (≥1500 mg/day) and who were receiving either dapagliflozin (10 mg/day) or saxagliptin (5 mg/day). Failure of glycaemiccontrol was assessed using the slope of the change in HbA1c from baseline-over-time regression line (coefficient of failure [CoF]). CoF was compared directly (dapagliflozin vs saxagliptin) over the short term (NCT01606007, 24 weeks) and indirectly (placebo-adjusted) over the long term (NCT00528879 and NCT00121667, 102 weeks). A low CoF value indicated greater durability. CoF was lower for dapagliflozin versus saxagliptin over 18-24 weeks (-1.38%/year; 95% CI, -2.41 to -0.35; P = .009) and 20-102 weeks (-0.37%/year; 95% CI, -0.73 to -0.02; P = .04). Fewer dapagliflozin-treated patients versus saxagliptin-treated patients required rescue medication or discontinued the study because of failure to achieve glycaemic control at 24 weeks (3.4% vs 9.4%; P = .0191). In patients with T2DM who were inadequately controlled with metformin, dapagliflozin was associated with greater durability of glycaemic control than saxagliptin over 18-24 and 20-102 weeks.
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http://dx.doi.org/10.1111/dom.13841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851837PMC
November 2019

Treating T2DM and obesity with bariatric surgery and GLP1 agents.

Nat Rev Endocrinol 2019 09;15(9):504-506

Life and Health Sciences, Aston University, Birmingham, UK.

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http://dx.doi.org/10.1038/s41574-019-0240-4DOI Listing
September 2019

The future of new drugs for diabetes management.

Diabetes Res Clin Pract 2019 Sep 19;155:107785. Epub 2019 Jul 19.

Life and Health Sciences, Aston University, Birmingham, UK.

The future of the newer classes of glucose-lowering drugs, namely dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium/glucose co-transporter-2 (SGLT-2) inhibitors, is being redefined by the large prospective cardiovascular outcome trials (CVOTs). These trials have more than confirmed cardiovascular (CV) safety: indeed, various cardio-renal parameters have improved during some of the trials with GLP-1RAs and SGLT-2 inhibitors in type 2 diabetes. Benefits have included reductions in major adverse cardiovascular events such as fatal and non-fatal myocardial infarction and stroke, decreased hospitalization for heart failure, a slower decline in glomerular filtration rate and reduced onset and progression of albuminuria. In consequence, the CVOTs have raised expectations that newer glucose-lowering agents should offer advantages that extend beyond glycaemic control and weight management to address complications and comorbidities of type 2 diabetes, particularly cardio-renal diseases. Although large prospective outcome trials incur a high cost which may prompt reconsideration of their design, these trials are generating evidence to enable more exacting and more effective management of type 2 diabetes and its accompanying cardio-renal diseases.
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http://dx.doi.org/10.1016/j.diabres.2019.107785DOI Listing
September 2019

Phenotypic characteristics and risk factors in a multi-ethnic cohort of young adults with type 2 diabetes.

Curr Med Res Opin 2019 11 5;35(11):1893-1900. Epub 2019 Aug 5.

School of Life and Health Sciences, Aston University , Birmingham , UK.

Early onset of type 2 diabetes (T2DM) is associated with prolonged exposure to hyperglycaemia and increased propensity to chronic complications. The aim of this study was to characterize and compare the phenotypic characteristics and risk factors in a multi-ethnic cohort of young adults with type 2 diabetes (T2DMY). One hundred young adults (White European [WE], South Asian [SA] and African-Caribbean [AC]) diagnosed with T2DM before the age of 40 years were recruited. Demographics, family history, diabetes related complications, co-morbidities, anthropometry (body mass index [BMI], body composition), physical activity and biochemistry (HbA1c, lipid profile, liver and renal function) and autoantibodies (anti GAD, anti islet cell) were collected for all participants. Data were analysed for the most represented ethnic groups: (WE,  36 and SA,  53) using SPSS version 23. Mean (± standard deviation) age at diagnosis was 32.5 ± 5.5 years and mean diabetes duration was 7.7 ± 3.8 years. Overweight/obesity was present in 95% of participants, history of maternal diabetes in 68%, deprivation 75%, low physical activity 40%, polycystic ovarian disease 29% (in females), acanthosis nigricans 12% and non-alcoholic fatty liver 11%. There was considerable clustering of risk factors within the cohort with over 75% of all subjects having three or more of the above risk factors and 52% required insulin within 3 years of diagnosis. Two-thirds of the patients had evidence of at least one diabetes related microvascular complication. T2DMY is characterized by a high burden of commonly associated risk factors for both the disease and its long-term complications.
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http://dx.doi.org/10.1080/03007995.2019.1638239DOI Listing
November 2019

Insulin resistance: Impact on therapeutic developments in diabetes.

Diab Vasc Dis Res 2019 03;16(2):128-132

School of Life & Health Sciences, Aston University, Birmingham, UK.

Insulin resistance has a broad pathogenic impact affecting metabolic, cardio-renal and other disease areas. Extensive studies to dissect the mechanisms of insulin resistance have provided valuable insights to shape current clinical awareness and advance therapeutic practice. However, the development of direct interventions against insulin resistance has been hindered by its complex and highly variable presentations, especially in type 2 diabetes. Among glucose-lowering agents, metformin and thiazolidinediones provide cellular actions that counter some effects of insulin resistance: reduced glucotoxicity and weight-lowering with antidiabetic therapies also improve insulin action, except that endogenously- or exogenously-created hyperinsulinaemia may partially compromise these benefits. Increasing awareness of the pervasiveness and damaging ramifications of insulin resistance heightens the need for more specifically targeted and more effective therapies.
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http://dx.doi.org/10.1177/1479164119827570DOI Listing
March 2019

Rotational culture and integration with amniotic stem cells reduce porcine islet immunoreactivity in vitro and slow xeno-rejection in a murine model of islet transplantation.

Xenotransplantation 2019 07 8;26(4):e12508. Epub 2019 Apr 8.

The Islet Research Laboratory, Worcestershire Clinical Research Unit, Worcestershire Acute Hospitals NHS Trust, Worcester, UK.

Background: Pre-transplant modification of porcine islets may improve their suitability for clinical use in diabetes management by supporting graft function and reducing the potential for xeno-rejection. The present study investigates intra-graft incorporation of stem cells that secrete beta (β)-cell trophic and immunomodulatory factors to preserve function and alter immune cell responsiveness to porcine islets.

Methods: Isolated porcine islets were maintained in a three-dimensional rotational cell culture system (RCCS) to facilitate aggregation with human amniotic epithelial cells (AECs). Assembled islet constructs were assessed for functional integrity and ability to avoid xeno-recognition by CD4+ T-cells using mixed islet:lymphocyte reaction assays. To determine whether stem cell-mediated modification of porcine islets provided a survival advantage over native islets, structural integrity was examined in a pig-to-mouse islet transplant model.

Results: Rotational cell culture system supported the formation of porcine islet:AEC aggregates with improved insulin-secretory capacity compared to unmodified islets, whilst the xeno-response of purified CD4+ T-cells to AEC-bearing grafts was significantly (P < 0.05) attenuated. Transplanted AEC-bearing grafts demonstrated slower rejection in immune-competent recipients compared to unmodified islets.

Conclusions/interpretation: Rotational culture enables pre-transplant modification of porcine islets by integration with immunomodulatory stem cells capable of subduing xeno-reactivity to CD4+ T-cells. This reduces islet rejection and offers translational potential to widen availability and improve the clinical effectiveness of islet transplantation.
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http://dx.doi.org/10.1111/xen.12508DOI Listing
July 2019

Uric acid and the cardio-renal effects of SGLT2 inhibitors.

Diabetes Obes Metab 2019 06 15;21(6):1291-1298. Epub 2019 Mar 15.

School of Life and Health Sciences, Aston University, Birmingham, UK.

Sodium/glucose co-transporter-2 (SGLT2) inhibitors, which lower blood glucose by increasing renal glucose elimination, have been shown to reduce the risk of adverse cardiovascular (CV) and renal events in type 2 diabetes. This has been ascribed, in part, to haemodynamic changes, body weight reduction and several possible effects on myocardial, endothelial and tubulo-glomerular functions, as well as to reduced glucotoxicity. This review evaluates evidence that an effect of SGLT2 inhibitors to lower uric acid may also contribute to reduced cardio-renal risk. Chronically elevated circulating uric acid concentrations are associated with increased risk of hypertension, CV disease and chronic kidney disease (CKD). The extent to which uric acid contributes to these conditions, either as a cause or an aggravating factor, remains unclear, but interventions that reduce urate production or increase urate excretion in hyperuricaemic patients have consistently improved cardio-renal prognoses. Uric acid concentrations are often elevated in type 2 diabetes, contributing to the "metabolic syndrome" of CV risk. Treating type 2 diabetes with an SGLT2 inhibitor increases uric acid excretion, reduces circulating uric acid and improves parameters of CV and renal function. This raises the possibility that the lowering of uric acid by SGLT2 inhibition may assist in reducing adverse CV events and slowing progression of CKD in type 2 diabetes. SGLT2 inhibition might also be useful in the treatment of gout and gouty arthritis, especially when co-existent with diabetes.
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http://dx.doi.org/10.1111/dom.13670DOI Listing
June 2019

FDA guidance on cardiovascular risk of antidiabetic therapies: One decade later.

Diabetes Obes Metab 2019 05 15;21(5):1079-1080. Epub 2019 Mar 15.

Life and Health Sciences, Aston University, Birmingham, UK.

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http://dx.doi.org/10.1111/dom.13669DOI Listing
May 2019

Cardiovascular protection in type 2 diabetes: Insights from recent outcome trials.

Diabetes Obes Metab 2019 01 7;21(1):3-14. Epub 2018 Sep 7.

Department of Internal Medicine I, RWTH Aachen University, Aachen, Germany.

This review examines recent randomized controlled cardiovascular (CV) outcome trials of glucose-lowering therapies in type 2 diabetes and their impact on the treatment of patients with type 2 diabetes. The trials were designed to comply with regulatory requirements to confirm that major adverse cardiac events (MACE) are not detrimentally affected by such therapies. Trials involving dipeptidyl peptidase-4 (DPP-4) inhibitors did not alter a composite MACE outcome comprising CV deaths, non-fatal myocardial infarction and non-fatal stroke; however, the possibility that some members of this class might incur a small increased risk or worsening of heart failure cannot be excluded. Some studies on glucagon-like peptide-1 receptor agonists (liraglutide: LEADER trial; semaglutide: SUSTAIN-6 trial) found significant benefits for MACE, while treatment with sodium-glucose co-transporter-2 inhibitors (empagliflozin: EMPA-REG OUTCOME trial; canagliflozin: CANVAS trial) also significantly reduced MACE and reduced hospitalization for heart failure. Comparisons among trials are complicated by variance in the populations recruited, particularly CV status at randomization, and differences in trial design, data collection and analyses. A large proportion of patients recruited into these trials have previously experienced adverse CV events; thus, the therapies are mostly assessing secondary prevention of a further event. This contrasts with the overall type 2 diabetes population receiving glucose-lowering therapies, of whom the majority will not have had MACE and will be regarded as primary prevention. Overall, the trials provide reassuring evidence that new glucose-lowering medications do not adversely affect CV events and some of these agents may offer CV protection.
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http://dx.doi.org/10.1111/dom.13492DOI Listing
January 2019

Treatment of type 2 diabetes: future approaches.

Br Med Bull 2018 06;126(1):123-137

Department of Biomedical Sciences, School of Life and Health Sciences, Aston University, Birmingham, UK.

Introduction Or Background: Type 2 diabetes, which accounts for ~90% of all diabetes, is a heterogeneous and progressive disease with a variety of causative and potentiating factors. The hyperglycaemia of type 2 diabetes is often inadequately controlled, hence the need for a wider selection of glucose-lowering treatments.

Sources Of Data: Medline, PubMed, Web of Science and Google Scholar.

Areas Of Agreement: Early, effective and sustained control of blood glucose defers the onset and reduces the severity of microvascular and neuropathic complications of type 2 diabetes and helps to reduce the risk of cardiovascular (CV) complications.

Areas Of Controversy: Newer glucose-lowering agents require extensive long-term studies to confirm CV safety. The positioning of newer agents within therapeutic algorithms varies.

Growing Points: In addition to their glucose-lowering efficacy, some new glucose-lowering agents may act independently to reduce CV and renal complications.

Areas Timely For Developing Research: Studies of potential new glucose-lowering agents offer the opportunity to safely improve glycaemic control with prolonged efficacy and greater opportunity for therapeutic individualisation.
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http://dx.doi.org/10.1093/brimed/ldy013DOI Listing
June 2018

European Medicines Agency: Approval of new glucose-lowering medicines for type 2 diabetes.

Diabetes Obes Metab 2018 Sep 5;20(9):2057-2058. Epub 2018 Jun 5.

Life and Health Sciences, Aston University, Birmingham, UK.

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http://dx.doi.org/10.1111/dom.13360DOI Listing
September 2018

Glucose-lowering therapies in type 2 diabetes: Opportunities and challenges for peptides.

Peptides 2018 02;100:9-17

School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK. Electronic address:

This overview considers the opportunities and challenges that face the use of gluco-regulatory peptides to treat type 2 diabetes. New insulin analogues and formulations are being developed with pharmacokinetic properties to speed-up or prolong transfer from a subcutaneous injection site to the target tissues, or to selectively favour effects on the liver. Alternative routes of insulin administration continue to attract attention, and advances in the integration of glucose monitoring with insulin pump devices are improving miniaturised 'closed loop' artificial pancreas systems. Proof of concept has been established for non-cellular glucose-responsive insulin delivery ('smart insulins') to release insulin from implants or circulating depots in proportion to circulating glucose. The many peptides involved in blood glucose control offer diverse therapeutic opportunities. Exploitation of multiple selected receptor targets using constructs of hybrid and chimeric peptides, especially those based on glucagon and gastrointestinal hormones, has gained much credence from initial preclinical studies. Peptide templates identified from comparative endocrine studies have also provided valuable insights in this respect and indicated novel approaches to address associated conditions such as obesity and infections at the same time. Nevertheless, there are many challenges to the use of therapeutic peptides that impose on every step in the complex pathway from design and testing through to making a fully characterised therapeutic product, and optimising administration, tissue targeting and degradation. Stability of peptides and immunological uncertainties of novel structures require particular consideration as well as the need to avoid over-reduction of blood glucose into hypoglycaemia.
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http://dx.doi.org/10.1016/j.peptides.2017.11.012DOI Listing
February 2018

Plasma irisin is elevated in type 2 diabetes and is associated with increased E-selectin levels.

Cardiovasc Diabetol 2017 11 9;16(1):147. Epub 2017 Nov 9.

Aston Research Centre for Healthy Ageing and School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.

Background: Irisin is a hormone released mainly from skeletal muscle after exercise which increases adipose tissue energy expenditure. Adipocytes can also release irisin after exercise, acting as a local adipokine to induce white adipose tissue to take on a brown adipose tissue-like phenotype, suggesting that irisin and its receptor may represent a novel molecular target for the treatment of obesity and obesity-related diabetes. Previous reports provide conflicting evidence regarding circulating irisin levels in patients with type 2 diabetes (T2DM).

Methods: This study investigated plasma irisin concentrations in 79 T2DM individuals, assessing potential associations with measures of segmental body composition, markers of endothelial dysfunction and peripheral blood mononuclear cell telomere length (TL).

Results: Resting, overnight-fasted plasma irisin levels were significantly higher in this group of T2DM patients compared with levels we previously reported in healthy volunteers (p < 0.001). Moreover, plasma irisin displayed a positive correlation with body mass index (p = 0.04), body fat percentage (p = 0.03), HbA1c (p = 0.03) and soluble E-selectin (p < 0.001). A significant negative association was observed between plasma irisin and visceral adiposity (p = 0.006) in T2DM patients. Multiple regression analysis revealed that circulating soluble E-selectin levels could be predicted by plasma irisin (p = 0.004). Additionally, cultured human umbilical vein endothelial cells (HUVEC) exposed to 200 ng/ml irisin for 4 h showed a significant fourfold increase in E-selectin and 2.5-fold increase in ICAM-1 gene expression (p = 0.001 and p = 0.015 respectively), and there was a 1.8-fold increase in soluble E-selectin in conditioned media (p < 0.05).

Conclusion: These data suggest that elevated plasma irisin in T2DM is associated with indices of adiposity, and that irisin may be involved in pro-atherogenic endothelial disturbances that accompany obesity and T2DM. Accordingly, irisin may constitute a potentially novel therapeutic opportunity in the field of obesity and cardiovascular diabetology.
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http://dx.doi.org/10.1186/s12933-017-0627-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680831PMC
November 2017

The interdisciplinary team in type 2 diabetes management: Challenges and best practice solutions from real-world scenarios.

J Clin Transl Endocrinol 2017 Mar 9;7:21-27. Epub 2016 Dec 9.

School of Life and Health Sciences, Aston University, Birmingham, UK.

The has previously recommended the implementation of an interdisciplinary team (IDT) approach to type 2 diabetes (T2DM) management as one of 10 practical steps for health care professionals to help more people achieve their glycaemic goal. This article discusses some of the key contributors to success and also the challenges faced when applying IDT care, by examining case studies and examples from around the world. The real-world practices discussed show that implementing successful interdisciplinary care in diabetes is possible despite significant barriers such as established hierarchal structures and financial resource constraints. Instituting collaborative, integrated working relationships among multiple disciplines under strong leadership, together with enhanced and active communication and improved patient access to appropriate specialties is essential. Patients have a crucial role in the management of their own disease and including them as part of the treatment team is also critical. IDTs in diabetes care improve patient outcomes in terms of control of glycaemia and cardiometabolic risk factors, and decreased risk of diabetes complications. Ensuring access to an appropriate IDT, in whatever form, is paramount to enable the best care to be delivered.
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http://dx.doi.org/10.1016/j.jcte.2016.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5651292PMC
March 2017

Dapagliflozin in patients with type 2 diabetes mellitus: A pooled analysis of safety data from phase IIb/III clinical trials.

Diabetes Obes Metab 2018 03 26;20(3):620-628. Epub 2017 Oct 26.

Department of R&D, AstraZeneca Gothenburg, Mölndal, Sweden.

Aim: To evaluate the safety and tolerability of dapagliflozin, a highly selective sodium-glucose co-transporter-2 inhibitor, in patients with type 2 diabetes mellitus (T2DM).

Methods: Data were pooled from 13 placebo-controlled trials of up to 24 weeks' duration (dapagliflozin, n = 2360; placebo, n = 2295). Larger placebo-/comparator-controlled pools of 21 (≤208 weeks; dapagliflozin, n = 5936; control, n = 3403) and 30 trials (≥12 weeks; dapagliflozin, n = 9195; control, n = 4629) assessed the rare adverse events (AEs) of diabetic ketoacidosis (DKA) and lower limb amputation, respectively.

Results: Over 24 weeks, the overall incidence of AEs and serious AEs (SAEs) was similar for dapagliflozin and placebo: 60.0% vs 55.7% and 5.1% vs 5.4%, respectively. Rates of hypoglycaemia, volume depletion AEs, urinary tract infections (UTIs) and fractures were balanced between the groups. Genital infections were more frequent with dapagliflozin (5.5%) vs placebo (0.6%) and renal function AEs occurred in 3.2% vs 1.8% of patients (the most common renal AE was decreased creatinine clearance: 1.1% vs 0.7%). In the 21-study pool, 1 SAE of DKA and 3 AEs of ketonuria/metabolic acidosis occurred with dapagliflozin vs none with control; estimated combined incidence for these events was 0.03% (95% confidence interval 0.010-0.089). In the 30-study pool, lower limb amputation occurred in 8 (0.1%) and 7 (0.2%) patients receiving dapagliflozin and control, respectively.

Conclusion: The overall incidence rates of AEs and SAEs were similar in the dapagliflozin and placebo/control groups, including the incidence of hypoglycaemia, volume depletion, fractures, UTIs, amputations and DKA. Genital infections were more frequent with dapagliflozin than placebo.
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http://dx.doi.org/10.1111/dom.13124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836959PMC
March 2018

Type 2 diabetes in adolescents and young adults.

Lancet Diabetes Endocrinol 2018 01 25;6(1):69-80. Epub 2017 Aug 25.

Aston Research Centre for Healthy Ageing (ARCHA), Aston University, Birmingham, UK. Electronic address:

The prevalence of type 2 diabetes in adolescents and young adults is dramatically increasing. Similar to older-onset type 2 diabetes, the major predisposing risk factors are obesity, family history, and sedentary lifestyle. Onset of diabetes at a younger age (defined here as up to age 40 years) is associated with longer disease exposure and increased risk for chronic complications. Young-onset type 2 diabetes also affects more individuals of working age, accentuating the adverse societal effects of the disease. Furthermore, evidence is accumulating that young-onset type 2 diabetes has a more aggressive disease phenotype, leading to premature development of complications, with adverse effects on quality of life and unfavourable effects on long-term outcomes, raising the possibility of a future public health catastrophe. In this Review, we describe the epidemiology and existing knowledge regarding pathophysiology, risk factors, complications, and management of type 2 diabetes in adolescents and young adults.
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http://dx.doi.org/10.1016/S2213-8587(17)30186-9DOI Listing
January 2018

Metformin: historical overview.

Diabetologia 2017 09 3;60(9):1566-1576. Epub 2017 Aug 3.

School of Life and Health Sciences, Aston University, Gosta Green, Birmingham, B4 7ET, UK.

Metformin (dimethylbiguanide) has become the preferred first-line oral blood glucose-lowering agent to manage type 2 diabetes. Its history is linked to Galega officinalis (also known as goat's rue), a traditional herbal medicine in Europe, found to be rich in guanidine, which, in 1918, was shown to lower blood glucose. Guanidine derivatives, including metformin, were synthesised and some (not metformin) were used to treat diabetes in the 1920s and 1930s but were discontinued due to toxicity and the increased availability of insulin. Metformin was rediscovered in the search for antimalarial agents in the 1940s and, during clinical tests, proved useful to treat influenza when it sometimes lowered blood glucose. This property was pursued by the French physician Jean Sterne, who first reported the use of metformin to treat diabetes in 1957. However, metformin received limited attention as it was less potent than other glucose-lowering biguanides (phenformin and buformin), which were generally discontinued in the late 1970s due to high risk of lactic acidosis. Metformin's future was precarious, its reputation tarnished by association with other biguanides despite evident differences. The ability of metformin to counter insulin resistance and address adult-onset hyperglycaemia without weight gain or increased risk of hypoglycaemia gradually gathered credence in Europe, and after intensive scrutiny metformin was introduced into the USA in 1995. Long-term cardiovascular benefits of metformin were identified by the UK Prospective Diabetes Study (UKPDS) in 1998, providing a new rationale to adopt metformin as initial therapy to manage hyperglycaemia in type 2 diabetes. Sixty years after its introduction in diabetes treatment, metformin has become the most prescribed glucose-lowering medicine worldwide with the potential for further therapeutic applications.
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http://dx.doi.org/10.1007/s00125-017-4318-zDOI Listing
September 2017

Under-treatment of type 2 diabetes: Causes and outcomes of clinical inertia.

Int J Clin Pract 2016 Dec;70(12):988-995

Diabetes Research, Life and Health Sciences, Aston University, Birmingham, UK.

Aims: To assess the impact of clinical inertia on type 2 diabetes (T2D) care.

Methods: PubMed database search from January 2000 until December 2015.

Results: Clinical inertia, defined as resistance to initiate or intensify treatment in a patient not at the evidence-based glycated haemoglobin goal, is conservatively estimated to occur in at least 25% of patients with T2D. Consequently, many patients with diagnosed and treated T2D experience extended periods, in some cases years, of ineffectively controlled hyperglycaemia, potentially causing serious microvascular and macrovascular harm. Delayed treatment does not appear to be specific to primary care, but also occurs in the specialist setting. The causes of clinical inertia appear to be complex, involving both reasonable and unacceptable delays on the part of the clinician and poor compliance with treatment regimens on the part of the patient. Evidence suggests that the clinical and organisational context may be particularly important in reinforcing clinical inertia, notably the increasingly severe time constraints for diagnosis and management of multiple morbidities, consideration of complex guidelines, assessment of cost and appreciation of patient concerns, all of which may hamper prioritisation of the important issue of under-treatment.

Conclusions: Since the pharmacotherapeutic tools for good control of blood glucose exist in all advanced healthcare systems, initiatives to address the important and widespread problem of clinical inertia may require focused campaigns that encourage attention to guideline recommendations and their adaptation for individualised care.
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http://dx.doi.org/10.1111/ijcp.12906DOI Listing
December 2016

Pharmacology and therapeutic implications of current drugs for type 2 diabetes mellitus.

Nat Rev Endocrinol 2016 Oct 24;12(10):566-92. Epub 2016 Jun 24.

School of Life and Health Sciences, Aston University, Birmingham, B4 7ET, UK.

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.
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http://dx.doi.org/10.1038/nrendo.2016.86DOI Listing
October 2016

Future glucose-lowering drugs for type 2 diabetes.

Lancet Diabetes Endocrinol 2016 Apr 23;4(4):350-9. Epub 2016 Jan 23.

Department of Diabetes and Endocrinology, Heart of England NHS Foundation Trust, Birmingham, UK; Centre for Endocrinology, Diabetes and Metabolism, University of Birmingham, Birmingham, UK.

The multivariable and progressive natural history of type 2 diabetes limits the effectiveness of available glucose-lowering drugs. Constraints imposed by comorbidities (notably cardiovascular disease and renal impairment) and the need to avoid hypoglycaemia, weight gain, and drug interactions further complicate the treatment process. These challenges have prompted the development of new formulations and delivery methods for existing drugs alongside research into novel pharmacological entities. Advances in incretin-based therapies include a miniature implantable osmotic pump to give continuous delivery of a glucagon-like peptide-1 receptor agonist for 6-12 months and once-weekly tablets of dipeptidyl peptidase-4 inhibitors. Hybrid molecules that combine the properties of selected incretins and other peptides are at early stages of development, and proof of concept has been shown for small non-peptide molecules to activate glucagon-like peptide-1 receptors. Additional sodium-glucose co-transporter inhibitors are progressing in development as well as possible new insulin-releasing biological agents and small-molecule inhibitors of glucagon action. Adiponectin receptor agonists, selective peroxisome proliferator-activated receptor modulators, cellular glucocorticoid inhibitors, and analogues of fibroblast growth factor 21 are being considered as potential new approaches to glucose lowering. Compounds that can enhance insulin receptor and post-receptor signalling cascades or directly promote selected pathways of glucose metabolism have suggested opportunities for future treatments. However, pharmacological interventions that are able to restore normal β-cell function and β-cell mass, normalise insulin action, and fully correct glucose homoeostasis are a distant vision.
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http://dx.doi.org/10.1016/S2213-8587(15)00462-3DOI Listing
April 2016

Metformin and the gastrointestinal tract.

Diabetologia 2016 Mar 16;59(3):426-35. Epub 2016 Jan 16.

Pearson Group, Division of Cardiovascular and Diabetes Medicine, School of Medicine, University of Dundee, Ninewells Hospital, Mailbox 12, Level 5, Dundee, DD1 9SY, UK.

Metformin is an effective agent with a good safety profile that is widely used as a first-line treatment for type 2 diabetes, yet its mechanisms of action and variability in terms of efficacy and side effects remain poorly understood. Although the liver is recognised as a major site of metformin pharmacodynamics, recent evidence also implicates the gut as an important site of action. Metformin has a number of actions within the gut. It increases intestinal glucose uptake and lactate production, increases GLP-1 concentrations and the bile acid pool within the intestine, and alters the microbiome. A novel delayed-release preparation of metformin has recently been shown to improve glycaemic control to a similar extent to immediate-release metformin, but with less systemic exposure. We believe that metformin response and tolerance is intrinsically linked with the gut. This review examines the passage of metformin through the gut, and how this can affect the efficacy of metformin treatment in the individual, and contribute to the side effects associated with metformin intolerance.
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http://dx.doi.org/10.1007/s00125-015-3844-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4742508PMC
March 2016

Age-associated changes in long-chain fatty acid profile during healthy aging promote pro-inflammatory monocyte polarization via PPARγ.

Aging Cell 2016 Feb 2;15(1):128-39. Epub 2015 Nov 2.

Life & Health Sciences, Aston University, Birmingham, B4 7ET, UK.

Differences in lipid metabolism associate with age-related disease development and lifespan. Inflammation is a common link between metabolic dysregulation and aging. Saturated fatty acids (FAs) initiate pro-inflammatory signalling from many cells including monocytes; however, no existing studies have quantified age-associated changes in individual FAs in relation to inflammatory phenotype. Therefore, we have determined the plasma concentrations of distinct FAs by gas chromatography in 26 healthy younger individuals (age < 30 years) and 21 healthy FA individuals (age > 50 years). Linear mixed models were used to explore the association between circulating FAs, age and cytokines. We showed that plasma saturated, poly- and mono-unsaturated FAs increase with age. Circulating TNF-α and IL-6 concentrations increased with age, whereas IL-10 and TGF-β1 concentrations decreased. Oxidation of MitoSOX Red was higher in leucocytes from FA adults, and plasma oxidized glutathione concentrations were higher. There was significant colinearity between plasma saturated FAs, indicative of their metabolic relationships. Higher levels of the saturated FAs C18:0 and C24:0 were associated with lower TGF-β1 concentrations, and higher C16:0 were associated with higher TNF-α concentrations. We further examined effects of the aging FA profile on monocyte polarization and metabolism in THP1 monocytes. Monocytes preincubated with C16:0 increased secretion of pro-inflammatory cytokines in response to phorbol myristate acetate-induced differentiation through ceramide-dependent inhibition of PPARγ activity. Conversely, C18:1 primed a pro-resolving macrophage which was PPARγ dependent and ceramide dependent and which required oxidative phosphorylation. These data suggest that a midlife adult FA profile impairs the switch from proinflammatory to lower energy, requiring anti-inflammatory macrophages through metabolic reprogramming.
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http://dx.doi.org/10.1111/acel.12416DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4717269PMC
February 2016