The clinical utility of C-peptide measurement in the care of patients with diabetes

This is the final version of the article. Available from the publisher via the DOI in this record.C-peptide is produced in equal amounts to insulin and is the best measure of endogenous insulin secretion in patients with diabetes. Measurement of insulin secretion using C-peptide can be helpful in clinical practice: differences in insulin secretion are fundamental to the different treatment requirements of Type 1 and Type 2 diabetes. This article reviews the use of C-peptide measurement in the clinical management of patients with diabetes, including the interpretation and choice of C-peptide test and its use to assist diabetes classification and choice of treatment. We provide recommendations for where C-peptide should be used, choice of test and interpretation of results. With the rising incidence of Type 2 diabetes in younger patients, the discovery of monogenic diabetes and development of new therapies aimed at preserving insulin secretion, the direct measurement of insulin secretion may be increasingly important. Advances in assays have made C-peptide measurement both more reliable and inexpensive. In addition, recent work has demonstrated that C-peptide is more stable in blood than previously suggested or can be reliably measured on a spot urine sample (urine C-peptide:creatinine ratio), facilitating measurement in routine clinical practice. The key current clinical role of C-peptide is to assist classification and management of insulin-treated patients. Utility is greatest after 3-5 years from diagnosis when persistence of substantial insulin secretion suggests Type 2 or monogenic diabetes. Absent C-peptide at any time confirms absolute insulin requirement and the appropriateness of Type 1 diabetes management strategies regardless of apparent aetiology

More on STAT1 Gain of Function, Type 1 Diabetes, and JAK Inhibition

This is the final version. Available from the Massachusetts Medical Society via the DOI in this recor

Future Roadmaps for Precision Medicine Applied to Diabetes: Rising to the Challenge of Heterogeneity.

Precision medicine, the concept that specific treatments can be targeted to groups of individuals with specific genetic, cellular, or molecular features, is a key aspect of modern healthcare, and its use is rapidly expanding. In diabetes, the application of precision medicine has been demonstrated in monogenic disease, where sulphonylureas are used to treat patients with neonatal diabetes due to mutations in ATP-dependent potassium (KATP) channel genes. However, diabetes is highly heterogeneous, both between and within polygenic and monogenic subtypes. Making the correct diagnosis and using the correct treatment from diagnosis can be challenging for clinicians, but it is crucial to prevent long-term morbidity and mortality. To facilitate precision medicine in diabetes, research is needed to develop a better understanding of disease heterogeneity and its impact on potential treatments for specific subtypes. Animal models have been used in diabetes research, but they are not translatable to humans in the majority of cases. Advances in molecular genetics and functional laboratory techniques and availability and sharing of large population data provide exciting opportunities for human studies. This review will map the key elements of future diabetes research in humans and its potential for clinical translation to promote precision medicine in all diabetes subtypes.This article is freely available online via Open Access

Prior event rate ratio adjustment produced estimates consistent with randomized trial: a diabetes case study

Objectives: Electronic health records (EHR) provide a valuable resource for assessing drug side-effects, but treatments are not randomly allocated in routine care creating the potential for bias. We conduct a case study using the Prior Event Rate Ratio (PERR) Pairwise method to reduce unmeasured confounding bias in side-effect estimates for two second-line therapies for type 2 diabetes, thiazolidinediones, and sulfonylureas. Study design and settings: Primary care data were extracted from the Clinical Practice Research Datalink (n = 41,871). We utilized outcomes from the period when patients took first-line metformin to adjust for unmeasured confounding. Estimates for known side-effects and a negative control outcome were compared with the A Diabetes Outcome Progression Trial (ADOPT) trial (n = 2,545). Results: When on metformin, patients later prescribed thiazolidinediones had greater risks of edema, HR 95% CI 1.38 (1.13, 1.68) and gastrointestinal side-effects (GI) 1.47 (1.28, 1.68), suggesting the presence of unmeasured confounding. Conventional Cox regression overestimated the risk of edema on thiazolidinediones and identified a false association with GI. The PERR Pairwise estimates were consistent with ADOPT: 1.43 (1.10, 1.83) vs. 1.39 (1.04, 1.86), respectively, for edema, and 0.91 (0.79, 1.05) vs. 0.94 (0.80, 1.10) for GI. Conclusion: The PERR Pairwise approach offers potential for enhancing postmarketing surveillance of side-effects from EHRs but requires careful consideration of assumptions.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.The MASTERMIND (MRC APBI Stratification and Extreme Response Mechanism IN Diabetes) consortium is funded by the U.K Medical Research Council funded study grant number MR/N00633X/1. The funder had no role in study design, data collection, data analysis, data interpretation, or writing of the report. IQVIA provided some funding for this project.published version, accepted version (12 month embargo), submitted versio

Development of oedema is associated with an improved glycaemic response in patients initiating thiazolidinediones: a MASTERMIND study

Abstracts of the 51st EASD Annual Meeting, Stockholm, Sweden, 14–18 September 2015This is the author accepted manuscript. The final version is available from Springer VerlagBackground and aims: Oedema is a common and serious side effect of thiazolidinedione therapy. A stratified medicines approach would aim to give thiazolidinediones to patients likely to have a good glycaemic response but to not develop oedema. We investigated whether oedema was associated with glycaemic response to thiazolidinedione therapy. Materials and methods: We retrospectively studied 11,459 patients initiating a thiazolidinedione from UK primary care data (Clinical Practice Research Datalink), and identified medical records of new oedema in the subsequent twelve months. Response was defined as change in HbA1c at twelve months and was adjusted for baseline HbA1c, baseline BMI, gender and compliance (medication possession ratio). In secondary analyses we restricted oedema classification to patients with concomitant weight gain. As a comparison the same analysis was performed in 13,089 patients initiating a sulfonylurea. Results: The 5% of patients with recorded oedema on thiazolidinediones had a mean (CI) 2.2 (1.1-3.2)mmol/mol greater fall in HbA1c (p3 kg (p< 0.001) and a 3.6 (1.8-5.4)mmol/mol greater fall when weight gain >5 kg (p3 kg (p=0.19). Conclusion: Patients with Type 2 diabetes who develop oedema on initiating thiazolidinediones have an improved glycaemic response, and more severe oedema may be associated with greater reductions in HbA1c. An association between oedema and glycaemic response was not observed in patients initiating sulfonylureas. This supports glycaemic lowering and fluid retention being mediated by a common pathway of thiazolidinedione drug action.Supported by: MRC grant MR-K005707-

What to do with diabetes therapies when HbA1c lowering is inadequate:add, switch, or continue? A MASTERMIND study

This is the author accepted manuscript. The final version is available from BioMed Central via the DOI in this record.Background: It is unclear what to do when people with type 2 diabetes have had no or a limited glycemic response to a recently introduced medication. Intra-individual HbA1c variability can obscure true response. Some guidelines suggest stopping apparently ineffective therapy, but no studies have addressed this issue. Methods: In a retrospective cohort analysis using the UK Clinical Practice Research Datalink (CPRD), we assessed the outcome of 55,530 patients with type 2 diabetes starting their second or third non-insulin glucose lowering medication, with a baseline HbA1c >58mmol/mol (7.5%). For those with no HbA1c improvement or a limited response at 6 months (HbA1c fall <5.5mmol/mol [0.5%]) we compared HbA1c 12 months later in those who continued their treatment unchanged, switched to new treatment, or added new treatment. Results: An increase or a limited reduction in HbA1c was common, occurring in 21.9% (12,168/55,230), who had a mean HbA1c increase of 2.5mmol/mol (0.2%). After this limited response, continuing therapy was more frequent (n=9,308; 74%) than switching (n=1,177; 9%) or adding (n=2,163; 17%). Twelve months later, in those who switched medication HbA1c fell (-6.8mmol/mol [-0.6%], 95%CI -7.7, -6.0) only slightly more than those who continued unchanged (-5.1 mmol/mol [-0.5%], 95%CI -5.5, -4.8). Adding another new therapy was associated with a substantially better reduction (-12.4mmol/mol [-1.1%], 95%CI -13.1, -11.7). Propensity score matched subgroups demonstrated similar results. Conclusions: Where glucose lowering therapy does not appear effective on initial HbA1c testing, changing agents does not improve glycemic control. The initial agent should be continued with another therapy added.Medical Research Council (MRC)National Institute for Health Research (NIHR

Patients who develop oedema on initiating thiazolidinedione therapy have an improved glycaemic response: a MASTERMIND study

Special Issue: Abstracts of the Diabetes UK Professional Conference 2015, ExCeL London, 11–13 March 2015This is the author accepted manuscript. The final version is available from WileyBackground/aim: Oedema is a common and serious side effect ofthiazolidinedione therapy. A stratified medicine approach wouldaim to give thiazolidinediones to patients likely to have a goodglycaemic response but not to develop oedema. We investigatedwhether oedema was associated with glycaemic response tothiazolidinedione therapy.Methods: We studied 10,486 patients initiating a thiazolidinedionefrom Clinical Practice Research Datalink (CPRD), and identifiedmedical records of oedema in the subsequent 12 months. Responsewas defined as change in HbA1c at 12 months and was adjusted forbaseline HbA1c, baseline body mass index, gender and adherence(medication possession ratio). In secondary analyses we restrictedoedema classification to patients with concomitant weight gain. As acomparison the same analysis was performed in 13,089 patientsinitiating a sulfonylurea.Results: The 3% of patients with recorded oedema onthiazolidinediones had a mean (confidence interval) 3 (1.7–4.3)mmol/mol greater fall in HbA1c (p 3kg (p 8kg (p 3kg (p=0.19).Conclusion: Patients with Type 2 diabetes who develop oedemaon initiating thiazolidinediones have an improved glycaemicresponse, and more severe oedema is associated with greaterHbA1c reduction. This supports glycaemic lowering andfluid retention being mediated by a common pathway ofthiazolidinedione drug action

Two decades since the fetal insulin hypothesis: what have we learned from genetics?

This is the final version. Available from Springer via the DOI in this record. Data availability: This review did not generate any new data.In 1998 the fetal insulin hypothesis proposed that lower birthweight and adult-onset type 2 diabetes are two phenotypes of the same genotype. Since then, advances in research investigating the role of genetics affecting insulin secretion and action have furthered knowledge of fetal insulin-mediated growth and the biology of type 2 diabetes. In this review, we discuss the historical research context from which the fetal insulin hypothesis originated and consider the position of the hypothesis in light of recent evidence. In summary, there is now ample evidence to support the idea that variants of certain genes which result in impaired pancreatic beta cell function and reduced insulin secretion contribute to both lower birthweight and higher type 2 diabetes risk in later life when inherited by the fetus. There is also evidence to support genetic links between type 2 diabetes secondary to reduced insulin action and lower birthweight but this applies only to loci implicated in body fat distribution and not those influencing insulin resistance via obesity or lipid metabolism by the liver. Finally, we also consider how advances in genetics are being used to explore alternative hypotheses, namely the role of the maternal intrauterine environment, in the relationship between lower birthweight and adult cardiometabolic disease.Wellcome TrustNational Institute of Health Research (NIHR)Royal Societ

Studies of insulin and proinsulin in pancreas and serum support the existence of aetiopathological endotypes of type 1 diabetes associated with age at diagnosis

Aims/hypothesis: It is unclear whether type 1 diabetes is a single disease or if endotypes exist. Our aim was to use a unique collection of pancreas samples recovered soon after disease onset to resolve this issue. Methods: Immunohistological analysis was used to determine the distribution of proinsulin and insulin in the islets of pancreas samples recovered soon after type 1 diabetes onset (<2 years) from young people diagnosed at age <7 years, 7-12 years and ≥13 years. The patterns were correlated with the insulitis profiles in the inflamed islets of the same groups of individuals. C-peptide levels and the proinsulin:C-peptide ratio were measured in the circulation of a cohort of living patients with longer duration of disease but who were diagnosed in these same age ranges. Results: Distinct patterns of proinsulin localisation were seen in the islets of people with recent-onset type 1 diabetes, which differed markedly between children diagnosed at <7 years and those diagnosed at ≥13 years. Proinsulin processing was aberrant in most residual insulin-containing islets of the younger group but this was much less evident in the group ≥13 years (p < 0.0001). Among all individuals (including children in the middle [7-12 years] range) aberrant proinsulin processing correlated with the assigned immune cell profiles defined by analysis of the lymphocyte composition of islet infiltrates. C-peptide levels were much lower in individuals diagnosed at <7 years than in those diagnosed at ≥13 years (median <3 pmol/l, IQR <3 to <3 vs 34.5 pmol/l, IQR <3-151; p < 0.0001), while the median proinsulin:C-peptide ratio was increased in those with age of onset <7 years compared with people diagnosed aged ≥13 years (0.18, IQR 0.10-0.31) vs 0.01, IQR 0.009-0.10 pmol/l; p < 0.0001). Conclusions/interpretation: Among those with type 1 diabetes diagnosed under the age of 30 years, there are histologically distinct endotypes that correlate with age at diagnosis. Recognition of such differences should inform the design of future immunotherapeutic interventions designed to arrest disease progression.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.We are grateful to Diabetes UK for financial support via project grant 16/0005480 (to NGM and SJR) and to JDRF for a Career Development Award to SJR (5-CDA-2014-221-A-N). The research was performed with the support of the Network for Pancreatic Organ Donors with Diabetes (nPOD), a collaborative type 1 diabetes research project sponsored by JDRF. Organ Procurement Organizations (OPO) partnering with nPOD to provide research resources are listed at http://www.jdrfnpod.org//for-partners/npod-partners/. ATH and BMS are supported by the NIHR Exeter Clinical Research Facility. BMS is supported as part of the MRC MASTERMIND consortium. TJM is funded by an NIHR clinical senior lecturer fellowship. ATH is supported by a Wellcome Trust Senior Investigator Award (WT098395/Z/12/Z) and an NIHR Senior Investigator award. RAO is supported by a Diabetes UK Harry Keen Fellowship.published version, accepted version (12 month embargo

Are the new drugs better? Changing UK prescribing of Type 2 diabetes medications and effects on HbA1c and weight, 2010 to 2016

This is the author accepted manuscript. The final version is available from Wiley via the DOI in this record.Aim: The availability of new glucose‐lowering drugs has changed UK National Institute of Clinical Excellence Type 2 diabetes guidelines, but there has been little evaluation of real‐world use of these drugs, or of the population‐level impact of their use. We examined changes in UK prescribing for patients starting second‐ and third‐line medications, and population‐level trends in glycaemic response and weight change. Methods: We extracted incident second‐ and third‐line oral prescription records for patients with Type 2 diabetes in the UK‐representative Clinical Practice Research Datalink, 2010 to 2016 (n = 68,902). Each year we calculated the proportion of each drug prescribed as the percentage of the total prescribed. We estimated annual mean six‐month HbA1c response and weight change using linear regression, standardised for clinical characteristics. Results: Use of Dipeptidyl peptidase‐4 (DPP4) inhibitors has increased markedly to overtake sulfonylureas as the most commonly prescribed second‐line drug in 2016 (43% vs 34% of total prescriptions compared with 18% v 59% in 2010). Use of sodium‐glucose co‐transporter‐2 (SGLT2) inhibitors has increased rapidly to 14% of second‐line and 27% of third‐line prescriptions in 2016. Mean HbA1c response at six months was stable over time (2016: 13.5 (95% confidence interval 12.8, 14.1) mmol/mol vs 2010: 13.9 (13.6;14.2) mmol/mol, p = 0.21). We found mean weight loss at six months in 2016, in contrast to 2010 where there was mean weight gain (2016: −1.2 (−0.9; −1.5) kg vs 2010: +0.4 (+0.3; +0.5) kg, p < 0.001). Conclusion: The pattern of drug prescribing to manage patients with Type 2 diabetes has changed rapidly in the United Kingdom. Increasing use of DPP4 inhibitors and SGLT2 inhibitors has not resulted in improved glycaemic control but has improved the body weight of patients starting second‐ and third‐line therapy. Acknowledgement: This abstract is submitted on behalf of the MASTERMIND consortium