From glucose lowering agents to disease/diabetes modifying drugs: a "SIMPLE" approach for the treatment of type 2 diabetes.

During the last decade we experienced a surge in the number of glucose lowering agents that can be used to treat patients with type 2 diabetes. Especially important are the discoveries that sodium glucose co-transporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve patients' cardiovascular and renal outcomes. Accordingly, various medical associations have updated their guidelines for the treatment of diabetes in this new era. Though not agreeing on every issue, these position-statements generally share a detailed and often complex workflow that may be too complicated for the busy and overworked primary care setting, where the majority of patients with type 2 diabetes are managed in many countries. Other guidelines, generally those from the cardiology associations focus primarily on the population of patients with high risk for or pre-existing cardiovascular disease, which represent only the minority of patients with type 2 diabetes. We believe that we should re-define SGLT2i and GLP-1 RA as diabetes/disease modifying drugs (DMDs) given the recent evidence of their cardiovascular and renal benefits. Based on this definition we have designed a SIMPLE approach in order to assist primary care teams in selecting the most appropriate therapy for their patients. We believe that most subjects newly diagnosed with type 2 diabetes should initiate early combination therapy with metformin and a prognosis changing DMD. The decision whether to use GLP-1 RA or SGLT2i should be made based on specific patient's risk factors and preferences. Importantly, DMDs are known to have a generally safe side-effect profile, with lower risk for hypoglycemia and weight gain, further promoting their wider usage. Early combination therapy with DMDs may improve the multiple pathophysiological abnormalities responsible for type 2 diabetes and its complications, thus resulting in the greatest long term benefits.

SGLT2 inhibitors and GLP1 agonists administered without metformin compared to other glucose-lowering drugs in patients with type 2 diabetes mellitus to prevent cardiovascular events: A systematic review.

OBJECTIVES: To assess the efficacy of glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose co-transporter 2 (SGLT2) inhibitors, administered without metformin on cardiovascular outcomes in type 2 diabetes patients. METHODS: A systematic review was performed according to Cochrane's methodological standards. We included randomized clinical trials (RCTs) on adult type 2 diabetes patients, assessing the efficacy of SGLT2 inhibitors and GLP1-RAs compared to other glucose-lowering drugs and/or RCTs that presented data of a subgroup of type 2 diabetes patients without metformin use at baseline. The main outcome was the reduction of the risk of any major adverse cardiovascular events (MACE) reported individually or as a composite outcome. RESULTS: Five RCTs including 50,725 type 2 diabetes patients, of whom 10,013 had not received metformin, were included in this meta-analysis. Three of these studies assessed the efficacy of GLP1-RAs and two of SGLT2 inhibitors. In patients without metformin at baseline, GLP1-RAs in comparison with placebo reduced the risk of MACE significantly by 20% (HR: 0.80; 95% CI: 0.71-0.89). SGLT2 inhibitors also significantly reduced the risk of MACE by 32% (HR: 0.68; 95% CI: 0.57-0.81). CONCLUSIONS: SGLT2 inhibitors and GLP1-RAs provided without metformin at baseline may reduce the risk of MACE in comparison with placebo in type 2 diabetes patients at increased risk of cardiovascular events.

Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis.

AIMS: We aimed to assess the comparative efficiency and safety of the use of glyburide, metformin, and insulin in gestational diabetes mellitus (GDM). METHODS: We searched for randomized controlled trials that compared glyburide, metformin, and insulin in GDM. Data regarding glycemic control and neonatal safety were collected and analyzed in pairwise and network meta-analyses. RESULTS: A total of 4533 individuals from 23 trials were included. Compared with glyburide, metformin reduced 2-h postprandial blood glucose (2HPG) to a greater extent (standard mean difference (SMD) 0.18; 95% credible interval (CI) 0.01, 0.34). There were significantly lower prevalence of neonatal hypoglycemia (risk difference (RD) - 0.07; 95%CI - 0.11, - 0.02) and preeclampsia (RD - 0.03; 95%CI - 0.06, 0) in the metformin group than in the insulin group. The metformin group had significantly lower birth weight (SMD - 0.17; 95%CI - 0.25, - 0.08) and maternal weight gain (SMD - 0.61; 95%CI - 0.86,- 0.35) compared with the insulin group. Network meta-analysis suggested that metformin had the highest probability of successfully controlling glycemia and preventing neonatal complications. CONCLUSIONS: The present meta-analysis suggests that metformin may be as effective as insulin for glycemic control and is the most promising drug for the prevention of neonatal and maternal complications.

The association between diabetes medication and weight change in a non-surgical weight management intervention: an intervention cohort study.

AIM: To compare weight change in a lifestyle-based weight management programme between participants taking weight-gaining, weight-neutral/loss and mixed diabetes medications. METHODS: Electronic health records for individuals (≥ 18 years) with Type 2 diabetes who had been referred to a non-surgical weight management programme between February 2008 and May 2014 were studied. Diabetes medications were classified into three categories based on their effect on body weight. In this intervention cohort study, weight change was calculated for participants attending two or more sessions. RESULTS: All 998 individuals who took oral diabetes medications and attended two or more sessions of weight management were included. Some 59.5% of participants were women, and participants had a mean BMI of 41.1 kg/m2 (women) and 40.2 kg/m2 (men). Of the diabetes medication combinations prescribed, 46.0% were weight-neutral/loss, 41.3% mixed and 12.7% weight-gaining. The mean weight change for participants on weight-gaining and weight-neutral/loss diabetes medications respectively was -2.5 kg [95% confidence interval (CI) -3.2 to -1.8) and -3.3 kg (95% CI -3.8 to -2.9) (P = 0.05) for those attending two or more sessions (n = 998). Compared with those prescribed weight-neutral medications, participants prescribed weight-gaining medication lost 0.86 kg less (95% CI 0.02 to 1.7; P = 0.045) in a model adjusted for age, sex, BMI and socio-economic status. CONCLUSIONS: Participants on weight-neutral/loss diabetes medications had a greater absolute weight loss within a weight management intervention compared with those on weight-gaining medications. Diabetes medications should be reviewed ahead of planned weight-loss interventions to help ensure maximal effectiveness of the intervention.

Intensive monitoring of adverse drug events associated with the use of new glucose-lowering drugs: results from an inception cohort study in Portugal.

AIMS: To determine the frequency and the time-course profile of adverse drug events associated with new glucose-lowering drugs in daily practice and to explore factors potentially associated to these events. METHODS: An inception cohort study was implemented. Adults with type 2 diabetes mellitus initiating a dipeptidyl peptidase-4 inhibitor, a glucagon-like peptide-1 receptor agonist or a sodium-glucose co-transporter-2 inhibitor were eligible for inclusion. Data were collected through baseline and follow-up telephone questionnaires, administered at 2 weeks, 3 months and 6 months. Kaplan-Meier curves and log-rank were computed to compare the time to adverse drug event onset. Cox models were used to explore potential factors associated with adverse drug events. RESULTS: A total of 1328 participants were recruited to the study. In all, 1118 adverse drug events were reported (of which 36% were not listed in the summary of product characteristics) by 41% of participants. The median latency time of adverse drug events reported in ≥1% of participants ranged from 0 to 2 days. Glucagon-like peptide-1 receptor agonist and sodium-glucose co-transporter-2 inhibitor subgroups were associated with an increased likelihood of adverse drug event reporting when compared with the dipeptidyl peptidase-4 inhibitor subgroup. A total of 328 glucose-lowering drugs were withdrawn, more than half as a result of an adverse drug event. CONCLUSIONS: More than two-fifths of participants reported an adverse drug event; dipeptidyl peptidase-4 inhibitors led to the highest proportion of unlabelled adverse drug events. Adverse drug event latency time data show that counselling and adverse drug event management should be proactively addressed from treatment initiation. There should be greater focus on prevalent new users of glucose-lowering drugs, who were more complex participants in this study in terms of type 2 diabetes disease, as they were more likely to report an adverse drug event than the incident new users.

Management of type 2 diabetes using non-insulin glucose-lowering therapies: a critical appraisal of clinical practice guidelines with the AGREE II instrument.

AIM: Type 2 diabetes is a major global epidemic affecting over 400 million people worldwide. The objective of this systematic review was to provide an overview of recommendations from clinical practice guidelines (guidelines) addressing non-insulin based pharmacological management of among non-pregnant adults in an outpatient setting, and critically appraise their methodological development. METHODS: We systematically searched MEDLINE and Embase databases, for relevant guidelines using the Ovid interface. We scanned the bibliographies of all eligible guidelines for additional relevant citations. Teams of two reviewers, independently and in duplicate, screened titles and abstracts and potentially eligible full text reports to determine eligibility and appraised the reporting quality of guidelines using the Advancing Guideline Development, Reporting and Evaluation in Health Care instrument II (AGREE II) instrument. RESULTS: Our search yielded 11264 unique citations, of which 124 were retrieved for full-text review; 17 guidelines proved eligible. The highest scoring AGREE domain was 'clarity of presentation' (66%; range 7-92%), followed by 'scope and purpose' (58%; range 25-92%), 'editorial independence' (55%; range 0-91%), 'stakeholder involvement' (45%; range 11-90%) and 'rigour of development' (43%; range 4-92%). The poorest domain was 'applicability' (37%; range 6-84%). The guidelines authored by the World Health Organization group achieved the highest AGREE overall score. CONCLUSIONS: Most of the guidelines provided recommendations with a local jurisdictional focus and showed significant variation in the quality. Nevertheless, only a small number of those scored well overall.

Renal outcomes with the newer antidiabetes drugs: the era before and after CREDENCE.

In 2008, the US Food and Drug Administration provided guidance for the evaluation of the cardiovascular safety of antidiabetes drugs. The newer antidiabetes drugs, approved after 2008, were therefore evaluated in long-term cardiovascular outcome trials, designed and powered for the assessment of cardiovascular safety. Accordingly, the primary endpoint of these trials was a cardiac composite endpoint. Since 2008, the data from various cardiovascular outcome trials have been reported, including SAVOR-TIMI 53 (saxagliptin), EXAMINE (alogliptin), TECOS (sitagliptin), CARMELINA (linagliptin), CAROLINA (linagliptin), ELIXA (lixisenatide), LEADER (liraglutide), EXSCEL (exenatide once-weekly), SUSTAIN-6 (injectable semaglutide), HARMONY Outcomes (albiglutide), REWIND (dulaglutide), PIONEER-6 (oral semaglutide), EMPA-REG OUTCOME (empagliflozin), the CANVAS Program (canagliflozin) and DECLARE-TIMI 53 (dapagliflozin). Some of these trials subsequently also published data on renal outcomes, although these were secondary or exploratory analyses. Dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists had beneficial effects on albuminuria, while sodium-glucose co-transporter-2 inhibitors additionally showed a positive effect on 'hard' renal outcomes. In contrast to the cardiovascular outcome trials, the renal outcome trial of canagliflozin, CREDENCE, assessed a hard renal endpoint as its primary endpoint and showed positive effects on these hard renal outcomes. In this review, we aim to highlight the renal outcome data from the cardiovascular outcome trials and the CREDENCE trial and understand the differences between their results. The post CREDENCE era would appear to reinforce the position of sodium-glucose co-transporter-2 inhibitors as drugs providing cardiorenal protection, in addition to their anti-glycaemic effects.

Primary versus secondary cardiorenal prevention in type 2 diabetes: Which newer anti-hyperglycaemic drug matters?

We are observing a resurgence of major diabetic vascular complications after a period of dramatic decrease during the period 1990 to 2010. The classical division of cardiovascular prevention into primary (with an event) and secondary (without an event) is largely used to describe cardiovascular risk in type 2 diabetes (T2D); however, there is evidence that the cardiovascular risk in diabetes may range from highest in patients who experienced a previous cardiovascular event to mild in patients with the main risk factors at target. Herein, we present details of the 14 cardiovascular outcome trials (CVOTs) published to date, including the total population investigated, and their separation into primary (T2D + multiple risk factors) and secondary prevention (T2D + established cardiovascular disease [CVD]) populations as detailed within the trials. We also summarize evidence for the effects of dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP1-RA) and sodium glucose co-transporter-2 inhibitors (SGLT-2i) versus placebo on the risk of major cardiovascular events (MACE), heart failure (HF) and diabetic kidney disease (DKD). In primary prevention, SGLT-2i reduce both the risk of hospitalization for HF and progression of DKD; in secondary prevention, SGLT-2i are effective on the three endpoints, DPP-4i are neutral, while GLP1-RA show mixed results.

Fournier's gangrene in patients with type 2 diabetes using second-line antidiabetic medications.

Cases of a rare but serious infection called Fournier's gangrene have been reported with sodium-glucose co-transporter-2 inhibitors (SGLT-2i). To evaluate the safety signal in a population of patients with type 2 diabetes, we used administrative claims data from Horizon Blue Cross Blue Shield of New Jersey from 2014 through 2017 to estimate incidence rates of Fournier's gangrene or necrotizing fasciitis of the perineum among patients treated with a second-line antidiabetic drug. We found very low incidence rates of Fournier's gangrene or necrotizing fasciitis. While we found no indication of an increased risk among SGLT-2i users compared with similar patients treated with other second-line antidiabetic medications, the small number of events yielded wide confidence intervals.

Trends in antidiabetic drug utilization and expenditure in Denmark: A 22-year nationwide study.

AIMS: To examine the nationwide trends in antidiabetic drug utilization and expenditure in Denmark over the past 22 years. METHODS: Data on antidiabetic use and expenditure from 1996 to 2017 were retrieved from the Register of Medicinal Product Statistics. Antidiabetic drug use is reported as defined daily dose (DDD) in total counts and per 1000 inhabitants/d. Expenditure is reported as volume sold in total counts per 1000 inhabitants and as annual mean expenditure. RESULTS: Throughout the study period, the total use of antidiabetic drugs increased from 16.4 to 55.8 DDDs per 1000 inhabitants/d, while total expenditure increased from €59 to €286 m. The introduction of glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors and sodium-glucose co-transporter-2 inhibitors has, since 2005, led to considerable variation in the proportional use of the different drug classes. Use of insulin and insulin analogues accounted for the majority of the cost of antidiabetic drugs, peaking at 75% in 2008; however, its proportional impact on overall antidiabetic drug expenditure decreased to ~44% in 2017. In contrast, a steep increase in GLP-1RA expenditure was observed from 2010 to 2017, reaching an annual cost of €85 m (~29% of all antidiabetic expenditure). CONCLUSION: Antidiabetic drug utilization and cost in Denmark has increased considerably over the last 22 years, in accordance with the increased incidence of type 2 diabetes and changes in treatment guidelines. The release of several novel antidiabetic drugs seems to be responsible for the increase in antidiabetic drug expenditure.

Antidiabetic Drugs in Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review.

INTRODUCTION: Considering that Alzheimer's disease (AD) and diabetes mellitus share pathophysiological features and AD remains with no cure, antidiabetic drugs like intranasal insulin, glitazones, metformin, and liraglutide are being tested as a potential treatment. OBJECTIVE: The aim of this systematic review was to assess the efficacy of antidiabetic drugs in patients with AD, mild cognitive impairment (MCI), or subjective cognitive complaints (SCCs). Cognition was studied as the primary outcome and modulation of AD biomarkers, and imaging was also assessed as a secondary outcome. METHODS: We conducted a search in the electronic databases PubMed/MEDLINE, EMBASE, and Scopus seeking clinical trials evaluating the effect on cognition of antidiabetic drugs in patients with AD, MCI, or SCCs. RESULTS: A total of 23 articles were found eligible. Intranasal regular insulin improved verbal memory in most studies, especially in apoE4- patients, but results in other cognitive domains were unclear. Detemir improved cognition after 2 months of treatment, but it did not after 4 months. Pioglitazone improved cognition in diabetic patients with AD or MCI in 3 clinical trials, but it is controversial as 2 other studies did not show effect. Metformin and liraglutide showed promising results, but further research is needed as just 2 clinical trials involved each of these drugs. Almost all drugs tested were shown to modulate AD biomarkers and imaging. CONCLUSIONS: Intranasal insulin, pioglitazone, metformin, and liraglutide are promising drugs that could be useful in the treatment of AD. However, many questions remain to be answered in future studies, so no particular antidiabetic drug can currently be recommended to treat AD.

Diabetes Mellitus and Cardiovascular Disease.

Cardiovascular disease remains a leading cause of morbidity and mortality in people with types 1 or 2 diabetes mellitus. Although beneficial roles for strict control of hyperglycemia have been suggested, such a strategy is not without liabilities. Specifically, the risk of hypoglycemia and its consequences remain an omnipresent threat with such approaches. The advent of the CVOT (Cardiovascular Outcomes Trials) for new antidiabetes mellitus treatments has uncovered unexpected benefits of cardiovascular protection in some of the new classes of agents, such as the GLP-1 RAs (glucagon-like peptide-1 receptor agonists) and the SGLT-2 (sodium-glucose cotransporter-2) inhibitors. Further, state-of-the-art approaches, such as antibodies to PCKSK9 (proprotein convertase subtilisin-kexin type 9); RNA therapeutics; agents targeting distinct components of the immune/inflammatory response; and novel small molecules that block the actions of RAGE (receptor for advanced glycation end products) signaling, also hold potential as new therapies for diabetes mellitus and cardiovascular disease. Finally, interventions such as weight loss, through bariatric surgery, may hold promise for benefit in diabetes and cardiovascular disease. In this Brief Review, some of the novel approaches and emerging targets for the treatment of diabetes mellitus and cardiovascular disease are discussed. Ultimately, identification of the optimal timing and combinations of such interventions, especially in the context of personalized approaches, together with emerging disease-modifying agents, holds great promise to reduce the burden that diabetes poses to the cardiovascular system.

Decision aids for people with Type 2 diabetes mellitus: an effectiveness rapid review and meta-analysis.

AIMS: To perform a rapid review and meta-analysis of randomized controlled trials (RCTs) evaluating patient decision aids (PtDAs) for people with Type 2 diabetes mellitus. METHODS: We searched Medline and the Cochrane Library for RCTs assessing PtDAs in people with Type 2 diabetes. PtDAs were defined as tools designed to help people engage in decision-making about healthcare options, such as making treatment choices or setting therapeutic goals. The study selection process was facilitated by an automated screening tool to identify RCTs. We classified outcomes into seven domains and conducted meta-analyses using random effects models. RESULTS: We included a total of 15 studies, nine of which were cluster RCTs, that evaluated 10 PtDAs. Thirteen trials compared a PtDA with usual care or usual care plus educational material, whereas two RCTs compared individually tailored vs. non-tailored PtDAs. Meta-analyses showed a favourable effect of PtDAs compared with usual care in reducing decisional conflict [weighted mean difference (WMD) -4.66, 95% confidence interval (CI) -7.93 to -1.39] and in improving knowledge (WMD 20.46, 95% CI 9.13 to 3.77). Use of PtDAs resulted in more active involvement in decision-making during the consultation, although no effect was evident in terms of glycaemic control or self-reported medication adherence. CONCLUSIONS: PtDAs for people with Type 2 diabetes can improve the quality of decision-making and increase knowledge transfer. Interpretation of our findings is attenuated due to limitations related to the rapid review approach, including searching only two databases and performing data extraction and risk of bias assessment by a single reviewer.

Non-insulin treatments for Type 1 diabetes: critical appraisal of the available evidence and insight into future directions.

Intensive insulin therapy is the mainstay of treatment for people with Type 1 diabetes, but hypoglycaemia and weight gain are often limiting factors in achieving glycaemic targets and decreasing the risk of diabetes-related complications. The inclusion of pharmacological agents used traditionally in Type 2 diabetes as adjuncts to insulin therapy in Type 1 diabetes has been explored, with the goal of mitigating such drawbacks. Pramlintide and metformin result in modest HbA1c and weight reductions, but their use is limited by poor tolerability and, in the case of pramlintide, by frequency of injections and cost. The addition of glucagon-like peptide-1 receptor agonists to insulin results in improved glycaemic control, reduced insulin doses and weight loss, but this is at the expense of higher rates of hypoglycaemia and hyperglycaemia with ketosis. Sodium-glucose co-transporter-2 and dual sodium-glucose co-transporter-2 and -1 inhibitors also improve glucose control, but with reductions in weight and insulin requirements potentiating the risk of acidosis-related events and hypoglycaemia. The high proportion of people with Type 1 diabetes not achieving glycaemic targets, the negative clinical impact of intensive insulin therapy and the rise in obesity and cardiovascular disease and mortality, underline the need for individualized clinical care. The evaluation of new therapies, effective in Type 2 diabetes, as adjuncts to insulin therapy represents a promising strategy, particularly given the beneficial effects on cardiovascular and renal outcomes in people with Type 2 diabetes with or at high risk of complications that are also observed in patients with Type 1 diabetes. As the population with Type 1 diabetes ages, our mission is to evolve and provide better tools and improved therapies to excel, not only in glycaemic control but also in risk reduction and reduction of complications.

Effect of SGLT2 inhibitors on cardiovascular, renal and safety outcomes in patients with type 2 diabetes mellitus and chronic kidney disease: A systematic review and meta-analysis.

AIM: The use of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD) has been limited, primarily because glycaemic efficacy is dependent on kidney function. We performed a systematic review and meta-analysis to assess the efficacy and safety of SGLT2 inhibitors in patients with T2DM and CKD, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 . MATERIALS AND METHODS: We searched MEDLINE, EMBASE and the Cochrane Library until 7 August 2018 and websites of the US, European and Japanese regulatory authorities until 27 July 2018 for data from randomized controlled trials of SGLT2 inhibitors that included reporting of effects on biomarkers, cardiovascular, renal or safety outcomes in individuals with T2DM and CKD. Random effects models and inverse variance weighting were used to calculate relative risks with 95% confidence intervals. RESULTS: Data were obtained from 27 studies with up to 7363 participants involved. In patients with T2DM and CKD, SGLT2 inhibitors lowered glycated haemoglobin (-0.29%; 95% CI, -0.39 to -0.19) as well as blood pressure, body weight and albuminuria. SGLT2 inhibition reduced the risk of cardiovascular death, nonfatal myocardial infarction or nonfatal stroke (RR, 0.81; 95% CI, 0.70-0.94) and heart failure (RR, 0.61; 95% CI, 0.48-0.78), without a clear effect on all-cause mortality (HR, 0.86; 95% CI, 0.73-1.01). These agents also attenuated the annual decline in eGFR slope (placebo-subtracted difference of 1.35 mL/1.73 m2 /y; 95% CI, 0.78-1.93) and reduced the risk of the composite renal outcome (HR, 0.71; 95% CI, 0.53-0.95). There was no evidence of additional risks with SGLT2 inhibition in CKD beyond those already known for the class, although heterogeneity was observed across individual agents for some safety outcomes. CONCLUSION: Currently available data suggest that, despite only modest reductions in glycated haemoglobin, SGLT2 inhibitors reduce the risk of cardiovascular and renal outcomes in patients with T2DM and CKD, without clear evidence of additional safety concerns.

Managing Diabetes and Preventing Heart Disease: Have We Found a Safe and Effective Agent?

OBJECTIVE: While improving glycemic control with antihyperglycemics has been demonstrated to reduce microvascular complications, the benefits of reduction in cardiovascular diseases (CVDs) have not been demonstrated with older agents. This article reviews current evidence of the CV outcomes of newer antihyperglycemics approved since 2008. DATA SOURCES: Peer-reviewed articles were identified from MEDLINE (1966 to October 31, 2018) using search terms exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide, alogliptin, linagliptin, saxagliptin, sitagliptin, canagliflozin, dapagliflozin, empagliflozin, mortality, myocardial infarction (MI), heart failure (HF), and stroke. STUDY SELECTION AND DATA EXTRACTION: A total of 12 pertinent double-blinded randomized controlled trials were included. DATA SYNTHESIS: Liraglutide, empagliflozin, and canagliflozin have been shown in patients with CV diseases and high risk of developing CV disease to be superior to placebo in improving CV outcomes. Saxagliptin and alogliptin have both been demonstrated to increase HF hospitalization, whereas sitagliptin has not. Relevance to Patient Care and Clinical Practice: In contrast to older-generation antihyperglycemics, selected new antihyperglycemic agents have been shown to be superior to placebo in improving CV outcomes. Clinicians may now be able to provide high-risk patients agents that not only help in providing glycemic control, but also prevent both macrovascular and microvascular complications. CONCLUSION: Liraglutide, empagliflozin, and canagliflozin have been shown to be superior to placebo in improving CV outcomes. However, there are differences among agents in terms of HF and peripheral arterial disease outcomes. Future studies should focus on evaluating other clinical CV outcomes in patients without existing CVD and perhaps single drug regimens for diabetes.

Impact of differing glucose-lowering regimens on the pattern of association between glucose control and survival.

AIMS: To characterize survival in relation to achieved glycated haemoglobin (HbA1c) level within alternative glucose-lowering regimens with differing risks of hypoglycaemia. METHODS: Data were extracted from the UK Clinical Practice Research Datalink and the corresponding Hospital Episode Statistics. Patients with type 2 diabetes prescribed glucose-lowering therapy in monotherapy or dual therapy with metformin between 2004 and 2013 were identified. Risk of all-cause mortality within treatment cohorts was evaluated using the Cox proportional hazards model, introducing mean HbA1c as a quarterly updated, time-dependent covariable. RESULTS: There were 6646 deaths in a total follow-up period of 374 591 years. Survival for lower (<7%) vs moderate HbA1c levels (≥7%, <8.5%) differed by cohort: metformin, adjusted hazard ratio (aHR) 1.03 (95% confidence interval [CI] 0.95-1.12); sulphonylurea, aHR 1.11 (95% CI 0.99-1.25); insulin, aHR 1.47 (95% CI 1.25-1.72); combined regimens with low hypoglycaemia risk, aHR 1.02 (95% CI 0.94-1.10); and combined regimens with higher hypoglycaemia risk excluding insulin, aHR 1.24 (95% CI 1.13-1.35) and including insulin, aHR 1.28 (95% CI 1.18-1.37). Higher HbA1c levels were associated with increased mortality in regimens with low hypoglycaemia risk. Post hoc analysis by HbA1c deciles revealed an elevated risk of all-cause mortality for the lowest deciles across all cohorts, but particularly in those regimens associated with hypoglycaemia. High HbA1c was associated with no difference, or a small increase in mortality risk in regimens with increased risk of hypoglycaemia. CONCLUSIONS: The pattern of mortality risk across the range of HbA1c differed by glucose-lowering regimen. Lower HbA1c was associated with increased mortality risk compared with moderate control, especially in those regimens associated with hypoglycaemia. High levels of HbA1c were associated with the expected elevated mortality risk in regimens with low hypoglycaemia risk.

Oral diabetes medications other than dipeptidyl peptidase 4 inhibitors are not associated with bullous pemphigoid: A Finnish nationwide case-control study.

BACKGROUND: Dipeptidyl peptidase 4 inhibitors (DPP4is) used to treat diabetes have been reported to be associated with an increased risk of bullous pemphigoid (BP). There are no previous reports analyzing the risk of BP in patients who are using other diabetes medications. OBJECTIVE: To evaluate the association between diabetes medications other than DPP4i and development of BP. METHODS: We investigated the prevalence of diabetes among patients with BP and the association between the use of diabetes drugs (excluding DPP4i, metformin, and insulin) and BP by analyzing national Finnish registry data for 3397 patients with BP and 12,941 patients with basal cell carcinoma as controls. RESULTS: Our results show that 19.6% of patients with BP have type 2 diabetes. Use of none of the investigated medications was associated with an increased risk of BP. LIMITATIONS: Because this was a registry-based study, it was not possible to verify the accuracy of the diagnoses. The risk of BP in users of glucagon-like peptide 1 receptor agonists could not be analyzed. CONCLUSION: Our study shows that the investigated diabetes drugs are not associated with an increased risk of BP in a Finnish patient database, indicating they can be safely used in this population. Generalization of these results to other populations will require further study.

HYPOGLYCEMIA IN THE ELDERLY WITH DIABETES: A GROWING PROBLEM WITH EMERGING SOLUTIONS.

Hypoglycemia is the major side effect of insulin therapy. The elderly are especially vulnerable to episodes of hypoglycemia, and with greater risks of complications such as falls. Two new long-acting basal insulins, glargine-300 (Gla-300) and degludec, are associated with lower incidences of hypoglycemia than previously available basal insulins. One of them, Gla-300, was studied in the elderly and has a lower incidence of hypoglycemia in patients over 65 years old. These new data should be incorporated into decision making when treating the elderly patient with insulin, whether they have type 1 or 2 diabetes. ABBREVIATIONS: A1c = glycated hemoglobin A1c Gla-100 = glargine 100 U/mL Gla-300 = glargine 300 U/mL GLP-1 RA = glucagon-like peptide-1 receptor analogue.

Impact of an integrated care program on glycemic control and cardiovascular risk factors in patients with type 2 diabetes in Saudi Arabia: an interventional parallel-group controlled study.

BACKGROUND: Long intervals between patient visits and limited time with patients can result in clinical inertia and suboptimal achievement of treatment goals. These obstacles can be improved with a multidisciplinary care program. The present study aimed to assess the impact of such a program on glycemic control and cardiovascular risk factors. METHODS: In a randomized, parallel-group trial, we assigned 263 patients with poorly controlled type 2 diabetes mellitus (T2DM) to either a control group, standard care program, or a multidisciplinary care program involving a senior family physician, clinical pharmacy specialist, dietician, diabetic educator, health educator, and social worker. The participants were followed for a median of 10 months, between September 2013 and September 2014. Glycated hemoglobin (HbA1c), fasting blood glucose (FBG), lipid profiles, and blood pressure (BP) were measured. The assignment was blinded for the assessors of the study outcomes. The study registry number is. RESULTS: In the intervention group, there were statistically significant (p < 0.05) post-intervention (relative) reductions in the levels of HbA1c (-27.1%, 95% CI = -28.9%, -25.3%), FBG (-17.10%, 95% CI = -23.3%, -10.9%), total cholesterol (-9.93%, 95% CI = -12.7%, -7.9%), LDL cholesterol (-11.4%, 95% CI = -19.4%, -3.5%), systolic BP (-1.5%, 95% CI = -2.9%, -0.03%), and diastolic BP (-3.4%, 95% CI = -5.2%, -1.7%). There was a significant decrease in the number of patients with a HbA1c ≥10 (86 mmol/mol) from 167 patients at enrollment to 11 patients after intervention (p < 0.001). However, the intervention group experienced a statistically significant increase in body weight (3.7%, 95% CI = 2.9%, 4.5%). In the control group, no statistically significant changes were noticed in different outcomes with the exception of total cholesterol (-4.10%, p = 0.07). In the linear regression model, the intervention and the total number of clinic visits predicted HbA1c improvement. CONCLUSIONS: Implementation of a patient-specific integrated care program involving a multidisciplinary team approach, frequent clinic visits, and intensified insulin treatment was associated with marked improvement in glycemic control and cardiovascular risk factors of poorly controlled T2DM patients in a safe and reproducible manner. TRIAL REGISTRATION: ISRCTN Identifier: ISRCTN83437562 September 19, 2016 Retrospectively registered.