Incretin-based Therapies Research Articles

HNF4\u03b1 is a novel regulator of intestinal glucose-dependent insulinotropic polypeptide

Mutations in the HNF4A gene cause MODY1 and are associated with an increased risk of Type 2 diabetes mellitus. On the other hand, incretins are hormones that potentiate reductions in blood glucose levels. Given the established role of incretin-based therapy to treat diabetes and metabolic disorders, we investigated a possible regulatory link between intestinal epithelial HNF4α and glucose-dependent insulinotropic polypeptide (GIP), an incretin that is specifically produced by gut enteroendocrine cells. Conditional deletion of HNF4α in the whole intestinal epithelium was achieved by crossing Villin-Cre and Hnf4αloxP/loxP C57BL/6 mouse models. GIP expression was measured by qPCR, immunofluorescence and ELISA. Gene transcription was assessed by luciferase and electrophoretic mobility shift assays. Metabolic parameters were analyzed by indirect calorimetry and dual-energy X-ray absorptiometry. HNF4α specific deletion in the intestine led to a reduction in GIP. HNF4α was able to positively control Gip transcriptional activity in collaboration with GATA-4 transcription factor. Glucose homeostasis and glucose-stimulated insulin secretion remained unchanged in HNF4α deficient mice. Changes in GIP production in these mice did not impact nutrition or energy metabolism under normal physiology but led to a reduction of bone area and mineral content, a well described physiological consequence of GIP deficiency. Our findings point to a novel regulatory role between intestinal HNF4α and GIP with possible functional impact on bone density.

Incretin Mimetics as Rational Candidates for the Treatment of Traumatic Brain Injury.

Traumatic brain injury (TBI) is becoming an increasing public health issue. With an annually estimated 1.7 million TBIs in the United States (U.S) and nearly 70 million worldwide, the injury, isolated or compounded with others, is a major cause of short- and long-term disability and mortality. This, along with no specific treatment, has made exploration of TBI therapies a priority of the health system. Age and sex differences create a spectrum of vulnerability to TBI, with highest prevalence among younger and older populations. Increased public interest in the long-term effects and prevention of TBI have recently reached peaks, with media attention bringing heightened awareness to sport and war related head injuries. Along with short-term issues, TBI can increase the likelihood for development of long-term neurodegenerative disorders. A growing body of literature supports the use of glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and glucagon (Gcg) receptor (R) agonists, along with unimolecular combinations of these therapies, for their potent neurotrophic/neuroprotective activities across a variety of cellular and animal models of chronic neurodegenerative diseases (Alzheimer's and Parkinson's diseases) and acute cerebrovascular disorders (stroke). Mild or moderate TBI shares many of the hallmarks of these conditions; recent work provides evidence that use of these compounds is an effective strategy for its treatment. Safety and efficacy of many incretin-based therapies (GLP-1 and GIP) have been demonstrated in humans for the treatment of type 2 diabetes mellitus (T2DM), making these compounds ideal for rapid evaluation in clinical trials of mild and moderate TBI.

Incretin-based therapies for patients with type 1 diabetes: a meta-analysis.

ObjectiveCombined treatment with an incretin-based drug, such as a glucagon-like peptide 1 receptor agonist (GLP-1 RA) or a dipeptidyl peptidase-4 (DPP-4) inhibitor, and basal insulin is a new strategy for improving glucose control in type 1 diabetes mellitus (T1DM). We performed a meta-analysis to assess the effect of this combined treatment on glycaemic control, insulin dose, severe hypoglycaemia, weight gain and gastrointestinal side effects in T1DM patients.MethodsWe searched PubMed, EMBASE and the Cochrane Library for relevant studies published before July 16, 2018. The primary outcome was glycosylated haemoglobin (HbA1c). Secondary outcomes included total daily insulin dose, body weight, severe hypoglycaemia and gastrointestinal side effects.ResultsNine randomized controlled trials (RCTs) involving 2389 patients were ultimately included in the meta-analysis. The pooled data suggested that incretin-based therapy was associated with a reduction in HbA1c levels (weighted mean difference (WMD) −0.17%, 95% confidence interval (CI) −0.24 to −0.11, P < 0.001), total daily insulin dose (WMD −5.53 IU/day, 95% CI −8.89 to −2.17, P = 0.001) and body weight (WMD −3.24 kg, 95% CI −4.43 to −2.04, P < 0.001). Incretins did not increase the risk of severe hypoglycaemia (odds ratio (OR) 0.83, 95% CI 0.60–1.16, P = 0.287) but increased the occurrence of gastrointestinal side effects (OR 3.46, 95% CI 2.20–5.45, P < 0.001).ConclusionsIn T1DM patients, GLP-1 RAs, but not DPP-4 inhibitors, combined with insulin appear to be an effective therapy but may increase the occurrence of gastrointestinal side effects.

Comparison of biochemical parameters among DPP4 inhibitor users and other oral hypoglycaemic drug users: a cross-sectional study from Anuradhapura, Sri Lanka

BackgroundHigher efficacy of incretin-based therapies for type 2 diabetes mellitus has been reported from Asia. Pancreatitis and hepatitis have also been suspected to occur due to dipeptidyl peptidase-4 inhibitor (DPP4I) treatment. The present study aims at comparing selected biochemical parameters among DPP4 inhibitor users and other oral hypoglycaemic drug users.MethodsPatients were recruited from the State Pharmaceutical Corporation, Anuradhapura, Sri Lanka, for a comparative cross-sectional study. Two groups were involved: “DPP4I” user group (n = 63) and “other oral hypoglycaemic” user group (n = 126). Mann-Whitney U test was performed to find a significant difference (p < 0.05) in the distributions of HbA1C, pancreatic amylase, serum lipase, AST and ALT levels between the two groups.ResultsContradicting to previous Asian studies, distribution of HbA1C (p = 0.569) between anti-diabetic regimes with and without DPP4 inhibitors showed no significant difference. Also, amylase (p = 0.171), AST (p = 0.238) and ALT (p = 0.347) failed to show significance. However, lipase was significantly (p = 0.012) high in the DPP4I group.ConclusionThe study showed a significantly higher lipase level among the DPP4I users in comparison to other oral hypoglycaemic drug users, and possible reasons were discussed.

The effects of incretin-based therapies on β-cell function and insulin resistance in type 2 diabetes: A systematic review and network meta-analysis combining 360 trials.

To evaluate the comparative effects of incretin-based therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 inhibitors (DPP-4Is), on β-cell function and insulin resistance in patients with type 2 diabetes mellitus (T2DM). Medline, Embase, the Cochrane Library and www.clinicaltrials.gov were searched for randomized controlled trials (RCTs) with a duration of at least 4 weeks. Network meta-analysis was performed, followed by subgroup analysis and meta-regression. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the quality of evidence. Outcomes of interest include homeostasis model assessment for β cell function (HOMA-β) and insulin resistance (HOMA-IR), fasting C-peptide and fasting plasma glucose (FPG). Weighted mean difference (WMD) with 95% confidence interval (CI) was calculated as the measure of effect size. A total of 360 RCTs (74% at least double-blinded) with 157 696 patients were included. Incretin-based therapies were compared with six other classes of glucose-lowering drugs or with placebo. Compared with placebo, a significant increase in HOMA-β and fasting C-peptide was detected for GLP-1RAs (WMD = 20.31 [95% CI, 16.34-24.39] with low quality; WMD = 0.16 ng/mL [95% CI, 0.03-0.29] with low quality) and for DPP-4Is (WMD = 9.90 [95% CI, 8.27-11.61] with moderate quality; WMD = 0.09 ng/mL [95% CI, 0.04-0.14] with moderate quality) separately, while a significant reduction in HOMA-IR and FPG were found in favour of GLP-1RAs (WMD = -0.67 [95% CI, -1.08 to -0.27] with low quality; WMD = -1.04 mmol/L [95% CI, -1.26 to -0.83] with moderate quality) and DPP-4Is (WMD = -0.23 [95% CI, -0.38 to -0.08] with low quality; WMD = -0.77 mmol/L [95% CI, -0.98 to -0.57] with moderate quality), respectively. Incretin-based therapies not only show an increase in HOMA-β and fasting C-peptide level, but also achieve a reduction in HOMA-IR and FPG in comparison with placebo. Although GRADE scores indicate low to moderate for most comparisons, incretin-based therapies seem to be an advisable option for long-term treatment to preserve β-cell function.

Neurological Manifestation of Incretin-Based Therapies in Patients with Type 2 Diabetes: A Systematic Review and Network Meta-Analysis.

As a new class of antidiabetic drug, incretin-based therapies, which include dipeptidyl peptidase-4 inhibitors (DPP-4Is) and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have raised concerns about symptoms of withdrawal in patients with type 2 diabetes mellitus (T2DM), such as dizziness and headache. To systematically evaluate whether incretin-based therapies may lead to dizziness and headache in patients with T2DM compared to other traditional antidiabetic drugs or placebo. We searched Medline, Embase, the Cochrane library, and clinicaltrials.gov from inception through June 23, 2017, to identify randomized controlled trials of the safety of DPP-4Is or GLP-1 RAs versus placebo or other antidiabetic drugs in T2DM patients. We used the network meta-analysis under the frequentist framework to compare the association between multiple antidiabetic drugs and dizziness and headache. A total of 233 clinical trials with nine treatments and 147,710 patients were included: two incretin-based therapies, one placebo, and six traditional antidiabetic drugs (metformin, insulin, sulfonylurea, thiazolidinediones, alpha-glucosidase inhibitor, and sodium-glucose co-transporter 2). Compared to insulin, thiazolidinediones, or placebo, GLP-1 RAs statistically significantly increased the risk of dizziness (odds ratios [ORs]: 1.92, 1.57, and 1.40, respectively) and headache (ORs: 1.34, 1.41, and 1.18, respectively). DPP-4Is increased the risk of headache (OR: 1.22, 95% confidence interval [CI]: 1.02 to 1.46; moderate quality) and dizziness (OR: 1.46, 95% CI: 1.05 to 2.03; moderate quality) compared to insulin. Of the incretin-based therapies, DPP-4Is had a lower risk of dizziness than GLP-1 RAs (OR: 0.76, 95% CI: 0.67 to 0.87; high quality). Ranking probability analysis indicated that GLP-1 RAs may have the greatest risk of both dizziness and headache among the nine treatments (22.5% and 23.4%, respectively), whereas DPP-4Is were in the middle (46.2% and 45.0%, respectively). Incretin-based therapies increase the risk of dizziness and headache compared to insulin, thiazolidinediones, and placebo.

Metformin use is associated with a lower risk of uterine leiomyoma in female type 2 diabetes patients.

Background:Whether metformin may reduce the risk of uterine leiomyoma in type 2 diabetes patients has not been investigated. This retrospective cohort study compared the risk of uterine leiomyoma in ever versus never users of metformin.Methods:Female patients with new-onset type 2 diabetes during 1999–2005 were enrolled from the reimbursement database of Taiwan’s National Health Insurance and followed up from 1 January 2006 until 31 December 2011. Analyses were conducted in a propensity score (PS) matched-pair cohort of 10,998 ever users and 10,998 never users of metformin. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using the PS.Results:A total of 321 never users and 162 ever users developed uterine leiomyoma during follow up, with respective incidence of 704.65 and 329.82 per 100,000 person-years. The overall hazard ratio was 0.467 (95% confidence interval: 0.387–0.564). The hazard ratios for the first (<23.3 months), second (23.3–53.1 months), and third (>53.1 months) tertiles of cumulative duration were 0.881 (0.685–1.132), 0.485 (0.367–0.642), and 0.198 (0.134–0.291), respectively; and were 0.751 (0.576–0.980), 0.477 (0.360–0.632), and 0.277 (0.198–0.386), respectively, for the first (<655,000 mg), second 655,000–1,725,500 mg), and third (>1,725,500) tertiles of cumulative dose. Sensitivity analyses after excluding users of sulfonylurea, users of estrogen, users of insulin, users of incretin-based therapies during follow up, patients with irregular drug refills, patients who discontinued the use of metformin, patients who received metformin prescription less than four times, or redefining uterine leiomyoma by using ‘diagnostic code’ plus ‘procedure codes’ consistently supported a lower risk of uterine leiomyoma in ever users of metformin.Conclusion:Metformin use is associated with a lower risk of uterine leiomyoma.

The Role of Glucagon-Like Peptide 1 Receptor Agonists and Sodium-Glucose Cotransporter 2 Inhibitors in Reducing Cardiovascular Events in Patients with Type 2 Diabetes.

The prevalence of type 2 diabetes mellitus (T2DM), which is associated with cardiovascular morbidity and mortality, is increasing worldwide. Although there have been advances in diabetes treatments that reduce microvascular complications (nephropathy, neuropathy, retinopathy), many clinical studies have found that conventional oral hypoglycemic agents and glucose control alone failed to reduce cardiovascular disease. Thus, incretin-based therapies including glucagon-like peptide 1 (GLP-1) receptor agonists (RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT-2Is) represent a new area of research, and may serve as novel therapeutics for treating hyperglycemia and modifying other cardiovascular risk factors. Recently, it has been confirmed that several drugs in these classes, including canagliflozin, empagliflozin, semaglutide, and liraglutide, are safe and possess cardioprotective effects. We review the most recent cardiovascular outcome trials on GLP-1RAs and SGLT-2Is, and discuss their implications for treating patients with T2DM in terms of protective effects against cardiovascular disease.

Diabetes pharmacotherapy and effects on the musculoskeletal system.

Persons with type 1 or type 2 diabetes have a significantly higher fracture risk than age-matched persons without diabetes, attributed to disease-specific deficits in the microarchitecture and material properties of bone tissue. Therefore, independent effects of diabetes drugs on skeletal integrity are vitally important. Studies of incretin-based therapies have shown divergent effects of different agents on fracture risk, including detrimental, beneficial, and neutral effects. The sulfonylurea class of drugs, owing to its hypoglycemic potential, is thought to amplify the risk of fall-related fractures, particularly in the elderly. Other agents such as the biguanides may, in fact, be osteo-anabolic. In contrast, despite similarly expected anabolic properties of insulin, data suggests that insulin pharmacotherapy itself, particularly in type 2 diabetes, may be a risk factor for fracture, negatively associated with determinants of bone quality and bone strength. Finally, sodium-dependent glucose co-transporter 2 inhibitors have been associated with an increased risk of atypical fractures in select populations, and possibly with an increase in lower extremity amputation with specific SGLT2I drugs. The role of skeletal muscle, as a potential mediator and determinant of bone quality, is also a relevant area of exploration. Currently, data regarding the impact of glucose lowering medications on diabetes-related muscle atrophy is more limited, although preclinical studies suggest that various hypoglycemic agents may have either aggravating (sulfonylureas, glinides) or repairing (thiazolidinediones, biguanides, incretins) effects on skeletal muscle atrophy, thereby influencing bone quality. Hence, the therapeutic efficacy of each hypoglycemic agent must also be evaluated in light of its impact, alone or in combination, on musculoskeletal health, when determining an individualized treatment approach. Moreover, the effect of newer medications (potentially seeking expanded clinical indication into the pediatric age range) on the growing skeleton is largely unknown. Herein, we review the available literature regarding effects of diabetes pharmacotherapy, by drug class and/or by clinical indication, on the musculoskeletal health of persons with diabetes.

Thromboxane-Dependent Platelet Activation in Obese Subjects with Prediabetes or Early Type 2 Diabetes: Effects of Liraglutide- or Lifestyle Changes-Induced Weight Loss.

Thromboxane (TX)-dependent platelet activation and lipid peroxidation, as reflected in vivo by the urinary excretion of 11-dehydro-TXB2 and 8-iso-prostaglandin (PG)F2α, play a key role in atherothrombosis in obesity and type 2 diabetes mellitus (T2DM) since the earlier stages. Thirty-five metformin-treated obese subjects with prediabetes or newly-diagnosed T2DM were randomized to the glucagon-like peptide receptor agonist (GLP-RA) liraglutide (1.8 mg/day) or lifestyle counseling until achieving a comparable weight loss (−7% of initial body weight), to assess whether changes in subcutaneous (SAT) and visceral (VAT) adipose tissue distribution (MRI), insulin sensitivity (Matsuda Index) and beta-cell performance (multiple sampling OGTT beta-index), with either intervention, might affect TX-dependent platelet activation, lipid peroxidation and inflammation. At baseline, Ln-8-iso-PGF2α (Beta = 0.31, p = 0.0088), glycosylated hemoglobin (HbA1c) (Beta = 2.64, p = 0.0011) Ln-TNF-α (Beta = 0.58, p = 0.0075) and SAT (Beta = 0.14, p = 0.044) were significant independent predictors of 11-dehydro-TXB2. After achievement of the weight loss target, a comparable reduction in U-11-dehydro-TXB2 (between-group p = 0.679) and 8-iso-PGF-2α (p = 0.985) was observed in both arms in parallel with a comparable improvement in glycemic control, insulin sensitivity, SAT, high-sensitivity C-reactive protein (hs-CRP). In obese patients with initial impairment of glucose metabolism, the extent of platelet activation is related to systemic inflammation, isoprostane formation and degree of glycemic control and abdominal SAT. Successful weight loss, achieved with either lifestyle changes or an incretin-based therapy, is associated with a significant reduction in lipid peroxidation and platelet activation.

Systematic review of incretin therapy during peri-operative and intensive care

BackgroundGlucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are incretin hormones. By lowering blood glucose in a glucose-dependent manner, incretin-based therapies represent a novel and promising intervention to treat hyperglycaemia in hospital settings. We performed a systematic review of the literature for all current applications of incretin-based therapies in the peri-operative and critical care settings.MethodsWe searched MEDLINE, the Cochrane Library, and Embase databases for all randomised controlled trials using exogenous GLP-1, GLP-1 receptor agonists, exogenous GIP and dipeptidyl peptidase IV inhibitors in the setting of adult peri-operative care or intensive care. We defined no comparator treatment. Outcomes of interest included blood glucose, frequency of hypoglycaemia and insulin administration.ResultsOf the 1190 articles identified during the initial literature search, 38 fulfilled criteria for full-text review, and 19 single-centre studies were subsequently included in the qualitative review. Of the 18 studies reporting glycaemic control, improvement was reported in 15, defined as lower glucose concentrations in 12 and as reduced insulin administration (with similar glucose concentrations) in 3. Owing to heterogeneity, meta-analysis was possible only for the outcome of hypoglycaemia. This revealed an incidence of 7.4% in those receiving incretin-based therapies and 6.8% in comparator groups (P = 0.94).ConclusionsIn small, single-centre studies, incretin-based therapies lowered blood glucose and reduced insulin administration without increasing the incidence of hypoglycaemia.Trial registrationPROSPERO, CRD42017071926.

Examining the risk of depression or self-harm associated with incretin-based therapies used to manage hyperglycaemia in patients with type 2 diabetes: a cohort study using the UK Clinical Practice Research Datalink

ObjectivesTo compare population-based incidence rates of new-onset depression or self-harm in patients initiating incretin-based therapies with that of sulfonylureas (SU) and other glucose-lowering agents.DesignPopulation-based cohort study.SettingPatients attending primary care practices...

The Beneficial Effects of Switching from Dipeptidyl Peptidase-4 Inhibitors to Dulaglutide on Plasma Glucose and Hemoglobin A1c Levels: A Case Report of Four Patients with Type 2 Diabetes

Incretin-based therapy consists of dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists. Whether switching from DPP-4 inhibitors to one of the GLP-1 receptor agonists, dulaglutide, has greater beneficial effects remains unknown. Therefore, this study aimed to investigate the effectiveness of switching from DPP-4 inhibitors to dulaglutide in four patients with type 2 diabetes. All four patients with hyperglycemia who switched from DPP-4 inhibitors to dulaglutide demonstrated noticeable decreased plasma glucose levels on the next day after switching. Two of the patients observed maintained a decreased plasma glucose level over 14 day after switching. Moreover, all patients demonstrated decreased glycosylated hemoglobin A1c levels during the observation period (1-6 months) after switching and lost weight from 6 to 27 day. Minor and manageable hypoglycemia, nausea, and diarrhea were observed as side effects in one case. The current findings suggest that dulaglutide is a suitable treatment alternative in patients with type 2 diabetes who are not currently achieving adequate glycemic control with DPP-4 inhibitors.

Влияние новых ингибиторов дипептидилпептидазы IV на депрессивноподобное поведение мышей

Значительная часть пациентов с депрессивными расстройствами имеет признаки нарушения утилизации глюкозы и инсулинорезистентности. Изучается вопрос возможности и перспективности применения инкретин-направленных средств для лечения депрессивных состояний. Целью работы было изучение влияния новых ингибиторов дипептидилпептидазы IV (ДПП-4) на депрессивноподобное поведение аутбредных мышей. Методы. В работе использовали тест «Подвешивание за хвост». Влияние соединений изучали при их однократном или субхроническом внутрибрюшинном введении аутбредным мышам. Результаты. Выявлена выраженная антидепрессивная активность у новых ингибиторов ДПП-4 в тесте «Подвешивание за хвост» у мышей, превосходящая соответствующую активность Ситаглиптина и Вилдаглиптина, что указывает на перспективность использования инкретин-направленных средств для лечения депрессивных состояний. A large proportion of patients with anxiety-depressive disorders exhibit signs of impaired glucose utilization and insulin resistance. Consequently, incretin-based therapies for the treatment of depressive disorders have attracted considerable attention. The goal of this study was to evaluate the effect of new dipeptidyl peptidase IV (DPP4) inhibitors on depressive behavior in outbred mice. Methods. The tail suspension test was used. The compounds were administered to outbred mice intraperitoneally either once or subchronically. Results. New DPP4 inhibitors exhibited pronounced antidepressant activity in the tail suspension test in outbred mice exceeding the activity of Sitagliptin and Vildagliptin. The results indicate that incretin-based therapies show promise for the treatment of anxiety-depressive disorders.

Noninsulin medication therapy for hospitalized patients with diabetes mellitus.

Published evidence regarding the role of noninsulin antidiabetic therapies in glycemic management of hospitalized patients with diabetes mellitus is reviewed. The American Diabetes Association recommends against the routine use of noninsulin antidiabetic therapies during hospitalization and supports insulin use instead. There are significant risks associated with insulin therapy, including hypoglycemia, and use of alternative therapies may be considered in hospitalized patients. A MEDLINE literature search was conducted to find articles on studies evaluating the use of noninsulin antidiabetic therapies in the inpatient setting; all full-text English-language publications presenting observational and randomized clinical trial data on the topic of interest were considered for inclusion in the review, with 9 publications selected for review. The majority of the reviewed research focused on incretin-based therapies, and favorable safety and efficacy outcomes were reported with the use of dipeptidyl peptidase-4 (DPP-4) inhibitors. The available evidence indicates that the use of other noninsulin medications, including glucagon-like peptide-1 receptor agonists and sulfonylureas, to achieve and maintain glycemic control in the inpatient setting may be limited by adverse effects. Optimal glycemic control in hospitalized patients with diabetes is necessary to avoid adverse effects. Insulin therapy is currently the primary medication recommended for this patient population. DPP-4 inhibitors have been demonstrated to be safe and effective for use in the inpatient setting in patients with well-controlled diabetes. Further research is needed to help define the role of noninsulin medications in the inpatient setting.

Pancreatic Cancer and Diabetes Mellitus.

The relationship between pancreatic ductal adenocarcinoma (PDAC) and diabetes mellitus (DM) is complex. We reviewed the recent medical literature regarding the effect of anti-diabetic medication on PDAC risk and survival, risk of PDAC in DM, and role of DM in early detection of PDAC. Studies report that while some anti-diabetic medications (e.g., metformin) may decrease the risk of PDAC, others (insulin, sulfonylureas and incretin-based therapies) may increase the risk. However, these observations may be subject to protopathic biases. Metformin's anti-tumor activity may have influence overall survival of PDAC, but epidemiological reports have largely been inconsistent to defend these findings due to heterogeneous methodologies. There is congruent data to support the association between DM and PDAC, with an inverse relationship to DM duration. Older subjects with new-onset DM are the only known high-risk group for PDAC, and strategy using this group for early detection has led to development of clinical risk prediction models that define a very high-risk PDAC group. Role of anti-diabetic medication in PDAC risk modification or survival is controversial. With successful efforts to distinguish type 2-DM from PDAC-DM using risk-stratifying models, there is an opportunity to initiate screening protocols for early detection of PDAC in a sub-set of DM subjects.

Combination of SGLT-2 Inhibitors and GLP-1 Receptor Agonists: Potential Benefits in Surrogate and Hard Endpoints.

The treatment of type 2 diabetes mellitus (T2DM) is complex; only a few patients successfully attain glycemic targets with monotherapy, most requiring drug combination therapy. The goal of this review was to identify in PubMed the complimentary ways of action leading to clinical benefit (in lowering HbA1c, body weight, renal, and cardiac risk factors and events) of the combination of sodium glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA). SGLT2i, an emerging class of antidiabetic agents with an insulin-independent mechanism of action, are suitable for use in combination with any other class of antidiabetics, including insulin. The use of SGLT2i causes a reduction in Cardiovascular Disease (CVD) morbidity (mainly heart failure-HF) as well as total and CVD mortality. Besides insulin, SGLT2i may also be combined with incretin-based therapies, such as GLP-1 RA. The latter appears to reduce the rate or the progression of both macrovascular (mainly myocardial infarction-MI and stroke) and microvascular complications of DM, having a beneficial effect on all-cause mortality and CVD mortality, as well as CVD events. SGLT2i and GLP-1 RA may have a synergic effect on glucose reduction, weight reduction, renal impairment (both an independent lethal disease and a CVD risk factor) improvement, and cardiac event reduction, because the first reduces HF and related events and the second decreases CVD risk (mainly MI and stroke). Both also reduce total mortality, especially when combined with a statin. The combination of metformin with SGLT2i, GLP-1 RA, and a potent statin, in high CVD risk patients with DM, is expected to substantially reduce CVD mortality and morbidity, improving the quality of life of patients with DM at the same time. Prospective studies are needed to confirm this finding.

History and development of incretin effect: the evidence and promise of incretin-based therapies in the clinical practice

The discovery and development of incretin effect has changed the landscape of diabetes treatment over past decades. Nowadays, incretin-based agents, such as glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors have been wildly used in the therapy of type 2 diabetes. These agents show the beneficial effects on the multiple pathophysiological defects of type 2 diabetes, and provide a safe approach for achieving glycemic control with low risk of hypoglycemia and weight gain. Moreover, incretin-based therapies are still in development. Novel incretin-related therapies, such as fixed-dose combinations of GLP-1 receptor agonists and basal insulins, oral GLP-1 receptor agonists, and GLP-1 secretagogues, will be available in clinical practice in the near future. (Chin J Endocrinol Metab, 2018, 34: 629-633) Key words: Incretin; Glucagon-like peptide-1; Diabetes mellitus, type 2

Glucagon-Like Peptide 1 and Its Cleavage Products Are Renoprotective in Murine Diabetic Nephropathy.

Incretin-based therapies, including glucagon-like peptide 1 (GLP-1) receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors, are potent glucose-lowering drugs. Still, only GLP-1 receptor agonists with close peptide homology to GLP-1 (liraglutide and semaglutide) but neither exenatide-based GLP-1 receptor agonists nor DPP-4 inhibitors were found to reduce cardiovascular events. This different response might relate to GLP-1 receptor-independent actions of GLP-1 caused by cleavage products only liberated by GLP-1 receptor agonists with close peptide structure to GLP-1. To test this hypothesis, we directly compared metabolic, renal, and cardiac effects of GLP-1 and its cleavage products in diabetic db/db mice. Using an adeno-associated viral vector system, we overexpressed DPP-4-resistant GLP-1 (7-37 Mut8) and the two GLP-1 cleavage products, GLP-1 (9-37) and GLP-1 (28-37), in diabetic db/db mice. Only GLP-1 (7-37 Mut8), but none of the cleavage products, significantly improved glucose metabolism. Still, all GLP-1 constructs significantly reduced tubulointerstitial renal damage, lowered expression of the tubular injury markers, and attenuated renal accumulation of macrophages and T cells. This was associated with a systemic immunomodulatory effect, which was similarly found in an acute renal ischemia/reperfusion injury model. In conclusion, GLP-1 cleavage products proved sufficient to mediate organ-protective effects, which might help to explain differences between GLP-1 receptor agonists.

Risk of heart failure hospitalization among users of dipeptidyl peptidase-4 inhibitors compared to glucagon-like peptide-1 receptor agonists

BackgroundIncretin-based therapies including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon like peptide-1 (GLP-1) receptor agonists are novel medications for type 2 diabetes management. Several studies have found cardioprotective effects of incretin-based therapies; however, it remains unclear whether there is any difference in heart failure (HF) risk between the two incretin-based therapies (DPP-4 inhibitors and GLP-1 receptor agonists). We aimed to assess the risk of hospitalization due to HF with the use of DPP-4 inhibitors compared to GLP-1 receptor agonists.MethodsUsing Truven Health Marketscan data, we conducted a retrospective cohort study of patients with type 2 diabetes, who were newly initiated on DPP-4 inhibitors or GLP-1 agonists. Follow-up continued from drug initiation until the first occurrence of: HF hospitalization (primary outcome), discontinuation of therapy (i.e. no fill for 7 days), switch to the comparator, end of enrollment, or end of study (December 2013). Cox proportional hazards models with propensity-score-matching were used to compare the risk of HF hospitalization between DPP-4 inhibitors and GLP-1 agonists.ResultsA total of 321,606 propensity score-matched patients were included in the analysis (n = 160,803 for DPP-4 inhibitors; n = 160,803 for GLP-1 agonists). After adjusting for baseline characteristics and disease risk factors, the use of DPP-4 inhibitors was associated with a 14% decreased risk of HF hospitalization compared to GLP-1 agonists use [hazard ratio (HR), 0.86; 95% confidence interval (CI) 0.83, 0.90]. The results were consistent in patients without baseline HF (HR, 0.85; 95% CI 0.82, 0.89), but the association was not statistically significant for patients with baseline HF (HR, 0.90; 95% CI 0.74, 1.07).ConclusionIn this retrospective matched cohort of patients with type 2 diabetes, the use of DPP-4 inhibitors was associated with a reduced risk of HF hospitalization compared to GLP-1 agonists. However, the association was not statistically significant in patients who had HF prior to the use of DPP-4 inhibitors.