glucagon-like-peptide-1 and Peripheral-Arterial-Disease

Peripheral arterial disease (PAD) is a common macrovascular complication of diabetes mellitus (DM). Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RAs) are among the latest class of antidiabetic medications that stimulate insulin synthesis and secretion and have been used for the management of type 2 DM. Apart from the effect on glycaemic control, GLP-1RAs also have a robust impact on weight reduction and have shown favorable effects on cardiovascular morbidity and mortality in cardiovascular outcome trials (CVOTs). The aim of this review was to examine the impact of GLP1-RAs on PAD among people with DM based on CVOTs, randomized controlled trials, observational studies as well as systematic reviews and meta-analyses. Data from retrospective studies and meta-analyses have shown superiority of these agents in comparison with other antidiabetic medications such as sodium-glucose cotransporter type 2 inhibitors and dipeptidyl peptidase-4 inhibitors in terms of PAD-related events. Nevertheless, data from CVOTs regarding the impact of GLP-1RAs on PAD are scarce and hence, safe conclusions regarding their effects cannot be drawn. Further prospective studies are needed to examine the impact of GLP-1RAs on PAD-related incidents including major adverse limb events, lower limb amputations and revascularization procedures.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Peripheral Arterial Disease; Retrospective Studies

The purpose of this review is to highlight the evidence behind landmark trials involving these two novel drug classes in conjunction with a review of long-standing therapies used to improve cardiovascular (CV) outcomes among patients with peripheral artery disease (PAD) patients and type 2 diabetes mellitus (T2DM).. Recently, societal guideline recommendations have expanded the management of T2DM to incorporate therapies with CV risk factor modification. This is due to CV outcome trials (CVOT) uncovering advantageous cardioprotective effects of several novel therapies, including glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i). Providers who manage high-risk patients with T2DM, such as those with concomitant PAD, are expected to incorporate these novel medical therapies into routine patient care. The body of evidence surrounding GLP-1 RA demonstrates a strong benefit in mitigating the innate heightened CV risk among patients with T2DM. Furthermore, SGLT2i not only have a favorable CV profile but also reduce the risk of HF hospitalizations and progression of renal disease. Patients with T2DM and PAD are known to be at a heightened risk for major adverse cardiac and lower extremity events, heart failure, and chronic kidney disease. As such, the use of novel therapies such as GLP-RA and SGLT2i should be strongly considered to minimize morbidity and mortality in this vulnerable population.

Topics: Cardiovascular Diseases; Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1; Glucagon-Like Peptide-1 Receptor; Humans; Hypoglycemic Agents; Peripheral Arterial Disease; Sodium-Glucose Transporter 2 Inhibitors

Dipeptidyl peptidase IV (DPP-IV) is a complex enzyme that acts as a membrane-anchored cell surface exopeptidase and transmits intracellular signals through a small intracellular tail. DPP-IV exists in human blood in a soluble form, and truncates a large number of peptide hormones, chemokines, cytokines, and growth factors in vitro and in vivo. DPP-IV has gained considerable interest as a therapeutic target, and a variety of DPP-IV inhibitors that prolong the insulinotropic effects of glucagon-like peptide-1 (GLP-1) are widely used in clinical settings as antidiabetic drugs. Indeed, DPP-IV is upregulated in proinflammatory states, including obesity and cardiovascular disease with and without diabetes mellitus. Consistent with this maladaptive role, DPP-IV inhibitors seem to exert a protective role in cardiovascular disease. In addition to their GLP-1-dependent vascular protective actions, DPP-IV inhibitors exhibit GLP-1-independent beneficial effects on angiogenesis/neovascularization via several signaling pathways (e.g., stromal cell-derived factor-1α/C-X-C chemokine receptor type-4, vascular endothelial growth factor-A/endothelial nitric oxide synthase, etc.). This review focuses on recent findings in this field, highlighting the role of DPP-IV in therapeutic angiogenesis/neovascularization in ischemic heart disease and peripheral artery disease.

Topics: Dipeptidyl-Peptidase IV Inhibitors; Glucagon-Like Peptide 1; Humans; Myocardial Ischemia; Neovascularization, Physiologic; Peripheral Arterial Disease; Signal Transduction

Results of clinical trials suggest that canagliflozin, a sodium-glucose cotransporter 2 (SGLT-2) inhibitor for treating type 2 diabetes, may be associated with lower extremity amputation.. To quantify the association between the use of oral medication for type 2 diabetes and 5 outcomes (lower extremity amputation, peripheral arterial disease, critical limb ischemia, osteomyelitis, and ulcer).. A retrospective cohort study was conducted using Truven Health MarketScan Commercial Claims and Encounters data on new users between September 1, 2012, and September 30, 2015. The study focused on 2.0 million commercially insured individuals and used propensity score weighting to balance baseline differences among groups. Sensitivity analyses varied statistical models, assessed the effect of combining dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists as a single referent group, adjusted for baseline use of older oral agents, and included people with baseline amputation.. New use of SGLT-2 inhibitors alone, DPP-4 inhibitors alone, GLP-1 agonists alone, or other antidiabetic agents (sulfonylurea, metformin hydrochloride, or thiazolidinediones).. Foot and leg amputation, defined by validated International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes.. Among 2.0 million potentially eligible individuals, a total of 953 906 (516 046 women and 437 860 men; mean [SD] age, 51.8 [10.9] years) were included in the final analyses, including 39 869 new users of SGLT-2 inhibitors (4.2%), 105 023 new users of DPP-4 inhibitors (11.0%), and 39 120 new users of GLP-1 agonists (4.1%). The median observation time ranged from 99 days for new users of GLP-1 agonists to 127 days for those using metformin, sulfonylureas, and thiazolidinediones, while the crude incident rates ranged from 4.90 per 10 000 person-years for those using metformin, sulfonylureas, and thiazolidinediones to 10.53 per 10 000 person-years for new users of SGLT-2 inhibitors. After propensity score weighting and adjustment for demographics, severity of diabetes, comorbidities, and medications, there was a nonstatistically significant increased risk of amputation associated with new use of SGLT-2 inhibitors compared with DPP-4 inhibitors (adjusted hazard ratio, 1.50; 95% CI, 0.85-2.67) and GLP-1 agonists (adjusted hazard ratio, 1.47; 95% CI, 0.64-3.36). New use of SGLT-2 inhibitors was statistically significantly associated with amputation compared with sulfonylureas, metformin, or thiazolidinediones (adjusted hazard ratio, 2.12; 95% CI, 1.19-3.77). These results persisted in sensitivity analyses.. Use of SGLT-2 inhibitors may be associated with increased risk of amputation compared with some oral treatments for type 2 diabetes. Further observational studies are needed with extended follow-up and larger sample sizes.

Topics: Amputation, Surgical; Blood Glucose; Canagliflozin; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Drug Therapy, Combination; Female; Follow-Up Studies; Glucagon-Like Peptide 1; Humans; Incidence; Lower Extremity; Male; Middle Aged; Peripheral Arterial Disease; Population Surveillance; Propensity Score; Retrospective Studies; Sodium-Glucose Transporter 2 Inhibitors; United States