2022 Canadian Cardiovascular Society Guideline for Use of GLP-1 Receptor Agonists and SGLT2 Inhibitors for Cardiorenal Risk Reduction in Adults.

This guideline synthesizes clinical trial data supporting the role of glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors (SGLT2i) for treatment of heart failure (HF), chronic kidney disease, and for optimizing prevention of cardiorenal morbidity and mortality in patients with type 2 diabetes. It is on the basis of a companion systematic review and meta-analysis guided by a focused set of population, intervention, control, and outcomes (PICO) questions that address priority cardiorenal end points. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system and a modified Delphi process were used. We encourage comprehensive assessment of cardiovascular (CV) patients with routine measurement of estimated glomerular filtration rate, urinary albumin-creatinine ratio, glycosylated hemoglobin (A1c), and documentation of left ventricular ejection fraction (LVEF) when evaluating symptoms of HF. For patients with HF, we recommend integration of SGLT2i with other guideline-directed pharmacotherapy for the reduction of hospitalization for HF when LVEF is > 40% and for the reduction of all-cause and CV mortality, hospitalization for HF, and renal protection when LVEF is ≤ 40%. In patients with albuminuric chronic kidney disease, we recommend integration of SGLT2i with other guideline-directed pharmacotherapy to reduce all-cause and CV mortality, nonfatal myocardial infarction, and hospitalization for HF. We provide recommendations and algorithms for the selection of glucagon-like peptide-1 receptor agonists and SGLT2i for patients with type 2 diabetes and either established atherosclerotic CV disease or risk factors for atherosclerotic CV disease to reduce all-cause and CV mortality, nonfatal stroke, and for the prevention of hospitalization for HF and decline in renal function. We offer practical advice for safe use of these diabetes-associated agents with profound cardiorenal benefits.

Facilitating barriers: Contextual factors and self-management of type 2 diabetes in urban settings.

Urban environments create unique challenges for the management of type 2 diabetes (T2D). City living is associated with unhealthy occupational, nutritional, and physical activity patterns. However, it has also been linked to behaviours that promote health, such as walking and cycling for transportation. Our research is situated at the intersection of these contradictory findings. We ask: What aspects of urban living impact the ability of those living with diabetes to reach optimal health? What contextual and structural factors influence how barriers are experienced in the everyday lives of those living with T2D? We conducted semi-structured interviews with 29 individuals living in Toronto and Vancouver. Interviews were recorded, transcribed, and systematically coded for themes and sub-themes. In addition to affirming readily acknowledged barriers to diabetes management, such as accessing healthy, culturally appropriate food and the cost of management, our findings suggest that the unpredictable nature of urban living creates barriers to routinizing self-management practices. As large, cosmopolitan centres with an abundance of activities on offer, cities pulls people away from home, making adherence to self-management recommendations more difficult. Moreover, our findings challenge commonly held assumptions about the mutually exclusive and static nature of barriers and facilitators. Public transit, a readily acknowledged facilitator of healthy living, can be experienced as a barrier to diabetes management. Participants report intentional non-adherence to their medication regimens for fear of hypoglycemia in subway or traffic delays. While the stimulating nature of cities promotes walkability, it produces barriers as well: participants partake in more restaurant eating than they would if they lived in a rural area and were home to cook their own meals. Understanding how barriers are experienced by people living with diabetes will help mitigate some of the unintended consequences associated with various contextual factors. We recommend that healthcare professionals acknowledge and support people with T2D in routinizing self-management and developing contingency plans for the unpredictability and complexity that urban living entails. We suggest further research be carried out to develop contextually-tailored municipal policies and interventions that will support self-management and improve outcomes for individuals living with T2D in urban settings.

CardioDiabetes: Core Competencies for Cardiovascular Clinicians in a Rapidly Evolving Era of Type 2 Diabetes Management.

A sea change in the management of diabetes is occurring with the publication of clinical trials showing unequivocal cardiovascular (CV) protection through the use of certain antihyperglycemic agents. This change is similar to the change that occurred when lipid lowering with statins was first shown to have CV benefits, an event necessitating changes in training and the proactive treatment of lipids by CV specialists. As was the case then, many CV specialists currently feel poorly equipped to address diabetes with this new information even though diabetes is common in CV practice. The purpose of this overview is to provide an updated, comprehensive, and evidence-based CV protection plan for patients with type 2 diabetes, intended specifically for cardiologists and vascular medicine specialists. We attempt to elucidate a set of "CardioDiabetes" core competencies by merging the CV-relevant elements of the Diabetes Canada 2018 guidelines within a framework of comprehensive vascular protection as supported by other CV guidelines. We review the rationale for measuring hemoglobin A1C, understanding its use for establishing a diagnosis and for monitoring treatment. We also provide a brief review of the medications most important for a CV specialist to know. We provide useful memory aids and a succinct set of reminders and tips ("ABCDEFR'S") that can serve as a comprehensive checklist in the clinic and help to motivate trainees and clinicians to consult the original guideline source documents to enrich their knowledge and improve treatment in this rapidly changing arena.

A Practical Guide to the Use of Glucose-Lowering Agents With Cardiovascular Benefit or Proven Safety.

Patients with type 2 diabetes continue to have a high residual risk for cardiovascular events despite intensive risk factor modification. Recent clinical trials have shown that the antihyperglycemic agents empagliflozin and liraglutide reduce cardiovascular events. Other drugs have been shown to have cardiovascular safety. With glucose-lowering agents proven to reduce adverse cardiovascular outcomes, many cardiologists have begun to prescribe or recommend glucose-lowering agents. Other cardiologists are not yet comfortable with this role because they are not accustomed to initiating these drugs. This document provides updated details of glucose-lowering agents associated with either proven cardiovascular benefit or safety, to help cardiologists to safely prescribe and monitor their patients with diabetes.

Diabetes for Cardiologists: Practical Issues in Diagnosis and Management.

Diabetes mellitus (DM), a chronic metabolic disease characterized by hyperglycemia, is a profound cardiovascular (CV) risk factor. It compounds the effects of all other risk factors, leads to premature micro- and macrovascular disease, facilitates development of heart failure, worsens the clinical course of all CV diseases, and shortens life expectancy. Established DM, unrecognized DM, and dysglycemia that may progress to DM are all commonly present at the time of presentation of overt CV disease. Thus, CV specialists and trainees frequently treat patients with dysglycemia. The traditional and proven role of cardiologists in reducing the risk of macrovascular events in this population is through aggressive lipid and blood pressure treatment. However, a more proactive role in the detection and management of DM is likely to become increasingly important as the prevalence continues to increase and therapies continue to improve. The latter include antihyperglycemic therapies with proven cardiovascular safety profiles and CV event reduction properties not yet fully elucidated and not necessarily related to glycemic control. Accordingly, the purpose of this article is to (1) expand the interest of cardiologists in earlier stages of the natural history of DM, when prevention or early detection might help achieve greatest benefit; (2) highlight principles of optimal glycemic management, with an emphasis on add-on choices showing promising reduction of CV events and lacking CV adverse effects; and (3) encourage cardiologists to become proactive partners in the multidisciplinary care needed to ensure optimal lifelong vascular health in patients with, or who are at risk of, DM.

The Role of Hypoglycemia in Cardiovascular Outcomes in Diabetes.

Intensive glucose management, targeting lower glycated hemoglobin (A1C) levels, has been shown to reduce the microvascular complications of diabetes, but the effect on cardiovascular (CV) outcomes is less clear. Observational follow-up of intensive glucose management studies suggest possible long-term CV benefits, but no clear reduction in CV events has been seen over 3 to 5 years. Intensive glucose management also increases the risk for hypoglycemia, particularly in patients with longstanding diabetes, cognitive impairment and hypoglycemia unawareness. Severe hypoglycemia has been linked to adverse consequences, including cardiac dysrhythmias, CV events and death, but the precise role of hypoglycemia in CV outcomes is uncertain. The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial was terminated early because of a higher rate of CV events in the intensive arm. Post hoc analyses of ACCORD and other trials suggest that cardiac autonomic neuropathy may be a predisposing factor to CV events. The Analyses of the Action in Diabetes and Vascular Disease (ADVANCE) trial and the Veterans Affairs Diabetes Trial (VADT) showed that subjects with severe hypoglycemia had more frequent adverse outcomes. However, rather than causing adverse events, it appears that severe hypoglycemia may be a marker of vulnerability for such events. This review focuses on the current understanding of the association between hypoglycemia and CV risk.

Evaluation of protocol-guided scheduled basal-nutritional-correction insulin over standard care for vascular surgery patients.

BACKGROUND: Practice guidelines have recommended scheduled basal, nutritional and correction insulin to manage hyperglycemia in the hospital setting. For many decades, however, the primary practice has been sliding scale insulin. OBJECTIVE: To evaluate the efficacy and safety of an institution-specific basal-nutritional-correction insulin preprinted order (BNC-PPO). METHODS: A retrospective, single-centre chart review was conducted on patients admitted to a vascular surgery service to compare inpatient glycemia control before and after implementation of the BNC-PPO. Patients were included if they were aged 19 years or more, admitted between June 2009 and December 2010 (for pre-BNC-PPO) or between April 2011 and August 2012 (for post-BNC-PPO), required insulin before admission for their diabetes mellitus (type 1 or 2) and were prescribed insulin during their admission. RESULTS: For the primary outcome, the mean (±SD) daily blood glucose during hospital stay was 9.83±1.74 mmol/L for the pre-BNC-PPO group and 8.79±1.60 mmol/L for the post-BNC-PPO group (p=0.005). Mean (±SD) severe hyperglycemia episodes per patient per day had decreased in the BNC-PPO group: 1.13±0.73 and 0.80±1.02 for the before and after groups, respectively (p=0.008). Hypoglycemia (blood glucose <2.2 mmol/L and <4 mmol/L) and mild and moderate hyperglycemia episodes were no different between groups. CONCLUSIONS: A structured and proactive approach to inpatient hyperglycemia management appears to be more effective (reduced mean daily blood glucose and severe hyperglycemia episodes) and safer (no increase in hypoglycemia episodes) in maintaining glycemia control in insulin-dependent diabetes patients.

Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy.

BACKGROUND: The effect of islet cell transplantation (ICT) on the progression of diabetic microvascular complications is not well understood. METHODS: We have conducted a prospective, crossover, cohort study comparing ICT with intensive medical therapy on the progression of diabetic nephropathy, retinopathy, and neuropathy. RESULTS: The rate of decline in glomerular filtration rate is slower after ICT than on medical therapy. There was significantly more progression of retinopathy in medically treated patients than post-ICT. There was a nonsignificant trend for improved nerve conduction velocity post-ICT. CONCLUSIONS: ICT is associated with less progression of microvascular complications than intensive medical therapy. Multicenter, randomized trials are needed to further study the role of ICT in slowing the progression of diabetic complications.

The First Step First Bite Program: guidance to increase physical activity and daily intake of low-glycemic index foods.

Practical lifestyle interventions are needed to help people with type 2 diabetes increase their physical activity and follow nutrition therapy guidelines. This study examined whether combining instructions to walk more and to eat more low-glycemic index (GI) foods (First Step First Bite Program) improved hemoglobin A1c and anthropometric and cardiovascular health outcomes in people with type 2 diabetes vs the First Step Program (instruction only on walking). Subjects were randomly assigned to the First Step Program or First Step First Bite Program (n=22 in each group) and attended four weekly group meetings with minimal follow-up during weeks 5 to 16. All subjects monitored steps per day throughout the study; First Step First Bite Program subjects also monitored daily intake of low-GI foods. At week 16 (n=19 per group), both groups had increased steps per day by approximately 3,000 compared with baseline (P<0.01). In the First Step Program vs First Step First Bite Program groups, respectively, waist girth decreased by 5.9+/-0.9 cm vs 3.7+/-0.5 cm and hip decreased by 3.7+/-0.6 cm vs 2.2+/-0.5 cm (P<0.01 over time, both groups). There was no significant difference between groups at week 16 for anthropometric or metabolic variables measured, including hemoglobin A1c. Both the First Step First Bite Program and First Step Program resulted in increased physical activity; First Step First Bite Program also increased daily intake of low-GI foods. Both groups experienced similar significant reductions in waist and hip girth. Thus, adding a low-GI component to a walking program in people with type 2 diabetes in good glycemic control did not improve anthropometric or metabolic outcomes. A great number and/or longer duration of low-GI foods may be required to observe improved clinical outcomes.

Quality of life after islet transplant: impact of the number of islet infusions and metabolic outcome.

The health-related quality of life (HRQL; Health Utilities Index Mark 2) and the fear of hypoglycemia (Hypoglycemia Fear Survey) were assessed after islet transplant; the impact of a single islet infusion and of the metabolic outcome were determined. A control group included 166 patients with type 1 diabetes. Islet transplant had no impact on overall HRQL. Prior to transplant, islet recipients had more fear of hypoglycemia than controls (P<0.000001), but this improved up to 36 months after transplant (P<0.00001, pretransplant vs. each time point). With a single islet infusion, this fear improved substantially (P<0.00001), but improved further with subsequent islet infusions (P

Assessment of glycemic control after islet transplantation using the continuous glucose monitor in insulin-independent versus insulin-requiring type 1 diabetes subjects.

BACKGROUND: The aim of this study was to assess and compare glycemic control using the continuous glucose monitor (CGMS, Medtronic Minimed, Northridge, CA) in type 1 diabetes mellitus (T1DM) subjects who are insulin-independent versus those who require insulin after islet transplantation alone (ITA). METHODS: Glycemic control was assessed using 72-h CGMS in eight T1DM subjects who were insulin-independent after ITA (ITA-II), eight T1DM subjects who were C-peptide-positive but insulin-requiring after ITA (ITA-IR), and eight non-transplanted (NT) T1DM subjects. RESULTS: Standard deviation of glucose values was not significantly different between ITA-II and ITA-IR subjects (ITA-II, 1.2 +/- 0.1 mM; ITA-IR, 2.0 +/- 0.3 mM; P = 0.072). Both ITA groups were more stable than NT subjects (NT, 3.3 +/- 0.3 mM; P = 0.001 vs. ITA). Mean high glucose values were significantly lower in ITA subjects compared with NT subjects (ITA-II, 10.5 +/- 0.6 mM; ITA-IR, 13.0 +/- 1.0 mM; NT, 16.1 +/- 1.1 mM; P = 0.002). Mean average glucose values were not significantly different among all groups (ITA-I, 6.7 +/- 0.2 mM; ITA-IR, 7.8 +/- 0.3 mM; NT, 7.7 +/- 0.6 mM; P = 0.198). Mean low glucose values were significantly higher in both ITA groups compared with NT subjects (ITA-II, 4.5 +/- 0.2 mM; ITA-IR, 4.3 +/- 0.3 mM; NT, 3.0 +/- 0.2 mM; P = 0.003). Duration of hypoglycemic excursions (<3.0 mM) was markedly reduced in both ITA groups (ITA-II, 0%; ITA-IR, 2.4 +/- 0.2%; NT, 11.8 +/- 4.2%). Glycated hemoglobin was not significantly different between ITA groups (ITA-II, 6.4 +/- 0.2%; ITA-IR, 6.5 +/- 0.3%) and was significantly higher in NT subjects (8.3 +/- 0.2%; P < 0.001 vs. ITA). CONCLUSIONS: CGMS monitoring demonstrates that glycemic lability and hypoglycemia are significantly reduced in C-peptide-positive islet transplant recipients, whether or not supplementary, exogenous insulin is used, compared with non-transplanted T1DM subjects.

Sirolimus-induced ulceration of the small bowel in islet transplant recipients: report of two cases.

Sirolimus (SRL) has been used for most islet recipients over the past 5 years. It provides balanced immunosuppression in combination with low-dose calcineurin inhibitors, while avoiding corticosteroids. This regimen decreases the risk of nephrotoxicity, neurotoxicity and diabetogenicity. SRL has also been used selectively in clinical liver and kidney transplantation. A number of common side effects including anemia, leucopenia, thrombocytopenia, hypercholesterolemia, mouth ulceration, joint pain, extremity edema and impaired wound healing have been associated with the use of SRL. As SRL is used more frequently, evidence has been gathered on its rare but severe side effects. We report 2 patients who underwent islet transplantation and developed symptomatic small bowel ulceration that resolved after complete withdrawal of SRL. Although small bowel ulceration is rare, it can potentially progress to more serious complications if not treated adequately. Our experience highlights an uncommon but potentially serious adverse effect of high-dose SRL in islet recipients.

Proteinuria developing after clinical islet transplantation resolves with sirolimus withdrawal and increased tacrolimus dosing.

Sirolimus is a potent immunosuppressant, which may permit the avoidance of nephrotoxic calcineurin inhibitors (CNI). However, cases of proteinuria associated with sirolimus have been reported following renal transplantation. Here, we report three cases of proteinuria (1, 2 and 7 g/day) developing during therapy with sirolimus plus low-dose tacrolimus following clinical islet transplantation (CIT) in type I diabetic subjects. The proteinuria resolved after discontinuation of sirolimus, substituted by mycophenolate mofetil (MMF) combined with an increased dose of tacrolimus. A renal biopsy in one case indicated only the presence of diabetic glomerulopathy. Five other CIT recipients developed microalbuminuria while on sirolimus which all resolved after switching to tacrolimus and MMF. The resolution of proteinuria from the native kidneys of CIT recipients after the discontinuation sirolimus suggests that, at least in some individuals, sirolimus itself may have adverse renal effects. Sirolimus should be used cautiously with close monitoring for proteinuria or renal dysfunction.

Five-year follow-up after clinical islet transplantation.

Islet transplantation can restore endogenous beta-cell function to subjects with type 1 diabetes. Sixty-five patients received an islet transplant in Edmonton as of 1 November 2004. Their mean age was 42.9 +/- 1.2 years, their mean duration of diabetes was 27.1 +/- 1.3 years, and 57% were women. The main indication was problematic hypoglycemia. Forty-four patients completed the islet transplant as defined by insulin independence, and three further patients received >16,000 islet equivalents (IE)/kg but remained on insulin and are deemed complete. Those who became insulin independent received a total of 799,912 +/- 30,220 IE (11,910 +/- 469 IE/kg). Five subjects became insulin independent after one transplant. Fifty-two patients had two transplants, and 11 subjects had three transplants. In the completed patients, 5-year follow-up reveals that the majority ( approximately 80%) have C-peptide present post-islet transplant, but only a minority ( approximately 10%) maintain insulin independence. The median duration of insulin independence was 15 months (interquartile range 6.2-25.5). The HbA(1c) (A1C) level was well controlled in those off insulin (6.4% [6.1-6.7]) and in those back on insulin but C-peptide positive (6.7% [5.9-7.5]) and higher in those who lost all graft function (9.0% [6.7-9.3]) (P < 0.05). Those who resumed insulin therapy did not appear more insulin resistant compared with those off insulin and required half their pretransplant daily dose of insulin but had a lower increment of C-peptide to a standard meal challenge (0.44 +/- 0.06 vs. 0.76 +/- 0.06 nmol/l, P < 0.001). The Hypoglycemic score and lability index both improved significantly posttransplant. In the 128 procedures performed, bleeding occurred in 15 and branch portal vein thrombosis in 5 subjects. Complications of immunosuppressive therapy included mouth ulcers, diarrhea, anemia, and ovarian cysts. Of the 47 completed patients, 4 required retinal laser photocoagulation or vitrectomy and 5 patients with microalbuminuria developed macroproteinuria. The need for multiple antihypertensive medications increased from 6% pretransplant to 42% posttransplant, while the use of statin therapy increased from 23 to 83% posttransplant. There was no change in the neurothesiometer scores pre- versus posttransplant. In conclusion, islet transplantation can relieve glucose instability and problems with hypoglycemia. C-peptide secretion was maintained in the majority of subjects for up to 5 years, although most reverted to using some insulin. The results, though promising, still point to the need for further progress in the availability of transplantable islets, improving islet engraftment, preserving islet function, and reducing toxic immunosuppression.