Remission of type 2 diabetes mellitus.

The surge in type 2 diabetes mellitus (T2DM) is tightly linked to obesity, leading to ectopic fat accumulation in internal organs. Weight management has become a cornerstone of T2DM treatment, with evidence suggesting that significant weight loss can induce remission. Remission, defined as sustained hemoglobin (HbA1c) below 6.5% for at least 3 months without medication, can be achieved through various approaches, including lifestyle, medical, and surgical interventions. Metabolic bariatric surgery offers significant remission rates, particularly for patients with severe obesity. Intensive lifestyle modifications, including low-calorie diets and exercise, have also demonstrated significant potential. Medications like incretin-based agents show robust results in improving beta-cell function, achieving glycemic control, and promoting weight loss. While complete remission without medication may not be attainable for everyone, especially those with severe insulin resistance or deficiency, early and aggressive glycemic control remains a crucial strategy. Maintaining HbA1c below 6.5% from the time of diagnosis reduces the risk of long-term complications and mortality. Moreover, considering a broader definition of remission, encompassing individuals with sustained control on medication, could offer a more comprehensive and inclusive approach to managing this chronic disease.

Bi-Directional Interactions between Glucose-Lowering Medications and Gut Microbiome in Patients with Type 2 Diabetes Mellitus: A Systematic Review.

Background: Although common drugs for treating type 2 diabetes (T2D) are widely used, their therapeutic effects vary greatly. The interaction between the gut microbiome and glucose-lowering drugs is one of the main contributors to the variability in T2D progression and response to therapy. On the one hand, glucose-lowering drugs can alter gut microbiome components. On the other hand, specific gut microbiota can influence glycemic control as the therapeutic effects of these drugs. Therefore, this systematic review assesses the bi-directional relationships between common glucose-lowering drugs and gut microbiome profiles. Methods: A systematic search of Embase, Web of Science, PubMed, and Google Scholar databases was performed. Observational studies and randomised controlled trials (RCTs), published from inception to July 2023, comprising T2D patients and investigating bi-directional interactions between glucose-lowering drugs and gut microbiome, were included. Results: Summarised findings indicated that glucose-lowering drugs could increase metabolic-healthy promoting taxa (e.g., Bifidobacterium) and decrease harmful taxa (e.g., Bacteroides and Intestinibacter). Our findings also showed a significantly different abundance of gut microbiome taxa (e.g., Enterococcus faecium (i.e., E. faecium)) in T2D patients with poor compared to optimal glycemic control. Conclusions: This review provides evidence for glucose-lowering drug and gut microbiome interactions, highlighting the potential of gut microbiome modulators as co-adjuvants for T2D treatment.

Exploring Metabolomic Patterns in Type 2 Diabetes Mellitus and Response to Glucose-Lowering Medications-Review.

The spectrum of information related to precision medicine in diabetes generally includes clinical data, genetics, and omics-based biomarkers that can guide personalized decisions on diabetes care. Given the remarkable progress in patient risk characterization, there is particular interest in using molecular biomarkers to guide diabetes management. Metabolomics is an emerging molecular approach that helps better understand the etiology and promises the identification of novel biomarkers for complex diseases. Both targeted or untargeted metabolites extracted from cells, biofluids, or tissues can be investigated by established high-throughput platforms, like nuclear magnetic resonance (NMR) and mass spectrometry (MS) techniques. Metabolomics is proposed as a valuable tool in precision diabetes medicine to discover biomarkers for diagnosis, prognosis, and management of the progress of diabetes through personalized phenotyping and individualized drug-response monitoring. This review offers an overview of metabolomics knowledge as potential biomarkers in type 2 diabetes mellitus (T2D) diagnosis and the response to glucose-lowering medications.

Contemporary trends in the utilization of second-line pharmacological therapies for type 2 diabetes in the United States and the United Kingdom.

AIM: To examine trends of second-line glucose-lowering therapies among patients with type 2 diabetes (T2D) initiating first-line metformin in the United States and the United Kingdom, overall and by subgroups of cardiovascular disease (CVD) and calendar time. METHODS: Using the US Optum Clinformatics and the UK Clinical Practice Research Datalink, we identified adults with T2D who initiated first-line metformin or sulphonylurea monotherapy, separately, from 2013 to 2019. Within both cohorts, we identified patterns of second-line medications through June 2021. We stratified patterns by CVD and calendar time to investigate the impact of rapidly evolving treatment guidelines. RESULTS: We identified 148 511 and 169 316 patients initiating treatment with metformin monotherapy in the United States and the United Kingdom, respectively. Throughout the study period, sulphonylureas and dipeptidyl peptidase-4 inhibitors were the most frequently initiated second-line medications in the United States (43.4% and 18.2%, respectively) and the United Kingdom (42.5% and 35.8%, respectively). After 2018, sodium-glucose co-transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists were more commonly used as second-line agents in the United States and the United Kingdom, although these agents were not preferentially prescribed among patients with CVD. Initiation of first-line sulphonylureas was much less common, and most sulphonylurea initiators had metformin added as the second-line agent. CONCLUSIONS: This international cohort study shows that sulphonylureas remain the most common second-line medications prescribed following metformin in both the United States and the United Kingdom. Despite recommendations, the use of newer glucose-lowering therapies with cardiovascular benefits remains low.

Disparities in SGLT2 Inhibitor or Glucagon-Like Peptide 1 Receptor Agonist Initiation Among Medicare-Insured Adults With CKD in the United States.

Rationale & Objective: Information regarding disparities in initiating sodium/glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide 1 receptor agonists (GLP-1RA) in patients with chronic kidney disease (CKD) is limited. We examined sociodemographic and clinical factors associated with the initiation of SGLT2i, GLP-1RA, or second-generation sulfonylureas in a Medicare Fee-For-Service patient population with CKD and type 2 diabetes. Study Design: Retrospective cohort study. Setting & Participants: The 20% random sample of Medicare Fee-For-Service claims, 2012-2018. Exposures: Patients' sociodemographic and clinical factors. Outcomes: Use of SGLT2i, GLP-1RA, or sulfonylureas. Analytical Approach: Patients with a newly initiated prescription of SGLT2i, GLP-1RA, or second-generation sulfonylureas from January 1, 2013, to December 31, 2018, were identified. Multinomial logistic regression model was used to evaluate demographic and clinical factors associated with the initiation of SGLT2i, GLP-1RA, or second-generation sulfonylureas. Results: The study cohort comprised 53,029 adults (aged greater than or equal to 18 years) with CKD and type 2 diabetes, of whom 10.0%, 17.4%, and 72.6% had a first prescription for SGLT2i, GLP-1RA, and sulfonylurea, respectively. Patients aged greater than or equal to 75 years versus those aged 65-74 years had lower odds to start SGLT2i or GLP-1RA compared with sulfonylureas. Black patients were associated with lower odds of initiation of SGLT2i (OR, 0.67; 95% CI, 0.61-0.74) and GLP-1RA (OR, 0.73; 95% CI, 0.68-0.79), compared with White patients. Hispanic and Asian patients had lower odds of initiation of GLP-1RA. Patients with cardiovascular disease or hyperlipidemia had higher odds to start SGLT2i or GLP-1RA. Limitations: CKD and type 2 diabetes diagnosis; CKD stage; and patient clinical status were identified with diagnosis or procedure codes. There is potential for residual confounding with the use of retrospective data. Conclusions: The results of this study identified disparities in the use of SGLT2i and GLP-1RA in patients with CKD. Black and older patients were significantly less likely to be initiated on SGLT2i or GLP-1RA than on second-generation sulfonylureas.

Emulating a Target Trial Using Primary-Care Electronic Health Records: Sodium-Glucose Cotransporter 2 Inhibitor Medications and Hemoglobin A1c.

Substantial effort has been dedicated to conducting randomized controlled experiments to generate clinical evidence for diabetes treatment. Randomized controlled experiments are the gold standard for establishing cause and effect. However, due to their high cost and time commitment, large observational databases such as those comprised of electronic health record (EHR) data collected in routine primary care may provide an alternative source with which to address such causal objectives. We used a Canadian primary-care data repository housed at the University of Toronto (Toronto, Ontario, Canada) to emulate a randomized experiment. We estimated the effectiveness of sodium-glucose cotransporter 2 inhibitor (SGLT-2i) medications for patients with diabetes using hemoglobin A1c (HbA1c) as a primary outcome and marker for glycemic control from 2018 to 2021. We assumed an intention-to-treat analysis for prescribed treatment, with analyses based on the treatment assigned rather than the treatment eventually received. We defined the causal contrast of interest as the net change in HbA1c (percent) between the group receiving the standard of care versus the group receiving SGLT-2i medication. Using a counterfactual framework, marginal structural models demonstrated a reduction in mean HbA1c level with the initiation of SGLT-2i medications. These findings provided effect sizes similar to those from earlier clinical trials on assessing the effectiveness of SGLT-2i medications.

Glycemic outcomes in patients with type 2 diabetes after bariatric surgery compared with routine care: a population-based, real-world cohort study in the United Kingdom.

BACKGROUND: Clinical trials have shown that bariatric surgery (BS) is associated with better glycemic control and diabetes remission in patients with type 2 diabetes (T2D) compared with routine care. OBJECTIVE: We conducted a real-world population-based study examining the impact of BS on glycemic control and medications in patients with T2D. SETTING AND METHODS: This was a retrospective, matched, controlled cohort study conducted between January 1, 1990, and January 31, 2018, using IQVIA Medical Research Data, a primary care electronic records database. Adults with body mass index (BMI) ≥30 kg/m2 and T2D who had BS (surgical) were matched for age, sex, BMI, and diabetes duration to two controls (with T2D and no BS). RESULTS: A total of 1126 patients in the surgical group and 2219 patients in the control group were analyzed. Mean (standard deviation) age was 50.0 (9.3) years, 67.6% were women, baseline glycocylated hemoglobin (HbA1C) was 7.8% (1.7 mmol/mol), and diabetes duration was 4.7 years (range, 2.0-8.4 years). Over a median (interquartile range) follow-up of 3.6 years (1.7-5.9 years), a higher proportion of patients in the surgical group achieved an HbA1C of ≤6.0% than the control group (65.8% versus 22.8%). The surgical group showed a decrease in mean HbA1C of 1.5% (95% confidence interval [CI]: 1.4%-1.7%), 1.4% (1.2%-1.5%), and 1.3% (1.1%-1.5%) at 1-, 2-, and 3-year follow-up, respectively, whereas HbA1C increased in the control group. The proportion of patients receiving glucose-lowering medications decreased in the surgical group (92.2% to 66.5%) but increased in the control group (85.3% to 90.2%). CONCLUSION: BS is associated with significant improvement in glycemic control, achievement of normal HbA1C levels, and reduced need for glucose-lowering therapy in patients with T2D.

Hypoglycemia Risk With SGLT2 Inhibitors or Glucagon-Like Peptide 1 Receptor Agonists Versus Sulfonylureas Among Medicare Insured Adults With CKD in the United States.

Rationale & Objective: Information on safety issues of newer glucose-lowering medications from a large population perspective in chronic kidney disease (CKD) patients with type 2 diabetes is limited. Our study aimed to examine hypoglycemia risk associated with sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP-1RAs) versus second-generation sulfonylureas in a general population of older patients with CKD and type 2 diabetes, across race, age, sex, and socioeconomic subgroups. Study Design: Retrospective cohort. Setting & Participants: The 20% random sample of Medicare fee-for-service claims, 2012-2018. Exposures: Use of SGLT2is, GLP-1RAs, or sulfonylureas. Outcomes: Hypoglycemic events resulting in health care utilization. Analytical Approach: Cox proportional hazard model evaluated the 90-day risk of hypoglycemia associated with SGLT2is or GLP-1RAs versus sulfonylureas. Results: A total of 18,567 adults (mean age: 73 years) with CKD and type 2 diabetes was included; 14.0% (n = 2,528) had a prescription for a SGLT2i or GLP-1RA, and 86.0% (n = 16,039) with a sulfonylurea. Compared with sulfonylureas, use of SGLT2is or GLP-1RAs was associated with a significantly lower risk of hypoglycemia (adjusted HR, 0.30; 95% CI, 0.14-0.65). Black individuals had higher risk of developing hypoglycemia than White individuals (adjusted HR, 1.55; 95% CI, 1.07-2.26). Low-income subsidy compared to no low-income subsidy status was associated with higher risk of hypoglycemic events. The risk of hypoglycemia also increased with higher comorbid condition score. Limitations: CKD and type 2 diabetes diagnosis, CKD stage, and patient clinical status were identified with diagnosis or procedure codes. There is potential for residual confounding with use of retrospective data. Conclusions: Use of SGLT2is or GLP-1RAs compared with sulfonylureas was associated with a lower risk of hypoglycemia among patients with CKD and type 2 diabetes. Black race was not only associated with lower use of newer agents with demonstrated cardiovascular and kidney benefits and lower hypoglycemia risk, but also with a higher rate of hypoglycemic events as compared with White individuals.

Metformin Treatment Among Men With Diabetes and the Risk of Prostate Cancer: A Population-Based Historical Cohort Study.

There is conflicting evidence regarding the association between metformin treatment and prostate cancer risk in diabetic men. We investigated this association in a population-based Israeli cohort of 145,617 men aged 21-89 years with incident diabetes who were followed over the period 2002-2012. We implemented a time-dependent covariate Cox model, using weighted cumulative exposure to relate metformin history to prostate cancer risk, adjusting for use of other glucose-lowering medications, age, ethnicity, and socioeconomic status. To adjust for time-varying glucose control variables, we used inverse probability weighting of a marginal structural model. With 666,553 person-years of follow-up, 1,592 men were diagnosed with prostate cancer. Metformin exposure in the previous year was positively associated with prostate cancer risk (per defined daily dose; without adjustment for glucose control, hazard ratio (HR) = 1.53 (95% confidence interval (CI): 1.19, 1.96); with adjustment, HR = 1.42 (95% CI: 1.04, 1.94)). However, exposure during the previous 2-7 years was negatively associated with risk (without adjustment for glucose control, HR = 0.58 (95% CI: 0.37, 0.93); with adjustment, HR = 0.60 (95% CI: 0.33, 1.09)). These positive and negative associations with previous-year and earlier metformin exposure, respectively, need to be confirmed and better understood.

Obesity and obesity-induced inflammatory disease contribute to atherosclerosis: a review of the pathophysiology and treatment of obesity.

Two billion people worldwide older than 18 years of age, or approximately 30% of the world population, are overweight or obese. In addition, more than 43 million children under the age of 5 are overweight or obese. Among the population in the United States aged 20 and greater, 32.8 percent are overweight and 39.8 percent are obese. Blacks in the United States have the highest age-adjusted prevalence of obesity (49.6%), followed by Hispanics (44.8%), whites (42.2%) and Asians (17.4%). The impact of being overweight or obese on the US economy exceeds $1.7 trillion dollars, which is equivalent to approximately eight percent of the nation's gross domestic product. Obesity causes chronic inflammation that contributes to atherosclerosis and causes >3.4 million deaths/year. The pathophysiologic mechanisms in obesity that contribute to inflammation and atherosclerosis include activation of adipokines/cytokines and increases in aldosterone in the circulation. The adipokines leptin, resistin, IL-6, and monocyte chemoattractant protein activate and chemoattract monocytes/macrophages into adipose tissue that promote visceral adipose and systemic tissue inflammation, oxidative stress, abnormal lipid metabolism, insulin resistance, endothelial dysfunction, and hypercoagulability that contribute to atherosclerosis. In addition in obesity, the adipokines/cytokines IL-1ß, IL-18, and TNF are activated and cause endothelial cell dysfunction and hyperpermeability of vascular endothelial junctions. Increased aldosterone in the circulation not only expands the blood volume but also promotes platelet aggregation, vascular endothelial dysfunction, thrombosis, and fibrosis. In order to reduce obesity and obesity-induced inflammation, therapies including diet, medications, and bariatric surgery are discussed that should be considered in patients with BMIs>35-40 kg/m2 if diet and lifestyle interventions fail to achieve weight loss. In addition, antihypertensive therapy, plasma lipid reduction and glucose lowering therapy should be prescribed in obese patients with hypertension, a 10-year CVD risk >7.5%, or prediabetes or diabetes.

Initial treatment of diabetes in Italy. A nationwide population-based study from of the ARNO Diabetes Observatory.

BACKGROUND AND AIMS: To investigate diabetes treatment initiation and continuation in the next sixth months in newly diagnosed Italian subjects. METHODS AND RESULTS: We analyzed administrative claims of 11,300,750 Italian residents. Subjects with incident diabetes were identified by glucose lowering drug prescriptions, disease-specific co-payment exemptions and hospital discharge codes occurring in 2018 but not in 2017. Incident cases were 65,932 of whom 91.4% received the prescription of a glucose lowering drug. Among the latter, those receiving a prescription of a noninsulin medication but no insulin were 84.8%, those receiving a prescription of insulin only were 9.4%, and those receiving prescriptions of both insulin and noninsulin drugs were 5.8%. Metformin was the most frequently drug initially prescribed in noninsulin treated subjects (~85%) and sulphonylurea receptor (SUR) agonists collectively ranked as second (~13%). Lispro (35%) and glargine (34%) were the most frequently prescribed molecules in subjects who were insulin treated. Differences in prescriptions were found in age categories, with increased use of SUR agonists across decades. In the first six months, as many as 50% of noninsulin treated patients continued with the initial drug, ~15% added a second agent, ~5% switched to another medication, and ~30% discontinued any glucose lowering treatment. CONCLUSIONS: These data document that current guidelines are often neglected because prescriptions of SUR agonists as first agent are still quite common and insulin is prescribed more than expected. They point out the urgent need to improve the dissemination and implementations of guidelines in diabetes care.

Role of Glucose-Lowering Medications in Erectile Dysfunction.

Erectile dysfunction (ED) is a long-term complication of type 2 diabetes (T2D) widely known to affect the quality of life. Several aspects of altered metabolism in individuals with T2D may help to compromise the penile vasculature structure and functions, thus exacerbating the imbalance between smooth muscle contractility and relaxation. Among these, advanced glycation end-products and reactive oxygen species derived from a hyperglycaemic state are known to accelerate endothelial dysfunction by lowering nitric oxide bioavailability, the essential stimulus of relaxation. Although several studies have explained the pathogenetic mechanisms involved in the generation of erectile failure, few studies to date have described the efficacy of glucose-lowering medications in the restoration of normal sexual activity. Herein, we will present current knowledge about the main starters of the pathophysiology of diabetic ED and explore the role of different anti-diabetes therapies in the potential remission of ED, highlighting specific pathways whose activation or inhibition could be fundamental for sexual care in a diabetes setting.

Glucose-Lowering Medication Use in CKD: Analysis of US Medicare Beneficiaries Between 2007 and 2016.

BACKGROUND: Information regarding the use of glucose-lowering medications in patients with chronic kidney disease (CKD) is limited. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: Medicare 5% random sample of patients with CKD with type 2 diabetes, 2007 to 2016. PREDICTORS: Study year, CKD stage, low-income subsidy status, and demographic characteristics (age, sex, and race/ethnicity). OUTCOMES: Trends in use of glucose-lowering medications. ANALYTICAL APPROACH: Yearly cohorts of patients with CKD and type 2 diabetes were created. Descriptive statistics were used to report proportions of patients using glucose-lowering medications. To test overall trends in glucose-lowering medication classes, linear probability models with adjustment for age, sex, race/ethnicity, CKD stage, and low-income subsidy status were used. RESULTS: Metformin use increased significantly from 32.7% in 2007 to 48.7% in 2016. Use of newer classes of glucose-lowering medications increased significantly, including dipeptidyl peptidase 4 inhibitors (5.6%, 2007; 21.7%, 2016), glucagon-like peptide 1 receptor agonists (2.3%, 2007; 6.1%, 2016), and sodium-glucose cotransporter 2 inhibitors (0.2%, 2013; 3.3%, 2016). Newer insulin analogue use increased from 37.2% in 2007 to 46.3% in 2013 and then remained steady. Use of sulfonylureas, thiazolidinediones, older insulins (human regular and neutral protamine Hagedorn), α-glucosidase inhibitors, amylin mimetics, and meglitinides decreased significantly. Insulin was the most highly used single medication class. Insulin use was higher among low-income subsidy than among non-low-income subsidy patients. Combination therapy was less common as CKD stage increased. LIMITATIONS: Patients with CKD and type 2 diabetes and the CKD stages were identified with diagnosis codes and could not be verified through medical record review. Our results may not be generalizable to younger patients with CKD with type 2 diabetes. CONCLUSIONS: Use of metformin and newer glucose-lowering medication classes is increasing in patients with CKD with type 2 diabetes. We anticipate that percentages of patients with CKD using these newer agents will increase.

Long-term impact of bariatric surgery on glycemic control and glucose-lowering therapy for people with type 2 diabetes: population-based cohort study.

BACKGROUND: Randomized controlled trials (RCTs) have demonstrated that bariatric surgery improves glycemic control among people with diabetes. However, evidence from RCTs may not be generalizable to real-world clinical care with unselected patients in routine clinical practice. OBJECTIVES: To examine long-term glycemic control and glucose-lowering drug regimens following bariatric surgery for people with type 2 diabetes (T2D) in unselected patients in routine clinical practice. SETTING: Population-based cohort study using linked routinely collected real-world data from Ontario, Canada. METHODS: Individuals with T2D who were assessed for bariatric surgery at any referral center in the province between February 2010 and November 2016 were identified and divided into those who received surgery within 2 years of the initial assessment and those who did not. RESULTS: There were 3674 people who had bariatric surgery and 1335 who did not. By 2 years, people who had undergone surgery had a significantly lower HbA1C (6.3 ± 1.2 % versus 7.8 ± 1.8 %, P < .0001), and this difference persisted at 3, 4, 5, and 6 years. Even by 6 years, half of those who had undergone surgery remained on no glucose-lowering drugs, and they were nearly 6 times less likely to be on insulin than those who had not undergone surgery. CONCLUSIONS: In real-world clinical care, bariatric surgery was associated with large and sustained improvements in glycemic control.

GLP-1RA and SGLT2i: Cardiovascular Impact on Diabetic Patients.

BACKGROUND: Diabetes is a chronic disease with high complexity that demands strategic medical care with a multifactorial risk-reduction approach. Over the past decade, the treatment of type 2 diabetes mellitus (T2DM) has entirely changed. One of the paradigm changes has been the arrival of new drugs that reduce cardiovascular risk beyond the reduction of A1C. OBJECTIVE: Sodium-glucose cotransporter 2 (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1RA) are two groups of antidiabetics drugs, which have demonstrated superiority compared to placebo for major cardiovascular events (MACE). METHODS: We update and discuss their impact on MACE expressed as relative risk (HR hazard ratio) and as the number needed to treat (NNT) to avoid one cardiovascular event in 5 years. We include the publications of the last 10 years. RESULTS: Empagliflozin, Canagliflozin and Dapagliflozin present an HR for MACE of 0.86, 0.86, 0.86 and an NNT of 38, 44, and 33, respectively (Dapagliflozin in secondary prevention). Regarding HHF (Hospitalization for Heart Failure), the HR was 0.65, 0.67, 0.73 and NNT was 44, 62, and 98, respectively. Lixisenatide, Exenatide, Liragutide, Semaglutide, Albiglutide and Dulaglutide presented for MACE an HR of 1.02, 0.91, 0.87, 0.74, 0.78, 0.88, respectively. There was no increase in the risk of HHF, but there was no benefit either. CONCLUSION: Cardiovascular benefits of the GLP-1RA and the SGLT2i are clinically significant. A number needed to treat under 50 is required to avoid one MACE in five years. These benefits have led to important changes in the Clinical Practice Guidelines and in the care of our patients with T2DM.

Order of discontinuation of glucose-lowering medications following bariatric surgery.

AIMS: To assess the order of glucose-lowering medication (GLM) discontinuation following bariatric surgery among patients taking ≥2 GLMs. METHODS: Patients with diabetes mellitus taking ≥2 GLM classes who underwent bariatric surgery were identified using health claims data from the United States. The order of discontinuation was assessed in patients taking ≥2 GLM classes by comparing each GLM class to the other classes in aggregate. Descriptive statistics and Poisson regression were used to assess the order of discontinuation and changes in trends in the order of discontinuation. RESULTS: Overall, 12,244 of 26,651 patients with type 2 diabetes who underwent bariatric surgery were taking ≥2 GLM classes. When each GLM class was assessed separately, fewer than 50% of patients had metformin, sulfonylurea, thiazolidinedione, DPP-4 inhibitor, SGLT2 inhibitor, glucosidase inhibitor, or insulin discontinued first when compared to the other classes in aggregate. Between 2008 and 2014, thiazolidinediones were increasingly more likely to be the first GLM discontinued (p = 0.0432). Slightly more than 50% of patients whose GLM regimen included a sulfonylurea discontinued the sulfonylurea first despite clinical recommendations. CONCLUSIONS: From a population level, there was no consistent approach in the order of discontinuation of GLM classes in patients following bariatric surgery.

Interactions between antihyperglycemic drugs and the renin-angiotensin system: Putative roles in COVID-19. A mini-review.

BACKGROUND: Diabetes mellitus is associated with a more severe course of coronavirus disease 2019 (COVID-19). The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) utilizes angiotensin-converting enzyme II (ACE2) receptor for host cell entry. We aimed to assess the interactions between antihyperglycemic drugs and the renin-angiotensin system (RAS) and their putative roles in COVID-19. METHODS: A literature search was performed using Pubmed to review the interrelationships between hyperglycemia, RAS and COVID-19, and the effects of antihyperglycemic medications. RESULTS: The RAS has an essential role in glucose homeostasis and may have a role in COVID-19-induced lung injury. Some antihyperglycemic medications modulate RAS and might hypothetically alleviate the deleterious effect of angiotensin II on lung injury. Furthermore, most antihyperglycemic medications showed anti-inflammatory effects in animal models of lung injury. CONCLUSIONS: Some antihyperglycemic medications might have protective effects against COVID-19-induced lung injury. Early insulin therapy seems very promising in alleviating lung injury.

Risk of hypoglycaemia associated with professional, recreational, and traffic-related activities in patients with type 2 diabetes: a cross-sectional study by questionnaire.

AIMS: We aimed to quantify the exposure to physical exercise associated with professional, recreational, or traffic-related activities in patients with type 2 diabetes, which may provoke or aggravate hypoglycaemic episodes, and to assess whether such risks determine the choice of medications minimizing the risk of hypoglycaemia. METHODS: In total, 203 patients with type 2 diabetes (98 women, 105 men, age 65 [56;72; median, inter-quartile range] years, diabetes duration 10 [5;15] years) were recruited from a German diabetes practice. A questionnaire assessed their engagement in professional, recreational, or traffic-related activities. The prescription insulin or sulphonylureas was quantified in relation to the number of such activities. RESULTS: 63.5% of the patients were treated with insulin, 7.4% with sulphonylureas, and 70.9% with either. Sixty-six patients (22.7%) were professionally active: 36 (54.4%) of those were professionally exposed to risky behaviour (14 [31.8%] patients with exposure to multiple risks and 20 (30.3%) who experienced hypoglycaemic episodes in the past year). In total, 194 (95.6%) patients were exposed to risky behaviour during recreational activities, 129 (63.6%) to multiple ones. All patients were exposed to traffic-related activities, 144 (70.9%) were exposed to more than being pedestrian, and 24 (11.8%) experienced hypoglycaemic episodes while in traffic. CONCLUSIONS: Patients with type 2 diabetes are exposed to risks associated with professional, recreational, and traffic-related activities. We recommend a careful assessment of such risks before glucose-lowering medications with a potential for provoking hypoglycaemic episodes are prescribed.

Glucose-lowering medications and the risk of cancer: A methodological review of studies based on real-world data.

AIM: To review the methodology of observational studies examining the association between glucose-lowering medications and cancer to identify the most common methodological challenges and sources of bias. METHODS: We searched PubMed systematically to identify observational studies on glucose-lowering medications and cancer published between January 2000 and January 2016. We assessed the design and analytical methods used in each study, with a focus on their ability to achieve study validity, and further evaluated the prevalence of major methodological choices over time. RESULTS: Of 155 studies evaluated, only 26% implemented a new-user design, 41% used an active comparator, 33% implemented a lag or latency period, and 51% adjusted for diabetes duration. Potential for immortal person-time bias was identified in 63% of the studies; 55% of the studies adjusted for variables measured during the follow-up without appropriate statistical methods. Aside from a decreasing trend in adjusting for variables measured during the follow-up, we observed no trends in methodological choices over time. CONCLUSIONS: The prevalence of well-known design and analysis flaws that may lead to biased results remains high among observational studies on glucose-lowering medications and cancer, limiting the conclusions that can be drawn from these studies. Avoiding known pitfalls could substantially improve the quality and validity of real-world evidence in this field.

Cardiovascular outcome trials of glucose-lowering medications: an update.

Three further cardiovascular (CV) outcome studies of glucose-lowering drugs (linagliptin, albiglutide and dapagliflozin) have recently been published, adding to the twelve earlier within-class studies. The linagliptin study (CARMELINA) recruited people with renal disease as well as prior CV events and confirms the overall CV safety (and other safety) of the dipeptidylpeptidase-4 (DPP4) inhibitors, with no heart failure risk associated with this agent. However, taken together with the findings from two previous studies of DPP4 inhibitors (sitagliptin and saxagliptin), the three DPP4 inhibitor CV outcome trials (CVOTs) have highlighted a safety signal regarding risk of pancreatitis. Like CARMELINA, the albiglutide study (Harmony Outcome) had a very high CV event rate. Despite being a short duration study, albiglutide showed strong superiority for reduction in the major adverse CV events (MACE) composite in people with extant cardiovascular disease (CVD), in line with the earlier studies on the GLP-1 receptor agonists (GLP-1RAs) liraglutide and semaglutide. Positive effects can be detected for all these medications from before 12 months and continue for the whole study duration. No new safety issues for albiglutide are identified and the lack of a pancreatitis or a pancreatic cancer signal for this class is now clear. For the sodium-glucose cotransporter-2 (SGLT2) inhibitor class, the DECLARE-TIMI 58 study (of dapagliflozin) clearly indicates strong protection for heart failure in those with CVD, and probably in those with no prior CVD. There is also strong protection against renal decline with dapagliflozin, with similar risk estimates in DECLARE as previously reported for empagliflozin and canagliflozin. However, findings for MACE outcomes with dapagliflozin are not concordant with the empagliflozin and canagliflozin studies, and are not convincingly superior across class and for the longer term. Care is required when prescribing the SGLT2 inhibitor class of medications to people with foot vascular issues or prior amputation, and to insulin users in regard of ketoacidosis. In summary, taking into account the findings from these new studies, it is suggested that a GLP-1RA should be offered to all people with CVD and type 2 diabetes, and SGLT2 inhibitors should be prescribed for those at high risk of heart failure or with progressive decline in eGFR. DPP4 inhibitors are a safe choice within the glucose-lowering stepped algorithm.