Assessment of Thyroid Carcinogenic Risk and Safety Profile of GLP1-RA Semaglutide (Ozempic) Therapy for Diabetes Mellitus and Obesity: A Systematic Literature Review.

The broadening application of glucagon-like peptide (GLP)-1 receptor agonists, specifically semaglutide (Ozempic) for the management of diabetes and obesity brings a critical need to evaluate its safety profile, considering estimates of up to 20 million prescriptions per year in the US until 2035. This systematic review aims to assess the incidence of thyroid cancer and detail the spectrum of adverse events associated with semaglutide, focusing on its implications for patient care. Through a systematic search of PubMed, Scopus, and Embase databases up to December 2023, ten randomized controlled trials (RCTs) involving 14,550 participants, with 7830 receiving semaglutide, were analyzed, with an additional number of 18 studies that were separately discussed because they reported data from the same RCTs. The review focused on thyroid cancer incidence, gastrointestinal symptoms, and other significant adverse events attributed to semaglutide. The incidence of thyroid cancer in semaglutide-treated patients was less than 1%, suggesting no significant risk. Adverse events were predominantly gastrointestinal, including nausea (2.05% to 19.95%) and diarrhea (1.4% to 13%). Nasopharyngitis and vomiting were also notable, with mean prevalences of 8.23% and 5.97%, respectively. Other adverse events included increased lipase levels (mean of 6.5%), headaches (mean prevalence of 7.92%), decreased appetite (reported consistently at 7%), influenza symptoms (mean prevalence of 5.23%), dyspepsia (mean prevalence of 5.18%), and constipation (mean prevalence of 6.91%). Serious adverse events varied from 7% to 25.2%, highlighting the need for vigilant patient monitoring. These findings underscore the gastrointestinal nature of semaglutide's adverse events, which, while prevalent, did not significantly deter from its clinical benefits in the treatment landscape. This systematic review provides a comprehensive assessment of semaglutide's safety profile, with a focus on gastrointestinal adverse events and a low incidence of thyroid cancer. Despite the prevalence of gastrointestinal symptoms, semaglutide remains an efficacious option for managing diabetes and obesity. The detailed characterization of adverse events underscores the importance of monitoring and managing these effects in clinical practice, excluding the hypothesis of carcinogenesis.

A short-term economic evaluation of early insulin therapy compared to oral anti-diabetic drugs in order to reduce the major adverse events in type 2 diabetes patients in Iran.

OBJECTIVE: While there are some recommendations about early insulin therapy in newly diagnosed Type 2 Diabetes Mellitus (T2DM) patients, there is not sufficient evidence on this strategy's cost-effectiveness. This study compared early insulin therapy versus oral anti-diabetic drugs (OADs) for managing T2DMusing a cost-effectiveness analysis approach in Iran. METHODS: In this economic evaluation, a decision analytic model was designed. The target population was newly diagnosed type 2 diabetic patients, and the study was carried out from the perspective of Iran's healthcare system with a one-year time horizon. Basal insulin, Dipeptidyl peptidase-4 (DPP-4) inhibitors, and Thiazolidinediones (TZDs) were compared in this evaluation. The main outcome for assessing the effectiveness of each intervention was the reduction in the occurrence of diabetes complications. Strategies were compared using the incremental cost-effectiveness ratio (ICER), and deterministic and probabilistic sensitivity analyses were carried out. RESULTS: The DPP-4 inhibitors strategy was the dominant strategy with the highest effectiveness and the lowest cost. Early insulin therapy was dominated (ICER: $-53,703.18), meaning that it was not cost-effective. The sensitivity analyses consistently affirmed the robustness of the base case findings. The probabilistic sensitivity analysis indicated probabilities of 77%, 22%, and 1% for DPP-4 inhibitors, TZDs strategies, and early insulin therapy, respectively, in terms of being cost-effective. CONCLUSION: In terms of cost-effectiveness, early insulin therapy was not cost-effective compared to OADs for managing newly diagnosed T2DM patients. Future studies in this regard, utilizing more comprehensive evidence, can yield more accurate results.

Cardiorenal effectiveness of empagliflozin vs. glucagon-like peptide-1 receptor agonists: final-year results from the EMPRISE study.

BACKGROUND: No randomized clinical trials have directly compared the cardiorenal effectiveness of empagliflozin and GLP-1RA agents with demonstrated cardioprotective effects in patients with a broad spectrum of cardiovascular risk. We reported the final-year results of the EMPRISE study, a monitoring program designed to evaluate the cardiorenal effectiveness of empagliflozin across broad patient subgroups. METHODS: We identified patients ≥ 18 years old with type 2 diabetes who initiated empagliflozin or GLP-1RA from 2014 to 2019 using US Medicare and commercial claims databases. After 1:1 propensity score matching using 143 baseline characteristics, we evaluated risks of outcomes including myocardial infarction (MI) or stroke, hospitalization for heart failure (HHF), major adverse cardiovascular events (MACE - MI, stroke, or cardiovascular mortality), a composite of HHF or cardiovascular mortality, and progression to end-stage kidney disease (ESKD) (in patients with chronic kidney disease stages 3-4). We estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years, overall and within subgroups of age, sex, baseline atherosclerotic cardiovascular disease (ASCVD), and heart failure (HF). RESULTS: We identified 141,541 matched pairs. Compared with GLP-1RA, empagliflozin was associated with similar risks of MI or stroke [HR: 0.99 (0.92, 1.07); RD: -0.23 (-1.25, 0.79)], and lower risks of HHF [HR: 0.50 (0.44, 0.56); RD: -2.28 (-2.98, -1.59)], MACE [HR: 0.90 (0.82, 0.99); RD: -2.54 (-4.76, -0.32)], cardiovascular mortality or HHF [HR: 0.77 (0.69, 0.86); RD: -4.11 (-5.95, -2.29)], and ESKD [0.75 (0.60, 0.94); RD: -6.77 (-11.97, -1.61)]. Absolute risk reductions were larger in older patients and in those with baseline ASCVD/HF. They did not differ by sex. CONCLUSIONS: The cardiovascular benefits of empagliflozin vs. cardioprotective GLP-1RA agents were larger in older patients and in patients with history of ASCVD or HF, while they did not differ by sex. In patients with advanced CKD, empagliflozin was associated with risk reductions of progression to ESKD.

Partnering for Better Health: Using Continuous Glucose Monitoring and Clinical Pharmacist Collaboration to Improve Glycemic Control in Underserved Patients With Type 2 Diabetes.

PURPOSE: The purpose of this study was to examine the effect of initiating use of a continuous glucose monitor (CGM) in patients being treated for type 2 diabetes mellitus, specifically those who face barriers to obtaining this device because of its cost. METHODS: This retrospective medical record review compared diabetes control of patients before and after use of a CGM device within a single primary care office. Patient medical records were reviewed 18 months after initial CGM was provided, and only those who received a CGM directly from the clinic were included in the review. Statistical analysis comparing the difference in mean baseline glycosylated hemoglobin (HbA1c) level with the first HbA1c level after CGM placement was completed using the paired t test for the primary outcome. FINDINGS: A total of 41 patients who obtained at least 1 CGM reader and a minimum of a 30-day supply of sensors from the clinic were included in the review. The primary outcome resulted in a significant reduction in the mean (SD) first HbA1c level after CGM placements of -1.9% (2.5%) (P < .001) with a total of 10 and 22 patients with an HbA1c level <7% and 8%, respectively. This mean (SD) reduction in HbA1c level was also seen in both insulin-treated patients (-1.8% [2.8%], n = 30) and non-insulin-treated patients (-2% [2.8%], n=11). The largest reduction in the first HbA1c level after CGM placement was seen in those patients provided a CGM along with collaborative care with a clinical pharmacist. These patients saw a mean (SD) decrease of -2.5% [2.7%] (n = 26) in their HbA1c level with a mean (SD) decrease of -0.8% (1.6%) (n = 15) for those not comanaged by the clinical pharmacist. IMPLICATIONS: The results of this study suggest that the use of CGM in the underserved population can lead to a significant improvement in glycemic control in patients with diabetes, regardless of treatment therapies used. Involving a multidisciplinary team in diabetes management, including clinical pharmacists, may further improve outcomes. Access to these devices in the underserved population may be crucial in reducing the risk of developing complications related to uncontrolled diabetes.

Validation of an international classification of disease, tenth revision, clinical modification (ICD-10-CM) algorithm in identifying severe hypoglycaemia events for real-world studies.

AIM: The transition to the ICD-10-CM coding system has reduced the utility of hypoglycaemia algorithms based on ICD-9-CM diagnosis codes in real-world studies of antidiabetic drugs. We mapped a validated ICD-9-CM hypoglycaemia algorithm to ICD-10-CM codes to create an ICD-10-CM hypoglycaemia algorithm and assessed its performance in identifying severe hypoglycaemia. MATERIALS AND METHODS: We assembled a cohort of Medicare patients with DM and linked electronic health record (EHR) data to the University of North Carolina Health System and identified candidate severe hypoglycaemia events from their Medicare claims using the ICD-10-CM hypoglycaemia algorithm. We confirmed severe hypoglycaemia by EHR review and computed a positive predictive value (PPV) of the algorithm to assess its performance. We refined the algorithm by removing poor performing codes (PPV ≤0.5) and computed a Cohen's κ statistic to evaluate the agreement of the EHR reviews. RESULTS: The algorithm identified 642 candidate severe hypoglycaemia events, and we confirmed 455 as true severe hypoglycaemia events, PPV of 0.709 (95% confidence interval: 0.672, 0.744). When we refined the algorithm, the PPV increased to 0.893 (0.862, 0.918) and missed <2.42% (<11) true severe hypoglycaemia events. Agreement between reviewers was high, κ = 0.93 (0.89, 0.97). CONCLUSIONS: We translated an ICD-9-CM hypoglycaemia algorithm to an ICD-10-CM version and found its performance was modest. The performance of the algorithm improved by removing poor performing codes at the trade-off of missing very few severe hypoglycaemia events. The algorithm has the potential to be used to identify severe hypoglycaemia in real-world studies of antidiabetic drugs.

Socio-economic disparities in hospital care among Dutch patients with diabetes mellitus.

AIM: Socio-economic status (SES) influences diabetes onset, progression and treatment. In this study, the associations between SES and use of hospital care were assessed, focusing on hospitalizations, technology and cardiovascular complications. MATERIALS AND METHODS: This was an observational cohort study comprising 196 695 patients with diabetes (all types and ages) treated in 65 hospitals across the Netherlands from 2019 to 2020 using reimbursement data. Patients were stratified in low, middle, or high SES based on residential areas derived from four-digit zip codes. RESULTS: Children and adults with low SES were hospitalized more often than patients with middle or high SES (children: 22%, 19% and 15%, respectively; p < .001, adults: 28%, 25% and 23%; p < .001). Patients with low SES used the least technology: no technology in 48% of children with low SES versus 40% with middle SES and 38% with high SES. In children, continuous subcutaneous insulin infusion (CSII) and real-time continuous glucose monitoring (rtCGM) use was higher in high SES {CSII: odds ratio (OR) 1.54 [95% confidence interval (CI) 1.35-1.76]; p < .001; rtCGM OR 1.39 [95% CI 1.20-1.61]; p < .001} and middle SES [CSII: OR 1.41 (95% CI 1.24-1.62); p < .001; rtCGM: OR 1.27 (95% CI 1.09-1.47); p = .002] compared with low SES. Macrovascular (OR 0.78 (95% CI 0.75-0.80); p < .001) and microvascular complications [OR 0.95 (95% CI 0.93-0.98); p < .001] occurred less in high than in low SES. CONCLUSIONS: Socio-economic disparities were observed in patients with diabetes treated in Dutch hospitals, where basic health care is covered. Patients with low SES were hospitalized more often, used less technology, and adults with high SES showed fewer cardiovascular complications. These inequities warrant attention to guarantee equal outcomes for all.

Factors and economic burden of non-severe hypoglycemia among insulin-treated type 2 diabetes patients: a cross-sectional study.

OBJECTIVE: This cross-sectional survey was performed to assess the prevalence, factors, and economic burden of non-severe hypoglycemia among insulin-treated type 2 diabetes (T2D) patients in northern Thailand. METHODS: Between April 2021 and August 2022, 600 participants were evaluated via structured questionnaires containing sociodemographic and clinical characteristics, medications, and economic burden. Patients were divided into two groups (having and not having non-severe hypoglycemia). Variables with a p value <.05 in the univariate model were included in the multivariate model. RESULTS: The percentage of non-severe hypoglycemia was 50.3% (302/600). Of all participants, the average age was 61.4 ± 26.0 years, 55.7% were female, 53.5% used premix insulin, and the average duration of diabetes was 16.1 ± 10.0 years. Multivariate logistic regression analysis indicated that age (OR = .96; p <.001), duration of diabetes (OR = 1.04; p <.001), BMI (OR = .95; p = .002), thiazolidinedione (OR = 1.56; p = .012) and insulin regimens were associated with having non-severe hypoglycemia. Compared to basal insulin, basal bolus (OR = 6.93; p = .001), basal plus (OR = 3.58; p <.001), and premix insulin (OR = 1.83; p =.003) were associated with hypoglycemia. Greater numbers of sick leave were found in the hypoglycemia group (14 vs 4 patients, p = .029). CONCLUSIONS: These findings help to individuate those patients who are at higher risk of non-severe hypoglycemia in insulin-treated T2D patients. Compared to the non-hypoglycemia group, patients with hypoglycemia were younger, had longer diabetes duration, lower BMI, received thiazolidinedione and insulin regimens such as premix, basal plus, or basal bolus insulins, and more productivity loss.

A population-based cohort defined risk of hyperkalemia after initiating SGLT-2 inhibitors, GLP1 receptor agonists or DPP-4 inhibitors to patients with chronic kidney disease and type 2 diabetes.

Hyperkalemia is a common adverse event in patients with chronic kidney disease (CKD) and type 2 diabetes and limits the use of guideline-recommended therapies such as renin-angiotensin system inhibitors. Here, we evaluated the comparative effects of sodium-glucose cotransporter-2 inhibitors (SGLT-2i), glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) on the risk of hyperkalemia. We conducted a population-based active-comparator, new-user cohort study using claims data from Medicare and two large United States commercial insurance databases (April 2013-April 2022). People with CKD stages 3-4 and type 2 diabetes who newly initiated SGLT-2i vs. DPP-4i (141671 patients), GLP-1RA vs. DPP-4i (159545 patients) and SGLT-2i vs. GLP-1RA (93033 patients) were included. The primary outcome was hyperkalemia diagnosed in inpatient or outpatient settings. Secondary outcomes included hyperkalemia diagnosed in inpatient or emergency department setting, and serum potassium levels of 5.5 mmol/L or more. Pooled hazard ratios and rate differences were estimated after propensity score matching to adjust for over 140 potential confounders. Initiation of SGLT-2i was associated with a lower risk of hyperkalemia compared with DPP-4i (hazard ratio 0.74; 95% confidence interval 0.68-0.80) and contrasted to GLP-1RA (0.92; 0.86-0.99). Compared with DPP-4i, GLP-1RA were also associated with a lower risk of hyperkalemia (0.80; 0.75-0.86). Corresponding absolute rate differences/1000 person-years were -24.8 (95% confidence interval -31.8 to -17.7), -5.0 (-10.9 to 0.8), and -17.7 (-23.4 to -12.1), respectively. Similar findings were observed for the secondary outcomes, among subgroups, and across single agents within the SGLT-2i and GLP-1RA classes. Thus, SGLT-2i and GLP-1RA are associated with a lower risk of hyperkalemia than DPP-4i in patients with CKD and type 2 diabetes, further supporting the use of these drugs in this population.

Real-World Analysis of Long-Acting and NPH-Containing Insulins on Glycemic Control.

Introduction Affordability of insulin products has become a concern in the past several years as the average price of various insulin products has increased. While awaiting legislation at the federal level that would address issues leading to high insulin costs, providers may have shifted prescribing practices to prescribe the lowest-priced insulin products to achieve patients' treatment goals. Objective To compare the prevalence of hypoglycemic events between patients receiving lower-cost neutral protamine Hagedorn (NPH)-containing human insulins and higher-cost long-acting insulin analogs in Medicare Part D enrollees within a management services organization, as well as assessing glycemic control and changes in body mass index. Methods This was a multicenter, retrospective study conducted at three primary care clinics. The co-primary outcomes were percent difference of documented mild and severe hypoglycemic events between individuals receiving NPH-containing human insulin and long-acting insulin. Results A total of 72 patients met inclusion criteria and were receiving NPH-containing human insulins or the long-acting insulin analogs, 15 and 57 patients, respectively. Severe hypoglycemic events occurred in 3.5% vs 0% of the long-acting insulin analog and NPH-containing human insulin group, respectively (P = 0.999). Mild hypoglycemic episodes were experienced by 31.6% versus 33.3% of long-acting insulin analog and NPH, respectively (P = 0.539). For secondary outcomes, no difference was observed in glycemic control outcomes across insulin groups. Conclusion Among Medicare Part D patients with type 2 diabetes mellitus, the use of NPH-containing human insulins was not associated with an increased risk of mild or severe hypoglycemia-related episodes or reduced glycemic control compared with long-acting insulin. Study findings suggest that lower-cost, NPH-containing human insulins may be an alternative to higher-cost, long-acting insulin analogs.

Comparative Cardiovascular Effectiveness and Safety of SGLT-2 Inhibitors, GLP-1 Receptor Agonists, and DPP-4 Inhibitors According to Frailty in Type 2 Diabetes.

OBJECTIVE: To evaluate the comparative cardiovascular effectiveness and safety of sodium-glucose cotransporter 2 inhibitors (SGLT-2is), glucagon-like peptide 1 receptor agonists (GLP-1RAs), and dipeptidyl peptidase 4 inhibitors (DPP-4is) in older adults with type 2 diabetes (T2D) across different frailty strata. RESEARCH DESIGN AND METHODS: We performed three 1:1 propensity score-matched cohort studies, each stratified by three frailty strata, using data from Medicare beneficiaries (2013-2019) with T2D who initiated SGLT-2is, GLP-1RAs, or DPP-4is. In time-to-event analyses, we assessed the primary cardiovascular effectiveness composite outcome of acute myocardial infarction, ischemic stroke, hospitalization for heart failure, and all-cause mortality. The primary safety outcome was a composite of severe adverse events that have been linked to SGLT-2i or GLP-1RA use. RESULTS: Compared with DPP-4is, the overall hazard ratio (HR) for the primary effectiveness outcome associated with SGLT-2is (n = 120,202 matched pairs) was 0.72 (95% CI 0.69-0.75), corresponding to an incidence rate difference (IRD) of -13.35 (95% CI -15.06 to -11.64). IRD ranged from -6.74 (95% CI -8.61 to -4.87) in nonfrail to -27.24 (95% CI -41.64 to -12.84) in frail people (P for interaction < 0.01). Consistent benefits were observed for GLP-1RAs compared with DPP-4is (n = 113,864), with an overall HR of 0.74 (95% CI 0.71-0.77) and an IRD of -15.49 (95% CI -17.46 to -13.52). IRD in the lowest frailty stratum was -7.02 (95% CI -9.23 to -4.81) and -25.88 (95% CI -38.30 to -13.46) in the highest (P for interaction < 0.01). Results for SGLT-2is versus GLP-1RAs (n = 89,865) were comparable. Severe adverse events were not more frequent with SGLT-2is or GLP-1RAs than DPP-4is. CONCLUSIONS: SGLT-2is and GLP-1RAs safely improved cardiovascular outcomes and all-cause mortality, with the largest absolute benefits among frail people.

In praise of pioglitazone: An economically efficacious therapy for type 2 diabetes and other manifestations of the metabolic syndrome.

Pioglitazone improves glycaemic control, not only by lowering insulin resistance, but also by improving beta cell function. Because of the improved beta cell function the glycaemic control that occurs with pioglitazone is prolonged. Pioglitazone has positive effects not only on cardiac risk factors and surrogate measures of cardiovascular disease, it also lowers the incidence of cardiac events in patients with diabetes. The recurrence of transient ischaemic attack and ischaemic stroke is also reduced in non-diabetic, insulin-resistant subjects. Utilized at preclinical stages (but not later) of heart failure, pioglitazone improves diastolic function and avoids progression to heart failure. Pioglitazone, through suppression of atrial remodelling, also decreases the incidence of atrial fibrillation. The manifestations of diseases associated with insulin resistance (non-alcoholic steatohepatitis and polycystic ovary disease) are also improved with pioglitazone. Pioglitazone may possibly improve psoriasis and other dermopathies. Pioglitazone is therefore an inexpensive and efficacious drug for the insulin-resistant subject with diabetes that is underutilized because of biases that have evolved from the toxicities of other thiazolidinediones.

Primary Occurrence of Cardiovascular Events After Adding Sodium-Glucose Cotransporter-2 Inhibitors or Glucagon-like Peptide-1 Receptor Agonists Compared With Dipeptidyl Peptidase-4 Inhibitors: A Cohort Study in Veterans With Diabetes.

BACKGROUND: The effectiveness of glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) in preventing major adverse cardiac events (MACE) is uncertain for those without preexisting cardiovascular disease. OBJECTIVE: To test the hypothesis that MACE incidence was lower with the addition of GLP1RA or SGLT2i compared with dipeptidyl peptidase-4 inhibitors (DPP4i) for primary cardiovascular prevention. DESIGN: Retrospective cohort study of U.S. veterans from 2001 to 2019. SETTING: Veterans aged 18 years or older receiving care from the Veterans Health Administration, with data linkage to Medicare, Medicaid, and the National Death Index. PATIENTS: Veterans adding GLP1RA, SGLT2i, or DPP4i onto metformin, sulfonylurea, or insulin treatment alone or in combination. Episodes were stratified by history of cardiovascular disease. MEASUREMENTS: Study outcomes were MACE (acute myocardial infarction, stroke, or cardiovascular death) and heart failure (HF) hospitalization. Cox models compared the outcome between medication groups using pairwise comparisons in a weighted cohort adjusted for covariates. RESULTS: The cohort included 28 759 GLP1RA versus 28 628 DPP4i weighted pairs and 21 200 SGLT2i versus 21 170 DPP4i weighted pairs. Median age was 67 years, and diabetes duration was 8.5 years. Glucagon-like peptide-1 receptor agonists were associated with lower MACE and HF versus DPP4i (adjusted hazard ratio [aHR], 0.82 [95% CI, 0.72 to 0.94]), yielding an adjusted risk difference (aRD) of 3.2 events (CI, 1.1 to 5.0) per 1000 person-years. Sodium-glucose cotransporter-2 inhibitors were not associated with MACE and HF (aHR, 0.91 [CI, 0.78 to 1.08]; aRD, 1.28 [-1.12 to 3.32]) compared with DPP4i. LIMITATION: Residual confounding; use of DPP4i, GLP1RA, and SGLT2i as first-line therapies were not examined. CONCLUSION: The addition of GLP1RA was associated with primary reductions of MACE and HF hospitalization compared with DPP4i use; SGLT2i addition was not associated with primary MACE prevention. PRIMARY FUNDING SOURCE: VA Clinical Science Research and Development and supported in part by the Centers for Diabetes Translation Research.

The improved health utility of once-weekly subcutaneous semaglutide 2.4 mg compared with placebo in the STEP 1-4 obesity trials.

AIM: To assess health utility values in the Semaglutide Treatment Effect in People with obesity (STEP) 1-4 trials. MATERIALS AND METHODS: The STEP 1-4 phase 3a, 68-week, double-blind randomized controlled trials assessed the efficacy and safety of semaglutide 2.4 mg versus placebo in individuals with a body mass index (BMI) of 30 kg/m2 or higher or a BMI of 27 kg/m2 or higher and at least one comorbidity (STEP 1, 3 and 4), or a BMI of 27 kg/m2 or higher and type 2 diabetes (STEP 2). Patients received lifestyle intervention plus intensive behavioural therapy in STEP 3. Health-related quality of life was assessed using the Short Form 36-item Health Survey version 2 (SF-36v2) at baseline and week 68. Scores were converted into Short Form Six-Dimension version 2 (SF-6Dv2) utility scores or mapped onto the European Quality of Life Five-Dimension Three-Level (EQ-5D-3L) utility index using UK health utility weights. RESULTS: At week 68, semaglutide 2.4 mg was associated with minor health utility score improvements from baseline (all trials), while scores for placebo typically decreased. SF-6Dv2 treatment differences by week 68 for semaglutide 2.4 mg versus placebo were significant in STEP 1 and 4 (P ≤ .001), but not STEP 2 or 3. EQ-5D-3L treatment differences by week 68 for semaglutide 2.4 mg versus placebo were significant in STEP 1, 2 and 4 (P < .001 for all), but not STEP 3. CONCLUSIONS: Semaglutide 2.4 mg was associated with improvement in health utility scores compared with placebo, reaching statistical significance in STEP 1, 2 and 4.

Sulfonylureas as second line therapy for type 2 diabetes among veterans: Results from a National Longitudinal Cohort Study.

AIMS: To assess if switching to or adding sulfonylureas increases major adverse cardiovascular events (MACE) or severe hypoglycemia versus remaining on metformin alone. MATERIALS AND METHODS: This was a retrospective, longitudinal cohort utilizing United States Veterans Health Administration and Medicare data. Veterans with type 2 diabetes on metformin monotherapy between 2004 and 2006 were identified. Follow-up occurred through 2016. Those treated with either metformin plus a second-generation sulfonylurea (N = 45,305) or converted from metformin to a second-generation sulfonylurea (N = 2813) were compared to those receiving metformin monotherapy (N = 65,550). Hazard ratios (HR) and 95%CI from longitudinal competing risk Cox models were used to measure the association between sulfonylureas and outcomes. RESULTS: Switching to or adding a sulfonylurea to metformin was associated with 3 times the risk of severe hypoglycemia versus metformin monotherapy (HR:3.44, 95% CI: 3.06,3.85 and HR: 3.08, 95% CI: 2.77,3.42, respectively). Switching to or adding a sulfonylurea to metformin was associated with a 7-19% higher risk of MACE versus metformin monotherapy (HR: 1.07, 95% CI: 1.00,1.14 and HR: 1.19, 95% CI: 1.13,1.25, respectively). CONCLUSIONS: Switching to and adding second-generation sulfonylureas was associated an increase in severe hypoglycemia and MACE versus remaining on metformin alone. In an era where guidelines recommend diabetes therapies based on compelling indications, safety outcomes should be a key consideration when selecting therapy.

Risk of Severe Hypoglycemia With Newer Second-line Glucose-lowering Medications in Older Adults With Type 2 Diabetes Stratified by Known Indicators of Hypoglycemia Risk.

BACKGROUND: Severe hypoglycemia is associated with adverse clinical outcomes. We evaluated the risk of severe hypoglycemia in older adults initiating newer glucose-lowering medications overall and across strata of known indicators of high hypoglycemia risk. METHODS: We conducted a comparative-effectiveness cohort study of older adults aged >65 years with type 2 diabetes initiating sodium-glucose cotransporter 2 inhibitors (SGLT2i) versus dipeptidyl peptidase-4 inhibitors (DPP-4i) or SGLT2i versus glucagon-like peptide-1 receptor agonists (GLP-1RA) using Medicare claims (3/2013-12/2018) and Medicare-linked-electronic health records. We identified severe hypoglycemia requiring emergency or inpatient visits using validated algorithms. After 1:1 propensity score matching, we estimated hazard ratios (HR) and rate differences (RD) per 1,000 person-years. Analyses were stratified by baseline insulin, sulfonylurea, cardiovascular disease (CVD), chronic kidney disease (CKD), and frailty. RESULTS: Over a median follow-up of 7 (interquartile range: 4-16) months, SGLT2i was associated with a reduced risk of hypoglycemia versus DPP-4i (HR 0.75 [0.68, 0.83]; RD -3.21 [-4.29, -2.12]), and versus GLP-1RA (HR 0.90 [0.82, 0.98]; RD -1.33 [-2.44, -0.23]). RD for SGLT2i versus DPP-4i was larger in patients using baseline insulin than in those not, although HRs were similar. In patients using baseline sulfonylurea, the risk of hypoglycemia was lower in SGLT2i versus DPP-4i (HR 0.57 [0.49, 0.65], RD -6.80 [-8.43, -5.16]), while the association was near-null in those without baseline sulfonylurea. Results stratified by baseline CVD, CKD and frailty were similar to the overall cohort findings. Findings for the GLP-1RA comparison were similar. CONCLUSIONS: SGLT2i was associated with a lower hypoglycemia risk versus incretin-based medications, with larger associations in patients using baseline insulin or sulfonylurea.

Identifying patients with type 2 diabetes who might benefit from insulin pump therapy: Literature review, clinical opportunities, potential benefits and challenges.

The global prevalence and increasing incidence rates of type 2 diabetes (T2D) have rippling effects on healthcare costs and diminishing quality of life. Despite advances in technology, continuous subcutaneous insulin infusion (CSII), or insulin pump therapy, is rarely being recommended by healthcare professionals and is underutilized in T2D management. This review analyses the available literature on CSII use in T2D patients. In addition, it discusses which groups of patients may benefit from CSII, identifies potential challenges associated with CSII use, and suggests future directions for research to expand the applicability of this technology to the broader T2D population.

Long-term cost-effectiveness analysis of tirzepatide versus semaglutide 1.0 mg for the management of type 2 diabetes in the United States.

AIM: To evaluate the long-term cost-effectiveness of tirzepatide (5, 10 and 15 mg doses), a novel glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, versus semaglutide 1.0 mg, an injectable glucagon-like peptide-1 receptor agonist, based on the results of the head-to-head SURPASS-2 trial, from a US healthcare payer perspective. MATERIALS AND METHODS: The PRIME Type 2 Diabetes Model was used to make projections of clinical and cost outcomes over a 50-year time horizon. Baseline cohort characteristics, treatment effects and adverse event rates were derived from the 40-week SURPASS-2 trial. Intensification to insulin therapy occurred when HbA1c reached 7.5%, in line with American Diabetes Association recommendations. Direct costs in 2021 US dollars (US$) and health state utilities were derived from published sources. Future costs and clinical benefits were discounted at 3% annually. RESULTS: All three doses of tirzepatide were associated with lower diabetes-related complication rates, improved life expectancy, improved quality-adjusted life expectancy and higher direct costs versus semaglutide. This resulted in incremental cost-effectiveness ratios of US$ 75 803, 58 908 and 48 785 per quality-adjusted life year gained for tirzepatide 5, 10 and 15 mg, respectively, versus semaglutide. Tirzepatide remained cost-effective versus semaglutide over a range of sensitivity analyses. CONCLUSIONS: Long-term projections based on the SURPASS-2 trial results indicate that 5, 10 and 15 mg doses of tirzepatide are likely to be cost-effective versus semaglutide 1.0 mg for the treatment of type 2 diabetes in the United States.

Cardiovascular outcomes trial data from EMPA-REG OUTCOME, CAROLINA and CARMELINA: Assessment of a novel staging system for type 2 diabetes.

AIMS: To apply the diabetes staging system (DSS), a novel disease staging system similar to what is used in oncology but designed to improve diabetes management, to three large type 2 diabetes (T2D) cardiovascular (CV) outcome trials to assess whether increasing DSS stage was associated with higher rates of all-cause mortality (ACM) and/or CV death. MATERIALS AND METHODS: The DSS uses discrete CV events (none to ≥3: Stage 1 to 4), end-stage kidney disease (Stage 5) and microvascular complications (none to 3: A to D) to determine disease stage in individuals with T2D. The DSS stage for patients from the CAROLINA, EMPA-REG OUTCOME and CARMELINA trials was determined. Incidence rates for ACM/CV death were calculated across DSS stages and Cox regression analyses were performed. RESULTS: The risk of ACM or CV death increased with increasing DSS (Stage 1 to 5; P for trend <0.0001) in all trials. In CAROLINA, the risk of ACM and CV death increased with increasing number of microvascular complications (A to D; both P for trend <0.0001), similar in CARMELINA (P for trend = 0.0020 and 0.0005, respectively). In EMPA-REG OUTCOME, having all three microvascular complications (Stage D), versus none, increased the risk of ACM and CV death (P = 0.0015 and 0.0010, respectively). CONCLUSIONS: Applying the DSS across T2D clinical trial populations with different CV risk revealed a significantly increased risk of ACM and CV death with higher DSS stage. The DSS may merit assessment in other T2D populations and evaluation of the impact of additional outcomes, such as heart failure, could also be worthwhile.

Post-Authorization Safety Study of Hospitalization for Acute Kidney Injury in Patients with Type 2 Diabetes Exposed to Dapagliflozin in a Real-World Setting.

INTRODUCTION: Dapagliflozin is a sodium-glucose cotransporter 2 inhibitor approved to treat type 2 diabetes mellitus (T2DM), among other conditions. When dapagliflozin was approved in Europe for treating T2DM (2012), potential safety concerns regarding its effect on kidney function resulted in this post-authorization safety study to assess hospitalization for acute kidney injury (hAKI) among dapagliflozin initiators in a real-world setting. OBJECTIVE: The aim of this study was to evaluate the incidence of hAKI in adults with T2DM initiating dapagliflozin compared with other glucose-lowering drugs (GLDs). METHODS: This noninterventional cohort study identified new users of dapagliflozin and comparator GLDs from November 2012 to February 2019 from three longitudinal, population-based data sources: Clinical Practice Research Datalink (CPRD; United Kingdom), the HealthCore Integrated Research Database (HIRD; United States [US]), and Medicare (US). Electronic algorithms identified occurrences of hAKI, from which a sample underwent validation. Incidence rates for hAKI were calculated, and incidence rate ratios (IRRs) compared hAKI in dapagliflozin with comparator GLDs. Propensity score trimming and stratification were conducted for confounding adjustment. RESULTS: In all data sources, dapagliflozin initiators had a lower hAKI incidence rate than comparator GLD initiators (adjusted IRRs: CPRD, 0.44 [95% confidence interval (CI), 0.22-0.86]; HIRD, 0.76 [95% CI, 0.62-0.93]; Medicare, 0.69 [95% CI, 0.59-0.79]). The adjusted IRR pooled across the data sources was 0.70 (95% CI, 0.62-0.78). Results from sensitivity and stratified analyses were consistent with the primary analysis. CONCLUSIONS: This study, with > 34,000 person-years of real-world dapagliflozin exposure, suggests a decreased risk of hAKI in patients with T2DM exposed to dapagliflozin, aligning with results from dapagliflozin clinical trials. STUDY REGISTRATION: European Union Post-Authorisation Studies Register, EUPAS 11684; ClinicalTrials.gov, NCT02695082.

Hybrid Closed-Loop Insulin Pump Technology Can Be Safely Used in the Inpatient Setting.

BACKGROUND: Hybrid closed-loop (HCL) systems, also known as automated insulin delivery systems, are a rapidly growing technology in diabetes management. Because more patients are using these systems in the outpatient setting, it is important to also assess inpatient safety to determine whether HCL use can be continued when those patients become hospitalized. METHODS: The records of patients using HCL technology on admission to our hospital between June 1, 2020, and June 30, 2021, were analyzed. RESULTS: The final analysis included 71 patients divided into 3 categories based on their pump use as an inpatient: (1) HCL users; (2) manual pump users; and (3) pump removed. All cohorts were similar in age, sex, race, hemoglobin A1C at admission, and in Medicare Severity Diagnosis Related Group. Pairwise comparisons indicated that patient-stay mean glucose levels, frequency of patient-specific hyperglycemic measurements, and frequency of hypoglycemic events were similar between all groups. No adverse events, particularly occurrences of diabetic ketoacidosis, pump site complications or infection, or equipment malfunction, were reported. CONCLUSION: This preliminary case series review indicates that continued use of HCL technology in the hospital is safe. Moreover, glycemic control in HCL users was comparable with that in those using insulin pump with manual settings and those converted to basal-bolus insulin therapy.