Glycemic control and neonatal outcomes in women with gestational diabetes mellitus treated using glyburide, metformin, or insulin: a pairwise and network meta-analysis.

AIMS: We aimed to assess the comparative efficiency and safety of the use of glyburide, metformin, and insulin in gestational diabetes mellitus (GDM). METHODS: We searched for randomized controlled trials that compared glyburide, metformin, and insulin in GDM. Data regarding glycemic control and neonatal safety were collected and analyzed in pairwise and network meta-analyses. RESULTS: A total of 4533 individuals from 23 trials were included. Compared with glyburide, metformin reduced 2-h postprandial blood glucose (2HPG) to a greater extent (standard mean difference (SMD) 0.18; 95% credible interval (CI) 0.01, 0.34). There were significantly lower prevalence of neonatal hypoglycemia (risk difference (RD) - 0.07; 95%CI - 0.11, - 0.02) and preeclampsia (RD - 0.03; 95%CI - 0.06, 0) in the metformin group than in the insulin group. The metformin group had significantly lower birth weight (SMD - 0.17; 95%CI - 0.25, - 0.08) and maternal weight gain (SMD - 0.61; 95%CI - 0.86,- 0.35) compared with the insulin group. Network meta-analysis suggested that metformin had the highest probability of successfully controlling glycemia and preventing neonatal complications. CONCLUSIONS: The present meta-analysis suggests that metformin may be as effective as insulin for glycemic control and is the most promising drug for the prevention of neonatal and maternal complications.

Trends in Insulin Types and Devices Used by Adults With Type 2 Diabetes in the United States, 2016 to 2020.

Importance: Despite rising costs and public scrutiny devoted to insulin, less is known regarding recent trends in its ambulatory use in the United States. Objective: To characterize trends in ambulatory insulin use, overall and based on insulin characteristics, among adults with type 2 diabetes in the United States from January 1, 2016, through December 31, 2020. Design, Setting, and Participants: This serial cross-sectional study included patients whose data were collected in IQVIA's National Disease and Therapeutic Index (NDTI), a 2-stage, all-payer, nationally representative audit of outpatient care. Approximately 4800 physicians each calendar quarter completed a form for 2 consecutive days regarding visits for each of their patients, including diagnoses, treatments, and demographic information. Data were collected from January 2016 through December 2020. Exposures: Ambulatory use of insulin. Main Outcomes and Measures: Nationally representative projections for ambulatory use of insulin (ie, treatment visits), overall and aggregated by insulin molecule (insulins regular, neutral protamine Hagedorn [NPH], lispro, glulisine, glargine, detemir, degludec, and aspart), delivery devices (vials/syringes or pens), therapeutic class (short-acting, rapid-acting, long-acting, intermediate-acting, and premixed insulin), insulin type (human, analog, and biosimilar), and date of approval (newer: before 2010; and older: after 2010). Results: There were 27 860 691 insulin treatment visits between 2016 and 2020. Among all patient encounters that indicated use of insulin in 2020, 1 989 154 (43.9%) were among those aged 60 to 74 years; 2 372 629 (52.4%) among men; 2 646 247 (58.4%) among White patients; 811 639 (17.9%) among Black patients; and 701 912 (15.5%) among Hispanic patients. Insulin glargine was the most frequently used insulin from 2016 to 2020, accounting for approximately half of treatment visits (eg, 2020: 2.6 of 4.9 million visits; 95% CI, 2.1-3.1 million). Among insulin classes, long-acting insulin accounted for approximately two-thirds of treatment visits during this period (eg, 2020: 3.7 million visits; 95% CI, 3.0-4.4 million). Treatment visits for insulin pens increased from 36.1% in 2016 (2.2 of 6.0 million visits; 95% CI, 1.7-2.7 million) to 58.7% in 2020 (2.9 million visits; 95% CI, 2.3-3.5 million), while use of insulin vials/syringes declined in parallel. Analog insulin use predominated and accounted for more than 80% of total treatment visits across all years (eg, 2020: 4.3 million visits; 95% CI, 3.4-5.1 million). Newer insulins were increasingly used, from 18.1% of total treatment visits in 2016 (1.1 million visits; 95% CI, 0.8-1.4 million) to 40.9% in 2020 (2.0 million visits; 95% CI, 1.5-2.5 million). The use of biosimilar insulin, which was first approved in 2015, increased from 2.6% in 2017 (0.1 of 5.3 million visits; 95% CI, 0.04-0.2 million) to 8.2% in 2020 (0.4 million visits; 95% CI, 0.2-0.6 million) of total insulin treatment visits. The total number of insulin treatment visits declined from a peak of 6.0 million visits in 2016 to a nadir of 4.9 million visits in 2020 (approximately 18% decline). Conclusions and Relevance: In this study, ambulatory insulin use in the United States during the past 5 years remained dominated by the use of insulin analogs and insulin pen delivery devices, with increasing uptake of newer products as they have been brought to market.

Health economics and effectiveness analysis of generic anti-diabetic medication from jan aushadhi: An ambispective study in community pharmacy.

BACKGROUND AND AIMS: The pharmacotherapy of diabetes mellitus has a colossal economic burden, which demands cost-effective therapy, as the patients have to be on treatment lifelong. Thus, our study aimed to study cost variation and effectiveness analysis among type 2 diabetic patients. METHODOLOGY: We conducted ambi-spective research for the adult type 2 diabetes patients who underwent substitution of branded anti-diabetic therapy with the generic alternative from "Jan Aushadhi" for more than one month and were not using any other anti-diabetic medicines. RESULTS: Among the monotherapy, glimepiride (2500%) and vildagliptin (20%) were found to have wide and narrow percentage cost variation respectively whereas, metformin Hcl 500 mg plus voglibose 0.2 mg was estimated to have the highest (891.7%), and teneligliptin 20 mg plus metformin 500 mg with the lowest (137.29%) cost variation in case of combined therapy. Similarly, generic substitutions were cost-effective in most patients, whereas the increased cost of brand drugs didn't justify its effectiveness. There was no significant difference between glycated hemoglobin (HbA1c) of brand and generic anti-diabetic drugs (t = 0.774, p = 0.22). CONCLUSION: The adaptation of generic drugs can significantly reduce the economic burden of treatment. Thus, healthcare professionals should promote generic medicines by prescribing & dispensing generic drugs and erasing misconceptions prevailing among patients.

The therapeutic effects of glucagon-like peptide-1 receptor agonists and metformin on polycystic ovary syndrome: A protocol for systematic review and meta-analysis.

BACKGROUND: Obesity and insulin resistance (IR) are common in polycystic ovary syndrome (PCOS), which contribute to reproductive and metabolic abnormalities. Metformin increases insulin sensitivity, but it is associated with unsatisfied benefits of weight loss. Recent studies have reported that glucagon-like peptide 1 (GLP-1) receptor agonists improve IR and reduce weight in women with PCOS. We conducted a systematic review and meta-analysis to compare the effects between GLP-1 receptor agonists and metformin, and between GLP-1 receptor agonist-metformin combination and GLP-1 receptor agonists in overweight/obese women with PCOS on anthropometric, metabolic, reproductive outcomes. METHODS: Databases including PubMed, EMBASE, Web of Science, and Cochrane Library were selected to search for randomized controlled trials (RCTs) published in English up to March 2020. Eligible studies were identified according to the inclusion criteria. The primary outcomes included menstrual frequency, body mass index (BMI), total testosterone, and the homeostatic model assessment of insulin resistance. GRADE criteria were implemented to assess the quality of evidence for primary outcomes. RESULTS: Seven RCTs were selected for analysis, comprising 464 overweight/obese women with PCOS. In the low-quality evidence, a meta-analysis demonstrated that GLP-1 receptor agonists showed better effects relative to metformin on the reduction of body mass index (mean difference - 1.72; 95% confidence interval -2.46 to -0.99, P < .001) and homeostatic model assessment of insulin resistance (standard mean difference -0.37; 95% confidence interval - 0.60,- 0.15, P = .001). Moreover, the combination therapy exhibited similar effects on primary outcomes relative to GLP-1 receptor agonist alone. GLP-1 receptor agonists were also found to be associated with lower abdominal girth compared to metformin. A meta-analysis of gastrointestinal discomfort showed no significant difference between GLP-1 receptor agonist and metformin therapies, and between the combination therapy and GLP-1 receptor agonist alone. CONCLUSIONS: GLP-1 receptor agonists appear to be more beneficial for weight loss and IR improvement compared to metformin for overweight/obese women with PCOS. However, the combination treatment displays comparable effects with GLP-1 receptor agonist alone. The incidence of gastrointestinal discomforts was similar in different groups. However, the quality of the body of evidence is "low." Further prospective RCTs and cost-effectiveness analyses are also warranted to guide GLP-1 receptor agonists to treat women with PCOS.

Diabetes and kidney disease: emphasis on treatment with SGLT-2 inhibitors and GLP-1 receptor agonists.

Kidney disease is a frequent microvascular complication of both type 1 and type 2 diabetes. Historic trials have demonstrated that a tight glycaemic control is the most powerful approach to decrease the chances of developing diabetic nephropathy. However, having an HbA1c < 7% does not completely suppress the risk of kidney disease. The observed residual risk is likely ascribable to two phenomena: 1- the presence of risk factors and alterations additive to and independent of glycaemia, and 2- the activation of long-lasting imbalances by periods of exposure to uncontrolled glycemia, a phenomenon referred to as metabolic memory or legacy effect. Long-lasting oxidative stress, epigenetic alterations, cellular senescence, and the resulting chronic low-grade inflammation are all candidate mechanisms explaining the development of nephropathy despite proper control of risk factors. Recently, two classes of drugs, i.e. glucagon-like peptide (GLP) 1 receptor agonists (RA) and sodium-glucose transporter 2 inhibitors (SGLT-i) have changed this scenario. Indeed, cardiovascular outcome and other trials have clearly shown a renoprotective effect for these drugs, well-beyond their glucose-lowering properties. In this review, we summarize: 1- selected key trials and mechanisms underlying the development of diabetic kidney disease and 2- the results relative to renal endpoints in clinical trials of GLP-1 RA and SGLT-2i. Then, we briefly discuss some of the hypotheses posited to explain the marked renoprotective properties of these two classes, evidencing the still existing gaps in knowledge and proposing future directions to further implement the use of these powerful, disease-modifying drugs.

Determinants of treatment modification before and after implementation of the updated 2015 NICE guideline on type 2 diabetes: A retrospective cohort study.

AIMS: To identify patient-specific factors associated with early metformin treatment modification among type 2 diabetes patients before and after implementation of the updated 2015 NICE (National Institute for Health and Care Excellence) guideline. METHODS: We conducted a population-based cohort study using data from the Clinical Practice Research Datalink GOLD database (2009-2016). Patients ≥ 18 years, newly treated with metformin only, during the period of valid data collection were included. The first prescription defined start of follow-up. Determinants of treatment modification in two cohorts (before and after implementation of the updated guideline) were studied by time-dependent Cox proportional hazards regression. RESULTS: After implementation of the updated guideline, patients were less likely to receive sulphonylureas (62.3% vs 41.3%) or thiazolidediones (4.7% vs 2.2%) and more likely to receive dipeptidyl peptidase-4 inhibitors (15.8% vs 27.1%) or sodium-glucose cotransporter-2 inhibitors (0.8% vs 9.9%). Some determinants influenced general practitioners' prescribing differently after implementation of the updated guideline compared to before, including a high body mass index and heart failure. CONCLUSIONS: Our results indicate that a first step towards tailored prescribing has been made. However, not all determinants that are important to consider when prescribing second-line glucose-lowering agents were of influence on general practitioners' prescribing.

From glucose lowering agents to disease/diabetes modifying drugs: a "SIMPLE" approach for the treatment of type 2 diabetes.

During the last decade we experienced a surge in the number of glucose lowering agents that can be used to treat patients with type 2 diabetes. Especially important are the discoveries that sodium glucose co-transporter type 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) improve patients' cardiovascular and renal outcomes. Accordingly, various medical associations have updated their guidelines for the treatment of diabetes in this new era. Though not agreeing on every issue, these position-statements generally share a detailed and often complex workflow that may be too complicated for the busy and overworked primary care setting, where the majority of patients with type 2 diabetes are managed in many countries. Other guidelines, generally those from the cardiology associations focus primarily on the population of patients with high risk for or pre-existing cardiovascular disease, which represent only the minority of patients with type 2 diabetes. We believe that we should re-define SGLT2i and GLP-1 RA as diabetes/disease modifying drugs (DMDs) given the recent evidence of their cardiovascular and renal benefits. Based on this definition we have designed a SIMPLE approach in order to assist primary care teams in selecting the most appropriate therapy for their patients. We believe that most subjects newly diagnosed with type 2 diabetes should initiate early combination therapy with metformin and a prognosis changing DMD. The decision whether to use GLP-1 RA or SGLT2i should be made based on specific patient's risk factors and preferences. Importantly, DMDs are known to have a generally safe side-effect profile, with lower risk for hypoglycemia and weight gain, further promoting their wider usage. Early combination therapy with DMDs may improve the multiple pathophysiological abnormalities responsible for type 2 diabetes and its complications, thus resulting in the greatest long term benefits.

Thiazolidinediones, alpha-glucosidase inhibitors, meglitinides, sulfonylureas, and hepatocellular carcinoma risk: A meta-analysis.

BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related death worldwide. Effects of second-line oral antidiabetic medications on incident HCC risk in individuals with type 2 diabetes mellitus remain unclear. This study evaluated associations between sulfonylureas, thiazolidinediones, meglitinides and alpha-glucosidase inhibitors, and incident HCC risk. METHODS: We systematically reviewed all studies on PubMed, Embase and Web of Science databases. Studies were included if they documented: (1) exposure to oral antidiabetic medication classes; (2) HCC incidence; (3) relative risks/odds ratios (OR) for HCC incidence. Eight eligible observational studies were identified. We performed random-effects meta-analyses to calculate pooled adjusted ORs (aORs) and 95% confidence intervals (CI). RESULTS: Thiazolidinedione use (7 studies, 280,567 participants, 19,242 HCC cases) was associated with reduced HCC risk (aOR = 0.92, 95% CI = 0.86-0.97, I2 = 43%), including among Asian subjects (aOR = 0.90, 95% CI = 0.83-0.97), but not Western subjects (aOR = 0.95, 95% CI = 0.87-1.04). Alpha-glucosidase inhibitor use (3 studies, 56,791 participants, 11,069 HCC cases) was associated with increased HCC incidence (aOR = 1.08; 95% CI = 1.02-1.14, I2 = 21%). Sulfonylurea use (8 studies, 281,180 participants, 19,466 HCC cases) was associated with increased HCC risk in studies including patients with established liver disease (aOR = 1.06, 95% CI = 1.02-1.11, I2 = 75%). Meglitinide use (4 studies, 58,237 participants, 11,310 HCC cases) was not associated with HCC incidence (aOR = 1.19; 95% CI = 0.89-1.60, I2 = 72%). CONCLUSIONS: Thiazolidinedione use was associated with reduced HCC incidence in Asian individuals with diabetes. Alpha-glucosidase inhibitor or sulfonylurea use was associated with modestly increased HCC risk; future research should determine whether those agents should be avoided in patients with chronic liver disease.

Gaps in Evidence-Based Therapy Use in Insured Patients in the United States With Type 2 Diabetes Mellitus and Atherosclerotic Cardiovascular Disease.

Background Evidence-based therapies are generally underused for cardiovascular risk reduction; however, less is known about contemporary patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. Methods and Results Pharmacy and medical claims data from within Anthem were queried for patients with established atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Using an index date of April 18, 2018, we evaluated the proportion of patients with a prescription claim for any of the 3 evidence-based therapies on, or covering, the index date ±30 days: high-intensity statin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and sodium glucose cotransporter-2 inhibitor or glucagon-like peptide-1 receptor agonist. The potential benefit of achieving 100% adoption of all 3 evidence-based therapies was simulated using pooled treatment estimates from clinical trials. Of the 155 958 patients in the sample, 24.7% were using a high-intensity statin, 53.1% were using an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, and 9.9% were using either an sodium glucose cotransporter-2 inhibitor or glucagon-like peptide-1 receptor agonists. Overall, only 2.7% of the population were covered by prescriptions for all 3 evidence-based therapies, and 37.4% were on none of them. Over a 12-month period, 70.6% of patients saw a cardiologist, while only 18% saw an endocrinologist. Increasing the use of evidence-based therapies to 100% over 3 years of treatment could be expected to reduce 4546 major atherosclerotic cardiovascular events (myocardial infarction, stroke, or cardiovascular death) in eligible but untreated patients. Conclusions Alarming gaps exist in the contemporary use of evidence-based therapies in this large population of insured patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease. These data provide a call to action for patients, providers, industry, regulators, professional societies, and payers to close these gaps in care.

Approach to the Patient with MODY-Monogenic Diabetes.

Maturity-onset diabetes of the young, or MODY-monogenic diabetes, is a not-so-rare collection of inherited disorders of non-autoimmune diabetes mellitus that remains insufficiently diagnosed despite increasing awareness. These cases are important to efficiently and accurately diagnose, given the clinical implications of syndromic features, cost-effective treatment regimen, and the potential impact on multiple family members. Proper recognition of the clinical manifestations, family history, and cost-effective lab and genetic testing provide the diagnosis. All patients must undergo a thorough history, physical examination, multigenerational family history, lab evaluation (glycated hemoglobin A1c [HbA1c], glutamic acid decarboxylase antibodies [GADA], islet antigen 2 antibodies [IA-2A], and zinc transporter 8 [ZnT8] antibodies). The presence of clinical features with 3 (or more) negative antibodies may be indicative of MODY-monogenic diabetes, and is followed by genetic testing. Molecular genetic testing should be performed before attempting specific treatments in most cases. Additional testing that is helpful in determining the risk of MODY-monogenic diabetes is the MODY clinical risk calculator (>25% post-test probability in patients not treated with insulin within 6 months of diagnosis should trigger genetic testing) and 2-hour postprandial (after largest meal of day) urinary C-peptide to creatinine ratio (with a ≥0.2 nmol/mmol to distinguish HNF1A- or 4A-MODY from type 1 diabetes). Treatment, as well as monitoring for microvascular and macrovascular complications, is determined by the specific variant that is identified. In addition to the diagnostic approach, this article will highlight recent therapeutic advancements when patients no longer respond to first-line therapy (historically sulfonylurea treatment in many variants). LEARNING OBJECTIVES: Upon completion of this educational activity, participants should be able to. TARGET AUDIENCE: This continuing medical education activity should be of substantial interest to endocrinologists and all health care professionals who care for people with diabetes mellitus.

Relationships between time in range, glycemic variability including hypoglycemia and types of diabetes therapy in Japanese patients with type 2 diabetes mellitus: Hyogo Diabetes Hypoglycemia Cognition Complications study.

AIMS/INTRODUCTION: Continuous glucose monitoring (CGM) metrics, such as times in range (TIR) and time below range, have been shown to be useful as clinical targets that complement glycated hemoglobin (HbA1c) for patients with type 2 diabetes mellitus. We investigated the relationships between TIR, glycemic variability and patient characteristics in patients with type 2 diabetes mellitus. MATERIALS AND METHODS: We carried out continuous glucose monitoring in 281 outpatients with type 2 diabetes mellitus who participated in a multicenter cohort (Hyogo Diabetes Hypoglycemia Cognition Complications) study. RESULTS: The results are shown as the median (interquartile range). The age, disease duration and HbA1c were 68 years (62-71 years), 13 years (7-23 years) and 6.9% (6.5-7.5%), respectively. TIR and standard deviation obtained by continuous glucose monitoring worsened significantly with increasing disease duration. Multiple regression analyses showed that disease duration (standard partial regression coefficient, ß = -0.160, P = 0.003), diabetic peripheral neuropathy (ß = -0.106, P = 0.033) and urinary albumin excretion (ß = -0.100, P = 0.043) were useful explanatory factors for TIR. In contrast, HbA1c (ß = -0.398, P < 0.001) and the use of antidiabetic drugs potentially associated with severe hypoglycemia (ß = 0.180, P = 0.028), such as sulfonylureas, glinides and insulin, were useful explanatory factors for time below range in the elderly patients with type 2 diabetes mellitus. CONCLUSIONS: The results of this study suggest that disease duration and diabetic complications are associated with TIR deterioration. In addition, low HbA1c levels and the use of antidiabetic drugs potentially associated with severe hypoglycemia might worsen the time below range in the elderly.

Metformin Use Is Associated with a Lower Risk of Inflammatory Bowel Disease in Patients with Type 2 Diabetes Mellitus.

AIM: Our aim was to compare the risk of developing inflammatory bowel disease [IBD] between ever users and never users of metformin. METHODS: Patients with newly diagnosed type 2 diabetes mellitus from 1999 to 2005 were enrolled from Taiwan's National Health Insurance. A total of 340 211 ever users and 24 478 never users who were free from IBD on January 1, 2006 were followed up until December 31, 2011. Hazard ratios were estimated by Cox regression incorporating the inverse probability of treatment weighting using a propensity score. RESULTS: New-onset IBD was diagnosed in 6466 ever users and 750 never users. The respective incidence rates were 412.0 and 741.3 per 100 000 person-years and the hazard ratio for ever vs never users was 0.55 [95% confidence interval: 0.51-0.60]. A dose-response pattern was observed while comparing the tertiles of cumulative duration of metformin therapy to never users. The respective hazard ratios for the first [<26.0 months], second [26.0-58.3 months] and third [>58.3 months] tertiles were 1.00 [0.93-1.09], 0.57 [0.52-0.62] and 0.24 [0.22-0.26]. While patients treated with oral antidiabetic drugs [OADs] without metformin were treated as a reference group, the hazard ratios for patients treated with OADs with metformin, with insulin without metformin [with/without other OADs] and with insulin and metformin [with/without other OADs] were 0.52 [0.42-0.66], 0.95 [0.76-1.20] and 0.50 [0.40-0.62], respectively. CONCLUSION: A reduced risk of IBD is consistently observed in patients with type 2 diabetes mellitus who have been treated with metformin.

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.

SGLT2 inhibitors and GLP1 agonists administered without metformin compared to other glucose-lowering drugs in patients with type 2 diabetes mellitus to prevent cardiovascular events: A systematic review.

OBJECTIVES: To assess the efficacy of glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose co-transporter 2 (SGLT2) inhibitors, administered without metformin on cardiovascular outcomes in type 2 diabetes patients. METHODS: A systematic review was performed according to Cochrane's methodological standards. We included randomized clinical trials (RCTs) on adult type 2 diabetes patients, assessing the efficacy of SGLT2 inhibitors and GLP1-RAs compared to other glucose-lowering drugs and/or RCTs that presented data of a subgroup of type 2 diabetes patients without metformin use at baseline. The main outcome was the reduction of the risk of any major adverse cardiovascular events (MACE) reported individually or as a composite outcome. RESULTS: Five RCTs including 50,725 type 2 diabetes patients, of whom 10,013 had not received metformin, were included in this meta-analysis. Three of these studies assessed the efficacy of GLP1-RAs and two of SGLT2 inhibitors. In patients without metformin at baseline, GLP1-RAs in comparison with placebo reduced the risk of MACE significantly by 20% (HR: 0.80; 95% CI: 0.71-0.89). SGLT2 inhibitors also significantly reduced the risk of MACE by 32% (HR: 0.68; 95% CI: 0.57-0.81). CONCLUSIONS: SGLT2 inhibitors and GLP1-RAs provided without metformin at baseline may reduce the risk of MACE in comparison with placebo in type 2 diabetes patients at increased risk of cardiovascular events.

Antidiabetic Drugs in Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review.

INTRODUCTION: Considering that Alzheimer's disease (AD) and diabetes mellitus share pathophysiological features and AD remains with no cure, antidiabetic drugs like intranasal insulin, glitazones, metformin, and liraglutide are being tested as a potential treatment. OBJECTIVE: The aim of this systematic review was to assess the efficacy of antidiabetic drugs in patients with AD, mild cognitive impairment (MCI), or subjective cognitive complaints (SCCs). Cognition was studied as the primary outcome and modulation of AD biomarkers, and imaging was also assessed as a secondary outcome. METHODS: We conducted a search in the electronic databases PubMed/MEDLINE, EMBASE, and Scopus seeking clinical trials evaluating the effect on cognition of antidiabetic drugs in patients with AD, MCI, or SCCs. RESULTS: A total of 23 articles were found eligible. Intranasal regular insulin improved verbal memory in most studies, especially in apoE4- patients, but results in other cognitive domains were unclear. Detemir improved cognition after 2 months of treatment, but it did not after 4 months. Pioglitazone improved cognition in diabetic patients with AD or MCI in 3 clinical trials, but it is controversial as 2 other studies did not show effect. Metformin and liraglutide showed promising results, but further research is needed as just 2 clinical trials involved each of these drugs. Almost all drugs tested were shown to modulate AD biomarkers and imaging. CONCLUSIONS: Intranasal insulin, pioglitazone, metformin, and liraglutide are promising drugs that could be useful in the treatment of AD. However, many questions remain to be answered in future studies, so no particular antidiabetic drug can currently be recommended to treat AD.

Comparative Effectiveness of the Sodium-Glucose Cotransporter 2 Inhibitor Empagliflozin Versus Other Antihyperglycemics on Risk of Major Adverse Kidney Events.

OBJECTIVE: To examine the comparative effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin and other non-SGLT2i antihyperglycemics on the risk of major adverse kidney events (MAKE) of estimated glomerular filtration rate (eGFR) decline >50%, end-stage kidney disease, or all-cause mortality. RESEARCH DESIGN AND METHODS: In a cohort study of 379,033 new users of empagliflozin or other non-SGLT2i antihyperglycemics, predefined variables and covariates identified by a high-dimensional variable selection algorithm were used to build propensity scores. Weighted survival analyses were then applied to estimate the risk of MAKE. RESULTS: Compared with other antihyperglycemics, empagliflozin use was associated with 0.99 (95% CI 0.51, 1.55) mL/min/1.73 m2 less annual reduction in eGFR, 0.25 (95% CI 0.16, 0.33) kg/m2 more annual decrease in BMI, and reduced risk of MAKE (hazard ratio [HR] 0.68 [95% CI 0.64, 0.73]). Empagliflozin use was associated with reduced risk of MAKE in eGFR ≥90, ≥60 to <90, ≥45 to <60, and ≥30 to <45 mL/min/1.73 m2 (HR 0.70 [95% CI 0.60, 0.82], 0.66 [0.60, 0.73], 0.78 [0.69, 0.89]), and 0.71 [0.55, 0.92], respectively), in participants without albuminuria, with microalbuminuria and macroalbuminuria (HR 0.65 [95% CI 0.57, 0.75], 0.72 [0.66. 0.79], and 0.74 [0.62, 0.88], respectively), and in participants with and without cardiovascular disease (HR 0.67 [95% CI 0.61, 0.74] and 0.76 [0.69, 0.83], respectively). The association was evident in per-protocol analyses, which required continuation of the assigned antihyperglycemic medication (empagliflozin or other antihyperglycemics) during follow-up (HR 0.64 [95% CI 0.60, 0.70]), and in analyses requiring concurrent use of metformin in at least the first 90 days of follow-up (HR 0.63 [0.57-0.69]). CONCLUSIONS: Among people with type 2 diabetes, empagliflozin use was associated with eGFR preservation, a greater decline in BMI, and a reduced risk of MAKE compared with other non-SGLT2i antihyperglycemics.

Diabetes medication regimens and patient clinical characteristics in the national patient-centered clinical research network, PCORnet.

We used electronic medical record (EMR) data in the National Patient-Centered Clinical Research Network (PCORnet) to characterize "real-world" prescription patterns of Type 2 diabetes (T2D) medications. We identified a retrospective cohort of 613,203 adult patients with T2D from 33 datamarts (median patient number: 12,711) from 2012 through 2017 using a validated computable phenotype. We characterized outpatient T2D prescriptions for each patient in the 90 days before and after cohort entry, as well as demographics, comorbidities, non-T2D prescriptions, and clinical and laboratory variables in the 730 days prior to cohort entry. Approximately half of the individuals in the cohort were females and 20% Black. Hypertension (60.3%) and hyperlipidemia (50.5%) were highly prevalent. Most patients were prescribed either a single T2D drug class (42.2%) or had no evidence of a T2D prescription in the EMR (42.4%). A smaller percentage was prescribed multiple T2D drug types (15.4%). Among patients prescribed a single T2D drug type, metformin was the most common (42.6%), followed by insulin (18.2%) and sulfonylureas (13.9%). Newer classes represented approximately 13% of single T2D drug type prescriptions (dipeptidyl peptidase-4 inhibitors [6.6%], glucagon-like peptide-1 receptor agonists [2.5%], thiazolidinediones [2.0%], and sodium-glucose cotransporter-2 inhibitors [1.6%]). Among patients prescribed multiple T2D drug types, the most common combination was metformin and sulfonylureas (63.5%). Metformin-based regimens were highly prevalent in PCORnet's T2D population, whereas newer agents were prescribed less frequently. PCORnet is a novel source for the potential conduct of observational studies among patients with T2D.

Factors Contributing to the Rising National Cost of Glucose-Lowering Medicines for Diabetes During 2005-2007 and 2015-2017.

OBJECTIVE: We examined changes in glucose-lowering medication spending and quantified the magnitude of factors that are contributing to these changes. RESEARCH DESIGN AND METHODS: Using the Medical Expenditure Panel Survey, we estimated the change in spending on glucose-lowering medications during 2005-2007 and 2015-2017 among adults aged ≥18 years with diabetes. We decomposed the increase in total spending by medication groups: for insulin, by human and analog; and for noninsulin, by metformin, older, newer, and combination medications. For each group, we quantified the contributions by the number of users and cost-per-user. Costs were in 2017 U.S. dollars. RESULTS: National spending on glucose-lowering medications increased by $40.6 billion (240%), of which insulin and noninsulin medications contributed $28.6 billion (169%) and $12.0 billion (71%), respectively. For insulin, the increase was mainly associated with higher expenditures from analogs (156%). For noninsulin, the increase was a net effect of higher cost for newer medications (+88%) and decreased cost for older medications (-34%). Most of the increase in insulin spending came from the increase in cost-per-user. However, the increase in the number of users contributed more than cost-per-user in the rise of most noninsulin groups. CONCLUSIONS: The increase in national spending on glucose-lowering medications during the past decade was mostly associated with the increased costs for insulin, analogs in particular, and newer noninsulin medicines, and cost-per-user had a larger effect than the number of users. Understanding the factors contributing to the increase helps identify ways to curb the growth in costs.