Novel Agents in the Management of Diabetes and Risk of Worsening Diabetic Retinopathy.

PURPOSE: Novel therapies for diabetes have potent effects on glycemic control, obesity and cardiovascular risk reduction but some, including the popular drug semaglutide, have also been implicated in worsening of diabetic retinopathy (DR). Given the ubiquity of these new agents, understanding the risks to vision is important. Here we review the data for several newly available agents in terms of systemic efficacy and retinal safety. METHODS: Literature review. RESULTS: Novel antihyperglycemic treatments include incretin mimetics and enhancers, sodium-glucose cotransporter inhibitors, long-acting insulins, and insulin delivery systems. All improve glycemic control and some have been shown to reduce major cardiovascular outcomes. In a pivotal trial, semaglutide was associated with ∼75% increased risk of DR worsening. The novel long-acting insulin icodec, formulated for once-weekly dosing, showed increased risk of DR worsening over a once-daily insulin. No other recent antihyperglycemic agent was associated with DR worsening, though following the semaglutide trials, nearly all studies excluded patients with pre-existing DR. Cases of DR worsening were rare in all instances. Dedicated safety studies for semaglutide in DR are currently underway. CONCLUSION: For most patients being considered for treatment with a novel anti-hyperglycemic agent, benefits on systemic metabolic and cardiovascular health are very likely to outweigh potential retinal harms. Although the true risks of the new agents on DR are unclear since their safety data come from secondary endpoints, the most vulnerable patients are those with pre-existing high-risk DR, poor baseline glycemic control and using insulin.

Perioperative Care of Patients Using Wearable Diabetes Devices.

The increasing prevalence of diabetes mellitus has been accompanied by a rapid expansion in wearable continuous glucose monitoring (CGM) devices and insulin pumps. Systems combining these components in a "closed loop," where interstitial glucose measurement guides automated insulin delivery (AID, or closed loop) based on sophisticated algorithms, are increasingly common. While these devices' efficacy in achieving near-normoglycemia is contributing to increasing usage among patients with diabetes, the management of these patients in operative and procedural environments remains understudied with limited published guidance available, particularly regarding AID systems. With their growing prevalence, practical management advice is needed for their utilization, or for the rational temporary substitution of alternative diabetes monitoring and treatments, during surgical care. CGM devices monitor interstitial glucose in real time; however, there are potential limitations to use and accuracy in the perioperative period, and, at the present time, their use should not replace regular point-of-care glucose monitoring. Avoiding perioperative removal of CGMs when possible is important, as removal of these prescribed devices can result in prolonged interruptions in CGM-informed treatments during and after procedures, particularly AID system use. Standalone insulin pumps provide continuous subcutaneous insulin delivery without automated adjustments for glucose concentrations and can be continued during some procedures. The safe intraoperative use of AID devices in their hybrid closed-loop mode (AID mode) requires the CGM component of the system to continue to communicate valid blood glucose data, and thus introduces the additional need to ensure this portion of the system is functioning appropriately to enable intraprocedural use. AID devices revert to non-AID insulin therapy modes when paired CGMs are disconnected or when the closed-loop mode is intentionally disabled. For patients using insulin pumps, we describe procedural factors that may compromise CGM, insulin pump, and AID use, necessitating a proactive transition to an alternative insulin regimen. Procedure duration and invasiveness is an important factor as longer procedures increase the risk of stress hyperglycemia, tissue malperfusion, and device malfunction. Whether insulin pumps should be continued through procedures, or substituted by alternative insulin delivery methods, is a complex decision that requires all parties to understand potential risks and contingency plans relating to patient and procedural factors. Currently available CGMs and insulin pumps are reviewed, and practical recommendations for safe glycemic management during the phases of perioperative care are provided.

The Current and Future Role of Insulin Therapy in the Management of Type 2 Diabetes: A Narrative Review.

Early initiation of intensive insulin therapy has been demonstrated to be effective in controlling glycemia and possibly preserving beta-cell function. Innovations in insulin formulations and delivery systems continue. However, we have seen an acceleration in the development of new classes of diabetes medications for individuals with type 2 diabetes and obesity, such as, for example, glucagon-like peptide-1 receptor agonists (GLP-1 RAs). These formulations have been shown to confer significant benefits in achieving good glycemic control with reduced hypoglycemia risk, weight loss, and cardiorenal protection. Therefore, it is reasonable to question whether there is still a role for insulin therapy in the management of type 2 diabetes. However, there are clear limitations inherent to GLP-1 RA therapy, including high rates of suboptimal adherence and treatment discontinuation due to high cost and side effects, which diminish long-term efficacy, and supply issues. In addition, newer formulations have shown improvements in convenience and tolerability, and have been shown to be even more effective when used in conjunction with basal insulin. In this narrative review, we discuss current evidence that supports GLP-1 RA use in combination with insulin therapy and the potential pitfalls of reliance on GLP-1 RAs as a substitute for insulin therapy.

Beta-Hydroxybutyrate Levels and Risk of Diabetic Ketoacidosis in Adults with Type 1 Diabetes Treated with Sotagliflozin.

Introduction: Sodium glucose cotransporter inhibitors may increase beta-hydroxybutyrate (BHB) in insulin-requiring patients. We determined factors associated with BHB changes from baseline (ΔBHB) and diabetic ketoacidosis (DKA) in patients with type 1 diabetes (T1D) receiving sotagliflozin as an insulin adjunct. Research Design and Methods: This post hoc analysis compared ΔBHB levels in adults with T1D receiving sotagliflozin 400 mg or placebo for 6 months. We evaluated clinical and metabolic factors associated with ΔBHB and used logistic regression models to determine predictors associated with BHB values >0.6 and >1.5 mmol/L (inTandem3 population; N = 1402) or with DKA events in a pooled analysis (inTandem1-3; N = 2453). Results: From baseline (median, 0.13 mmol/L), median fasting BHB increased by 0.04 mmol/L (95% confidence interval, 0.03-0.05; P < 0.001) at 24 weeks with sotagliflozin versus placebo; 67% of patients had no or minimal changes in BHB over time. Factors associated with on-treatment BHB >0.6 or >1.5 mmol/L included baseline BHB and sotagliflozin use. Age, insulin pump use, sotagliflozin use, baseline BHB, and ΔBHB were significantly associated with DKA episodes. Independent of treatment, DKA risk increased by 18% with each 0.1-mmol/L increase in baseline BHB and by 8% with each 0.1-mmol/L increase from baseline. Conclusion: Incremental increases in baseline BHB and ΔBHB were associated with a higher DKA risk independent of treatment. Adding sotagliflozin to insulin increased median BHB over 24 weeks in patients with T1D and was associated with increased DKA events. These results highlight the importance of BHB testing and monitoring and individualizing patient education on DKA risk, mitigation, identification, and treatment.

Decreased sarcoplasmic reticulum phospholipids in human skeletal muscle are associated with metabolic syndrome.

Metabolic syndrome affects more than one in three adults and is associated with increased risk of diabetes, cardiovascular disease, and all-cause mortality. Muscle insulin resistance is a major contributor to the development of the metabolic syndrome. Studies in mice have linked skeletal muscle sarcoplasmic reticulum (SR) phospholipid composition to sarcoplasmic/endoplasmic reticulum Ca2+-ATPase activity and insulin sensitivity. To determine if the presence of metabolic syndrome alters specific phosphatidylcholine (PC) and phosphatidylethanolamine (PE) species in human SR, we compared SR phospholipid composition in skeletal muscle from sedentary subjects with metabolic syndrome and sedentary control subjects without metabolic syndrome. Both total PC and total PE were significantly decreased in skeletal muscle SR of sedentary metabolic syndrome patients compared with sedentary controls, particularly in female participants, but there was no difference in the PC:PE ratio between groups. Total SR PC levels, but not total SR PE levels or PC:PE ratio, were significantly negatively correlated with BMI, waist circumference, total fat, visceral adipose tissue, triglycerides, fasting insulin, and homeostatic model assessment for insulin resistance. These findings are consistent with the existence of a relationship between skeletal muscle SR PC content and insulin resistance in humans.

Longitudinal Effects of Glucose-Lowering Medications on ß-Cell Responses and Insulin Sensitivity in Type 2 Diabetes: The GRADE Randomized Clinical Trial.

OBJECTIVE: To compare the long-term effects of glucose-lowering medications (insulin glargine U-100, glimepiride, liraglutide, and sitagliptin) when added to metformin on insulin sensitivity and ß-cell function. RESEARCH DESIGN AND METHODS: In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) cohort with type 2 diabetes (n = 4,801), HOMA2 was used to estimate insulin sensitivity (HOMA2-%S) and fasting ß-cell function (HOMA2-%B) at baseline and 1, 3, and 5 years on treatment. Oral glucose tolerance test ß-cell responses (C-peptide index [CPI] and total C-peptide response [incremental C-peptide/incremental glucose over 120 min]) were evaluated at the same time points. These responses adjusted for HOMA2-%S in regression analysis provided estimates of ß-cell function. RESULTS: HOMA2-%S increased from baseline to year 1 with glargine and remained stable thereafter, while it did not change from baseline in the other treatment groups. HOMA2-%B and C-peptide responses were increased to variable degrees at year 1 in all groups but then declined progressively over time. At year 5, CPI was similar between liraglutide and sitagliptin, and higher for both than for glargine and glimepiride [0.80, 0.87, 0.74, and 0.64 (nmol/L)/(mg/dL) * 100, respectively; P < 0.001], while the total C-peptide response was greatest with liraglutide, followed in descending order by sitagliptin, glargine, and glimepiride [1.54, 1.25, 1.02, and 0.87 (nmol/L)/(mg/dL) * 100, respectively, P < 0.001]. After adjustment for HOMA2-%S to obtain an estimate of ß-cell function, the nature of the change in ß-cell responses reflected those in ß-cell function. CONCLUSIONS: The differential long-term effects on insulin sensitivity and ß-cell function of four different glucose-lowering medications when added to metformin highlight the importance of the loss of ß-cell function in the progression of type 2 diabetes.

Poor Glycemic Control Is Associated With More Rapid Kidney Function Decline After the Onset of Diabetic Kidney Disease.

BACKGROUND: The role of glycemic control and its variability on the rate of kidney function decline after the onset of diabetic kidney disease (DKD) remains unclear. METHODS: The association between baseline glycated hemoglobin (HbA1c) and rates of estimated glomerular filtration rate (eGFR) loss during follow-up was examined by mixed-effects linear regression in 530 individuals with type 1 diabetes and early-to-moderate DKD from the Preventing Early Renal Loss (PERL) trial and 2378 individuals with type 2 diabetes and established DKD from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. The benefit of intensive vs standard glycemic control in slowing eGFR decline was examined in ACCORD. The associations between continuous glucose monitoring-derived short-term glycemic variability indices and rate of eGFR decline were also evaluated in PERL. RESULTS: A higher baseline HbA1c was associated with a more negative eGFR slope in both PERL and ACCORD (-0.87 and -0.27 mL/min/1.73 m2/year per Hba1c unit increment, P < .0001 and P = .0002, respectively). In both studies, the strength of this association progressively increased with increasing levels of albuminuria (P for interaction <.05). Consistent with this, the benefit of intensive glycemic control on eGFR decline was greater in ACCORD participants with severe rather than moderate albuminuria (+1.13 vs + 0.26 mL/min/1.73 m2/year, P = .01). No independent associations were found in PERL between short-term glycemic variability indices and rate of eGFR decline. CONCLUSION: In both type 1 and type 2 diabetes, poor glycemic control is associated with a more rapid rate of glomerular filtration rate decline after DKD onset, especially in persons with severe albuminuria.

Rationale and design of a randomised phase III registration trial investigating finerenone in participants with type 1 diabetes and chronic kidney disease: The FINE-ONE trial.

AIMS: Despite guideline-recommended treatments, including renin angiotensin system inhibition, up to 40 % of individuals with type 1 diabetes develop chronic kidney disease (CKD) putting them at risk of kidney failure. Finerenone is approved to reduce the risk of kidney failure in individuals with type 2 diabetes. We postulate that finerenone will demonstrate benefits on kidney outcomes in people with type 1 diabetes. METHODS: FINE-ONE (NCT05901831) is a randomised, placebo-controlled, double-blind phase III trial of 7.5 months' duration in ∼220 adults with type 1 diabetes, urine albumin/creatinine ratio (UACR) of ≥ 200-< 5000 mg/g (≥ 22.6-< 565 mg/mmol) and eGFR of ≥ 25-< 90 ml/min/1.73 m2. RESULTS: The primary endpoint is relative change in UACR from baseline over 6 months. UACR is used as a bridging biomarker (BB), since the treatment effect of finerenone on UACR was associated with its efficacy on kidney outcomes in the type 2 diabetes trials. Based on regulatory authority feedback, UACR can be used as a BB for kidney outcomes to support registration of finerenone in type 1 diabetes, provided necessary criteria are met. Secondary outcomes include incidences of treatment-emergent adverse events, treatment-emergent serious adverse events and hyperkalaemia. CONCLUSIONS: FINE-ONE will evaluate the efficacy and safety of finerenone in type 1 diabetes and CKD. Finerenone could become the first registered treatment for CKD associated with type 1 diabetes in almost 30 years. TRIAL REGISTRATION: ClinicalTrials.gov NCT05901831.

Short-term multifactorial intervention (STEMI): An approach using structured blood glucose monitoring (BGM) and conventional therapies in persons with diabetes.

Background: Achieving glucose and glycosylated hemoglobin (HbA1c) targets have been shown to reduce long-term microvascular complications of diabetes; however, suboptimal glucose control is common. We tested whether glucose control could be improved within 8 weeks by employing structured blood glucose monitoring (BGM) qid in addition to seven times per day prior to visits for diabetes education and medication management that occurred every 2-4 weeks. Methods: This single-center, prospective study was conducted on 78 adults with either type 1 diabetes (T1D) or type 2 diabetes (T2D), HbA1c >8%, and serum creatinine (sCr) <2.0 mg/dl. HbA1c was checked at baseline, Week 2, Week 4, and at Week 8. Patients were evaluated by a physician and a certified diabetes educator (CDE) at baseline, Week 2, and Week 4 for treatment adjustments and lifestyle advice based on a review of BGM done qid plus 7-point profiles conducted before Weeks 2, 4, and 8. Study outcomes were change in HbA1c from baseline to Week 8 and change in mean glucose on the 7-point profile from Week 2 to Week 8. These were compared using one-way repeated measures ANOVA. Results: Of the 78 patients, 64.1% had T2D, 50% were women, and 72% were Caucasian. Mean age (±SD) was 51.3.5 ± 11.1 years, and median diabetes duration was 9 (5-17) years. The percentage of patients using insulin increased from 58.9% at baseline to 67.9% at Week 8. The mean (±SD) HbA1c was 9.53% (±1.71) at baseline, declined -1.38% from baseline to week 8 (CI -1.62 to -0.14, P < 0.001). The mean (±SD) glucose on the 7-point profile was 187 (±52) mg/dl at Week 2, and 157 (±5) mg/dl at Week 8. (P < 0.01). Conclusions: An intensive glucose optimization program using structured BGM qid plus 7-point profiles, diabetes education, and conventional anti-diabetic therapies was successful in reducing HbA1c by 1.38% over 8 weeks in patients with poor glucose control.

Management of the 'wicked' combination of heart failure and chronic kidney disease in the patient with diabetes.

Patients with type 2 diabetes are at an increased risk of developing heart failure and chronic kidney disease. The presence of these co-morbidities substantially increases the risk of morbidity as well as mortality in patients with diabetes. The clinical focus has historically centred around reducing the risk of cardiovascular disease by targeting hyperglycaemia, hyperlipidaemia and hypertension. Nonetheless, patients with type 2 diabetes who have well-controlled blood glucose, blood pressure and lipid levels may still go on to develop heart failure, kidney disease or both. Major diabetes and cardiovascular societies are now recommending the use of treatments such as sodium-glucose co-transporter-2 inhibitors and non-steroidal mineralocorticoid receptor antagonists, in addition to currently recommended therapies, to promote cardiorenal protection through alternative pathways as early as possible in individuals with diabetes and cardiorenal manifestations. This review examines the most recent recommendations for managing the risk of cardiorenal progression in patients with type 2 diabetes.

ABCC8-Related Monogenic Diabetes Presenting Like Type 1 Diabetes in an Adolescent.

Background: Identifying cases of diabetes caused by single gene mutations between the more common type 1 diabetes (T1D) and type 2 diabetes (T2D) is a difficult but important task. We report the diagnosis of ATP-binding cassette transporter sub-family C member 8 (ABCC8)-related monogenic diabetes in a 35-year-old woman with a protective human leukocyte antigen (HLA) allele who was originally diagnosed with T1D at 18 years of age. Case Report: Patient A presented with polyuria, polydipsia, and hypertension at the age of 18 years and was found to have a blood glucose > 500 mg/dL (70-199 mg/dL) and an HbA1C (hemoglobin A1C) >14% (4%-5.6%). She had an unmeasurable C-peptide but no urine ketones. She was diagnosed with T1D and started on insulin therapy. Antibody testing was negative. She required low doses of insulin and later had persistence of low but detectable C-peptide. At the age of 35 years, she was found to have a protective HLA allele, and genetic testing revealed a pathogenic mutation in the ABCC8 gene. The patient was then successfully transitioned to sulfonylurea therapy. Discussion: Monogenic diabetes diagnosed in adolescence typically presents with mild to moderate hyperglycemia, positive family history and, in some cases, other organ findings or dysfunction. The patient in this report presented with very high blood glucose, prompting the diagnosis of T1D. When she was found to have a protective HLA allele, further investigation revealed the mutation in the sulfonylurea receptor gene, ABCC8. Conclusion: Patients suspected of having T1D but with atypical clinical characteristics such as negative autoantibodies, low insulin requirements, and persistence of C-peptide should undergo genetic testing for monogenic diabetes.

MODY5 and Serous Ovarian Carcinoma in 17q12 Recurrent Deletion Syndrome.

Background/Objective: Maturity-onset diabetes of the young type 5 (MODY5) is caused by a hepatocyte nuclear factor 1ß (HNF1ß) gene mutation on chromosome 17q12. HNF1ß mutations have also been found in ovarian clear cell carcinoma, whereas ovarian non-clear cell carcinoma expresses this mutation rarely. 17q12 recurrent deletion syndrome features include MODY5, urogenital anomalies, and psychiatric and neurodevelopmental disorders. This is a report of a patient with 17q12 recurrent deletion syndrome with MODY5, uterine abnormalities, and low-grade serous ovarian cancer. Case Report: A 25-year-old woman with recently diagnosed stage IIIC low-grade serous ovarian carcinoma was evaluated at the endocrinology clinic for diabetes, which was diagnosed at the age of 12 years. C-peptide level was detectable and T1DM antibodies were negative. The mother had diabetes, partially septated uterus, and solitary kidney. Abdominal computed tomography showed pancreatic atrophy, ascites, omental and peritoneal nodularity, and calcifications. Laparoscopy revealed bicornuate uterus, 2 cervices, and vaginal septum. The patient underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy, lymph node dissection, and omentectomy. Chromosomal microarray analysis revealed a pathogenic ∼1.8 Mb loss of 17q12, denoted arr[hg19]17q12(34477479_36283807)x1. Discussion: 17q12deletion has been described as a susceptibility locus in some ovarian cancers. However, to our knowledge, predisposition to ovarian cancer as a feature of 17q12 recurrent deletion syndrome or MODY5 was not reported previously. Conclusion: The disease association reported suggests that medical providers should periodically evaluate for ovarian cancer, gut, and urogenital abnormalities in individuals with MODY5. Likewise, individuals with diabetes plus urogenital tract abnormalities or 17q12deletion in an ovarian tumor should undergo genetic testing for MODY5.

The Nuances Surrounding Insulin Prescribing.

Knowledge of and expertise in insulin prescribing is crucial for health care providers who care for people with diabetes. This article reviews the available insulin preparations, how they are packaged, and nuances related to storage and use that inform the prescribing of this life-saving medication for patients. Insulin prescribing that is done correctly will save time and reduce problematic errors that could put patients at risk.

Comparative effectiveness of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, and sulfonylureas on risk of major adverse cardiovascular events: emulation of a randomised target trial using electronic health records.

BACKGROUND: Randomised clinical trials showed that compared with placebo, SGLT2 inhibitors and GLP-1 receptor agonists reduced risk of adverse cardiovascular events. The evidence base for the older antihyperglycaemic drug classes (DPP-4 inhibitors and sulfonylureas) is generally less well developed. Because most randomised trials evaluated one antihyperglycaemic medication versus placebo, a head-to-head comparative effectiveness analysis of the newer drug classes (SGLT2 inhibitors vs GLP-1 receptor agonists) or newer (SGLT2 inhibitors or GLP-1 receptor agonists) versus older (DPP-4 inhibitors or sulfonylureas) drug classes on risk of major adverse cardiovascular events (MACE) is not available. In this study, we aimed to evaluate the comparative effectiveness of incident use of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, or sulfonylureas on risk of MACE. METHODS: We first specified the protocol of a four-arm randomised pragmatic clinical trial and then emulated it using the health-care databases of the US Department of Veterans Affairs. We built a cohort of metformin users with incident use of SGLT2 inhibitors, GLP-1 receptor agonists, DPP-4 inhibitors, or sulfonylureas between Oct 1, 2016 and Sept 30, 2021, and followed up until Dec 31, 2022. We used the overlap weighting approach to balance the treatment groups using a battery of predefined variables and a set of algorithmically selected variables from high-dimensional data domains. Both intention-to-treat and per-protocol analyses (the latter estimated the effect of maintained use of the antihyperglycaemic throughout follow-up) were conducted to estimate risk of MACE-defined as a composite endpoint of stroke, myocardial infarction, and all-cause mortality. FINDINGS: The final cohort consisted of 283 998 new users of SGLT2 inhibitors (n=46 516), GLP-1 receptor agonists (n=26 038), DPP-4 inhibitors (n=55 310), or sulfonylureas (n=156 134). In intention-to-treat analyses, compared with sulfonylureas, SGLT2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors were associated with lower risk of MACE (hazard ratio [HR] 0·77 [95% CI 0·74-0.80], 0·78 [0·74-0·81), and 0·90 [0·86-0.93], respectively). Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of MACE when compared with DPP-4 inhibitors (HR 0·86 [0·82-0·89] and 0·86 [0·82-0·90], respectively). The risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists yielded an HR of 0·99 (0·94-1·04). In per-protocol analyses, compared with sulfonylureas, SGLT2 inhibitors, GLP1 receptor agonists, and DPP-4 inhibitors were associated with reduced risk of MACE (HR 0·77 [95% CI 0·73-0·82], 0·77 [0·72-0·82], and 0·88 [0·83-0·93], respectively). Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with a lower risk of MACE when compared with DPP-4 inhibitors (HR 0·88 [0·83-0·93] and 0·88 [0·82-0·93], respectively). The risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists yielded an HR of 1·01 (0·94-1·07). INTERPRETATION: Both SGLT2 inhibitors and GLP-1 receptor agonists were associated with reduced risk of MACE compared with DPP-4 inhibitors or sulfonylureas. DPP-4 inhibitors were associated with reduced risk of MACE compared with sulfonylureas. There was no statistically significant difference in risk of MACE between SGLT2 inhibitors and GLP-1 receptor agonists. The results provide evidence of the real-world comparative effectiveness of the four most commonly used second-line antihyperglycaemics and could guide choice of antihyperglycaemic therapy. FUNDING: US Department of Veterans Affairs and the American Society of Nephrology.

Coverage for Continuous Glucose Monitoring for Individuals with Type 2 Diabetes Treated with Nonintensive Therapies: An Evidence-Based Approach to Policymaking.

Numerous studies have demonstrated the clinical benefits of continuous glucose monitoring (CGM) in individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D) who are treated with intensive insulin regimens. Based on this evidence, CGM is now a standard of care for individuals within these diabetes populations and widely covered by commercial and public insurers. Moreover, recent clinical guidelines from the American Diabetes Association and American Association of Clinical Endocrinology now endorse CGM use in individuals treated with nonintensive insulin regimens. However, despite increasing evidence supporting CGM use for individuals treated with less-intensive insulin therapy or noninsulin medications, insurance coverage is limited or nonexistent. This narrative review reports key findings from recent randomized, observational, and retrospective studies investigating use of CGM in T2D individuals treated with basal insulin only and/or noninsulin therapies and presents an evidence-based rationale for expanding access to CGM within this population.

Comparative Effects of Glucose-Lowering Medications on Kidney Outcomes in Type 2 Diabetes: The GRADE Randomized Clinical Trial.

Importance: Type 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function. Objective: To evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D. Design, Setting, and Participants: A randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A1c level between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2 who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years). Data were analyzed from February 21, 2022, to March 27, 2023. Interventions: Addition of insulin glargine, glimepiride, liraglutide, or sitagliptin to metformin, with the medication combination continued until the HbA1c was greater than 7.5%; thereafter, insulin was added to maintain glycemic control. Main Outcomes and Measures: Chronic eGFR slope (change in eGFR between year 1 and trial end) and a composite kidney disease progression outcome (albuminuria, dialysis, transplant, or death due to kidney disease). Secondary outcomes included incident eGFR less than 60 mL/min/1.73 m2, 40% decrease in eGFR to less than 60 mL/min/1.73 m2, doubling of urine albumin-to-creatinine ratio (UACR) to 30 mg/g or greater, and progression of Kidney Disease Improving Global Outcomes stage. Analyses were intention-to-treat. Results: Of the 5047 participants, 3210 (63.6%) were men. Baseline characteristics were mean (SD) age 57.2 (10.0) years; HbA1c 7.5% (0.5%); diabetes duration, 4.2 (2.7) years; body mass index, 34.3 (6.8); blood pressure 128.3/77.3 (14.7/9.9) mm Hg; eGFR 94.9 (16.8) mL/min/1.73 m2; and median UACR, 6.4 (IQR 3.1-16.9) mg/g; 2933 (58.1%) were treated with renin-angiotensin-aldosterone inhibitors. Mean chronic eGFR slope was -2.03 (95% CI, -2.20 to -1.86) mL/min/1.73 m2 per year for patients receiving sitagliptin; glimepiride, -1.92 (95% CI, -2.08 to -1.75) mL/min/1.73 m2 per year; liraglutide, -2.08 (95% CI, -2.26 to -1.90) mL/min/1.73 m2 per year; and insulin glargine, -2.02 (95% CI, -2.19 to -1.84) mL/min/1.73 m2 per year (P = .61). Mean composite kidney disease progression occurred in 135 (10.6%) patients receiving sitagliptin; glimepiride, 155 (12.4%); liraglutide, 152 (12.0%); and insulin glargine, 150 (11.9%) (P = .56). Most of the composite outcome was attributable to albuminuria progression (98.4%). There were no significant differences by treatment assignment in secondary outcomes. There were no adverse kidney events attributable to medication assignment. Conclusions and Relevance: In this randomized clinical trial, among people with T2D and predominantly free of kidney disease at baseline, no significant differences in kidney outcomes were observed during 5 years of follow-up when a dipeptidyl peptidase 4 inhibitor, sulfonylurea, glucagonlike peptide 1 receptor agonist, or basal insulin was added to metformin for glycemic control. Trial Registration: ClinicalTrials.gov Identifier: NCT01794143.

Safety, tolerability, and effectiveness of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin in combination with standard chemotherapy for patients with advanced, inoperable pancreatic adenocarcinoma: a phase 1b observational study.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy. Thus, there is an urgent need for safe and effective novel therapies. PDAC's excessive reliance on glucose metabolism for its metabolic needs provides a target for metabolic therapy. Preclinical PDAC models have demonstrated that targeting the sodium-glucose co-transporter-2 (SGLT2) with dapagliflozin may be a novel strategy. Whether dapagliflozin is safe and efficacious in humans with PDAC is unclear. METHODS: We performed a phase 1b observational study (ClinicalTrials.gov ID NCT04542291; registered 09/09/2020) to test the safety and tolerability of dapagliflozin (5 mg p.o./day × 2 weeks escalated to 10 mg p.o./day × 6 weeks) added to standard Gemcitabine and nab-Paclitaxel (GnP) chemotherapy in patients with locally advanced and/or metastatic PDAC. Markers of efficacy including Response Evaluation Criteria in Solid Tumors (RECIST 1.1) response, CT-based volumetric body composition measurements, and plasma chemistries for measuring metabolism and tumor burden were also analyzed. RESULTS: Of 23 patients who were screened, 15 enrolled. One expired (due to complications from underlying disease), 2 dropped out (did not tolerate GnP chemotherapy) during the first 4 weeks, and 12 completed. There were no unexpected or serious adverse events with dapagliflozin. One patient was told to discontinue dapagliflozin after 6 weeks due to elevated ketones, although there were no clinical signs of ketoacidosis. Dapagliflozin compliance was 99.4%. Plasma glucagon increased significantly. Although abdominal muscle and fat volumes decreased; increased muscle-to-fat ratio correlated with better therapeutic response. After 8 weeks of treatment in the study, partial response (PR) to therapy was seen in 2 patients, stable disease (SD) in 9 patients, and progressive disease (PD) in 1 patient. After dapagliflozin discontinuation (and chemotherapy continuation), an additional 7 patients developed the progressive disease in the subsequent scans measured by increased lesion size as well as the development of new lesions. Quantitative imaging assessment was supported by plasma CA19-9 tumor marker measurements. CONCLUSIONS: Dapagliflozin is well-tolerated and was associated with high compliance in patients with advanced, inoperable PDAC. Overall favorable changes in tumor response and plasma biomarkers suggest it may have efficacy against PDAC, warranting further investigation.