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.

Astaxanthin, a natural antioxidant, lowers cholesterol and markers of cardiovascular risk in individuals with prediabetes and dyslipidaemia.

AIM: To determine the effects of astaxanthin treatment on lipids, cardiovascular disease (CVD) markers, glucose tolerance, insulin action and inflammation in individuals with prediabetes and dyslipidaemia. MATERIALS AND METHODS: Adult participants with dyslipidaemia and prediabetes (n = 34) underwent baseline blood draw, an oral glucose tolerance test and a one-step hyperinsulinaemic-euglycaemic clamp. They were then randomized (n = 22 treated, 12 placebo) to receive astaxanthin 12 mg daily or placebo for 24 weeks. Baseline studies were repeated after 12 and 24 weeks of therapy. RESULTS: After 24 weeks, astaxanthin treatment significantly decreased low-density lipoprotein (-0.33 ± 0.11 mM) and total cholesterol (-0.30 ± 0.14 mM) (both P < .05). Astaxanthin also reduced levels of the CVD risk markers fibrinogen (-473 ± 210 ng/mL), L-selectin (-0.08 ± 0.03 ng/mL) and fetuin-A (-10.3 ± 3.6 ng/mL) (all P < .05). While the effects of astaxanthin treatment did not reach statistical significance, there were trends toward improvements in the primary outcome measure, insulin-stimulated, whole-body glucose disposal (+0.52 ± 0.37 mg/m2 /min, P = .078), as well as fasting [insulin] (-5.6 ± 8.4 pM, P = .097) and HOMA2-IR (-0.31 ± 0.16, P = .060), suggesting improved insulin action. No consistent significant differences from baseline were observed for any of these outcomes in the placebo group. Astaxanthin was safe and well tolerated with no clinically significant adverse events. CONCLUSIONS: Although the primary endpoint did not meet the prespecified significance level, these data suggest that astaxanthin is a safe over-the-counter supplement that improves lipid profiles and markers of CVD risk in individuals with prediabetes and dyslipidaemia.

Accuracy and Glycemic Efficacy of Continuous Glucose Monitors in Critically Ill COVID-19 Patients: A Retrospective Study.

BACKGROUND: Continuous glucose monitoring (CGM) is approved for insulin dosing decisions in the ambulatory setting, but not currently for inpatients. CGM has the capacity to reduce patient-provider contact in inpatients with coronavirus disease 2019 (COVID-19), thus potentially reducing in hospital virus transmission. However, there are sparse data on the accuracy and efficacy of CGM to titrate insulin doses in inpatients. METHODS: Under an emergency use protocol, CGM (Dexcom G6) was used alongside standard point-of-care (POC) glucose measurements in patients critically ill from complications of COVID-19 requiring intravenous (IV) insulin. Glycemic control during IV insulin therapy was retrospectively assessed comparing periods with and without adjunctive CGM use. Accuracy metrics were computed and Clarke Error Grid analysis performed comparing CGM glucose values with POC measurements. RESULTS: Twenty-four critically ill patients who met criteria for emergency use of CGM resulted in 47 333 CGM and 5677 POC glucose values. During IV insulin therapy, individuals' glycemic control improved when CGM was used (mean difference -30.7 mg/dL). Among 2194 matched CGM: POC glucose pairs, a high degree of concordance was observed with a mean absolute relative difference of 14.8% and 99.5% of CGM: POC pairs falling in Zones A and B of the Clarke Error Grid. CONCLUSIONS: Continuous glucose monitoring use in critically ill COVID-19 patients improved glycemic control during IV insulin therapy. Continuous glucose monitoring glucose data were highly concordant with POC glucose during IV insulin therapy in critically ill patients suggesting that CGM could substitute for POC measurements in inpatients thus reducing patient-provider contact and mitigating infection transmission.

Practical Guidance for Healthcare Providers on Collaborating with People with Type 2 Diabetes: Advancing Treatment and Initiating Injectable Therapy.

Type 2 diabetes (T2D) progresses over time, and to achieve and maintain adequate glucose control, many people eventually require injectable therapies such as insulin. However, there can be significant barriers to the initiation of these medications, both from people living with T2D and from healthcare practitioners (HCPs). Misconceptions and misinformation relating to the potential risks and benefits of injectable therapies are common and can contribute to negative perceptions regarding their use. Additionally, HCPs are often unaware of the emotional burden associated with T2D. In particular, diabetes distress is a key contributory factor that needs to be addressed to alleviate fears before diabetes education can be successful. The onus is often on the HCP to initiate effective, individualized communication with each patient and make that person feel an active and equal participant in the management of their T2D. Shared decision-making has been demonstrated to improve understanding of the pathophysiology and treatment options, to increase risk awareness, adherence, and persistence, and to improve self-management behaviors (e.g., exercise, self-care) and patient satisfaction. While therapeutic inertia can result from both patient and HCP, HCPs need to bear the responsibility for escalating therapy when necessary. A proactive approach by the HCP, combined with shared decision-making and a patient-centric approach, are important for optimal T2D management; therefore, an open and effective relationship between the HCP and the person living with T2D is essential. This article is written by a person with T2D, a nurse practitioner/Certified Diabetes Care and Education Specialist, and a clinical endocrinologist, with the goal of providing a holistic view of the management experience, exploring patient needs and expectations, recognizing and avoiding HCP and patient barriers, and providing practical advice to HCPs to empower patients who would benefit from injectable therapy.Infographic and video abstract available for this article.

Type 2 diabetes can be managed with diet, exercise, and medicines. As type 2 diabetes progresses, the most effective treatment may change, and people may need to start taking insulin or other injections to manage their blood sugar. However, many people do not receive the information needed to understand why their type 2 diabetes has progressed or why they need to change treatment. Also, they may have received inaccurate information about the risks and benefits of insulin injections. The demands of managing type 2 diabetes can have an emotional impact (known as diabetes distress), which can lead to anxiety and make people reluctant to engage in their own care or start new medications. Healthcare professionals need to recognize the impact of diabetes distress so that they can help people with type 2 diabetes overcome these barriers. Understanding the factors driving the behaviors of people with type 2 diabetes and encouraging them to ask questions can help them overcome concerns about changing treatment. This is most likely to be achieved when people with diabetes are actively involved in treatment decisions. This article, written by a person with type 2 diabetes and two healthcare professionals, aims to provide practical guidance for healthcare professionals to recognize the emotional impact of diabetes, and to understand how this affects a person's ability to manage their condition. This article also provides advice on how to improve communication with patients and to provide effective diabetes education to meet the needs of people living with type 2 diabetes. In this video, the authors, a person with T2D, a nurse practitioner/certified diabetes care and education specialist, and a clinical endocrinologist, provide practical guidance for healthcare professionals. They focus on how to recognize the emotional impact of diabetes, understand how this affects a person's ability to manage their condition, how to improve communication with patients, and how to provide effective diabetes education to meet the needs of people living with type 2 diabetes, with an emphasis on the initiation and use of injectable therapy.

Glucagon receptor antagonist volagidemab in type 1 diabetes: a 12-week, randomized, double-blind, phase 2 trial.

Hyperglucagonemia contributes to hyperglycemia in patients with type 1 diabetes (T1D); however, novel therapeutics that block glucagon action could improve glycemic control. This phase 2 study evaluated the safety and efficacy of volagidemab, an antagonistic monoclonal glucagon receptor (GCGR) antibody, as an adjunct to insulin therapy in adults with T1D. The primary endpoint was change in daily insulin use at week 12. Secondary endpoints included changes in hemoglobin A1c (HbA1c) at week 13, in average daily blood glucose concentration and time within target range as assessed by continuous blood glucose monitoring (CGM) and seven-point glucose profile at week 12, incidence of hypoglycemic events, the proportion of subjects who achieve HbA1c reduction of ≥0.4%, volagidemab drug concentrations and incidence of anti-drug antibodies. Eligible participants (n = 79) were randomized to receive weekly subcutaneous injections of placebo, 35 mg volagidemab or 70 mg volagidemab. Volagidemab produced a reduction in total daily insulin use at week 12 (35 mg volagidemab: -7.59 units (U) (95% confidence interval (CI) -11.79, -3.39; P = 0.040 versus placebo); 70 mg volagidemab: -6.64 U (95% CI -10.99, -2.29; P = 0.084 versus placebo); placebo: -1.27 U (95% CI -5.4, 2.9)) without meeting the prespecified significance level (P < 0.025). At week 13, the placebo-corrected reduction in HbA1c percentage was -0.53 (95% CI -0.89 to -0.17, nominal P = 0.004) in the 35 mg volagidemab group and -0.49 (95% CI -0.85 to -0.12, nominal P = 0.010) in the 70 mg volagidemab group. No increase in hypoglycemia was observed with volagidemab therapy; however, increases in serum transaminases, low-density lipoprotein (LDL)-cholesterol and blood pressure were observed. Although the primary endpoint did not meet the prespecified significance level, we believe that the observed reduction in HbA1c and tolerable safety profile provide a rationale for further randomized studies to define the long-term efficacy and safety of volagidemab in patients with T1D.

Impact of the hepatoselective glucokinase activator TTP399 on ketoacidosis during insulin withdrawal in people with type 1 diabetes.

AIMS: To determine the effect of TTP399, a hepatoselective glucokinase activator, on the risk of ketoacidosis during insulin withdrawal in individuals with type 1 diabetes (T1D). MATERIALS AND METHODS: Twenty-three participants with T1D using insulin pump therapy were randomized to 800 mg TTP399 (n = 12) or placebo (n = 11) for 7 to 10 days. After the treatment period, an insulin withdrawal test (IWT) was performed, during which insulin pumps were removed to induce ketogenesis. The IWT was stopped after 10 hours or if blood glucose reached >399 mg/dL [22.1 mmol/L], if beta-hydroxybutyrate (BHB) was >3.0 mmol/L, or for patient discomfort. The primary endpoint was the proportion of participants who reached BHB concentrations of 1 mmol/L or greater. RESULTS: During the 7- to 10-day treatment period, mean fasting plasma glucose was significantly reduced ( -27.6 vs. -4.4 mg/dL [-1.5 vs. -0.2 mmol/L]; P = 0.03) and there were fewer adverse events, including hypoglycaemia, in the TTP399-treated arm. During the IWT, no differences were observed between TTP399 and placebo in mean serum BHB concentration, mean duration of IWT, or BHB at termination of IWT. However, serum bicarbonate was numerically higher and urine acetoacetate was quantitatively lower in the TTP399-treated participants. As a result of higher bicarbonate values, none of the TTP399-treated participants met the prespecified criteria for diabetic ketoacidosis (DKA), defined as BHB >3 mmol/L and serum bicarbonate <18 mEq/L, compared to 42% of placebo-treated participants. CONCLUSIONS: When used as an adjunctive therapy to insulin, TTP399 improves glycaemia without increasing hypoglycaemia in individuals with T1D. During acute insulin withdrawal, TTP399 did not increase BHB concentrations and decreased the incidence of DKA.

SGLT2 Inhibition Increases Fasting Glucagon but Does Not Restore the Counterregulatory Hormone Response to Hypoglycemia in Participants With Type 1 Diabetes.

Individuals with type 1 diabetes have an impaired glucagon counterregulatory response to hypoglycemia. Sodium-glucose cotransporter (SGLT) inhibitors increase glucagon concentrations. We evaluated whether SGLT inhibition restores the glucagon counterregulatory hormone response to hypoglycemia. Adults with type 1 diabetes (n = 22) were treated with the SGLT2 inhibitor dapagliflozin (5 mg daily) or placebo for 4 weeks in a randomized, double-blind, crossover study. After each treatment phase, participants underwent a hyperinsulinemic-hypoglycemic clamp. Basal glucagon concentrations were 32% higher following dapagliflozin versus placebo, with a median within-participant difference of 2.75 pg/mL (95% CI 1.38-12.6). However, increased basal glucagon levels did not correlate with decreased rates of hypoglycemia and thus do not appear to be protective in avoiding hypoglycemia. During hypoglycemic clamp, SGLT2 inhibition did not change counterregulatory hormone concentrations, time to recovery from hypoglycemia, hypoglycemia symptoms, or cognitive function. Thus, despite raising basal glucagon concentrations, SGLT inhibitor treatment did not restore the impaired glucagon response to hypoglycemia. We propose that clinical reduction in hypoglycemia associated with these agents is a result of changes in diabetes care (e.g., lower insulin doses or improved glycemic variability) as opposed to a direct, physiologic effect of these medications on α-cell function.

COVID-19 Severity Is Tripled in the Diabetes Community: A Prospective Analysis of the Pandemic's Impact in Type 1 and Type 2 Diabetes.

OBJECTIVE: To quantify and contextualize the risk for coronavirus disease 2019 (COVID-19)-related hospitalization and illness severity in type 1 diabetes. RESEARCH DESIGN AND METHODS: We conducted a prospective cohort study to identify case subjects with COVID-19 across a regional health care network of 137 service locations. Using an electronic health record query, chart review, and patient contact, we identified clinical factors influencing illness severity. RESULTS: We identified COVID-19 in 6,138, 40, and 273 patients without diabetes and with type 1 and type 2 diabetes, respectively. Compared with not having diabetes, people with type 1 diabetes had adjusted odds ratios of 3.90 (95% CI 1.75-8.69) for hospitalization and 3.35 (95% CI 1.53-7.33) for greater illness severity, which was similar to risk in type 2 diabetes. Among patients with type 1 diabetes, glycosylated hemoglobin (HbA1c), hypertension, race, recent diabetic ketoacidosis, health insurance status, and less diabetes technology use were significantly associated with illness severity. CONCLUSIONS: Diabetes status, both type 1 and type 2, independently increases the adverse impacts of COVID-19. Potentially modifiable factors (e.g., HbA1c) had significant but modest impact compared with comparatively static factors (e.g., race and insurance) in type 1 diabetes, indicating an urgent and continued need to mitigate severe acute respiratory syndrome coronavirus 2 infection risk in this community.

Utilizing continuous glucose monitoring in primary care practice: What the numbers mean.

Use of continuous glucose monitoring (CGM) has been shown to improve glycemia control, reduce hypoglycemia, lower glycemic variability and enhance quality of life for individuals with type 1 diabetes and type 2 diabetes. However, many primary care physicians may be unfamiliar with the how CGM data can interpreted and acted upon. As adoption of this technology continues to grow, primary care physicians will be challenged to integrate CGM into their clinical practices. This article is intended to provide clinicians with practical guidance in interpreting and utilizing CGM data with their patients.

Hospital care: improving outcomes in type 1 diabetes.

PURPOSE OF REVIEW: Caring for patients with type 1 diabetes (T1D) in the hospital presents unique challenges. This review provides an update on significant issues relevant to the inpatient management of T1D. Topics include trends in diabetic ketoacidosis (DKA), hypoglycemia, and adapting ambulatory technologies for inpatient use. RECENT FINDINGS: Rates of DKA in the United States are rising. Although socioeconomic status, health insurance coverage, and hemoglobin A1c are persistently associated with DKA in individuals with T1D, newer risk factors have also emerged. These include the off-label use of sodium-glucose cotransporter inhibitor medications, immune checkpoint inhibitor-induced diabetes, and infection with severe acute respiratory syndrome coronavirus 2. Hypoglycemia is common among hospitalized patients with T1D. Use of validated hypoglycemia risk prediction models and multidisciplinary care initiatives can reduce the risk of inpatient hypoglycemia. Finally, continuous glucose monitoring is being adapted for use in the hospital setting and has shown promise during the coronavirus disease 2019 (COVID-19) pandemic. SUMMARY: Evidence-based treatment algorithms, risk prediction calculators, multidisciplinary interventions, and wearable technology hold promise for improved outcomes in hospitalized patients with T1D.

Sodium-glucose co-transporter inhibitors as adjunctive treatment to insulin in type 1 diabetes: A review of randomized controlled trials.

Many patients with type 1 diabetes (T1D) struggle to achieve glycaemic control and experience significant fluctuations in glucose concentrations, despite insulin treatment. Sodium-glucose co-transporter (SGLT)-2 inhibitors and dual SGLT-1/2 inhibitors increase glucose elimination via the kidneys and reduce hyperglycaemia via insulin-independent mechanisms. This review examines available efficacy and safety data for these agents under investigation as adjunctive therapy for T1D. Across randomized trials of up to 52 weeks, SGLT-2 inhibitors or SGLT-1/2 inhibitors as an adjunct to insulin demonstrated significant reductions in glycated haemoglobin, glucose exposure, and measures of glycaemic variability, as well as increased time in the target glycaemic range, compared with placebo. Non-glycaemic benefits included reductions in body weight and insulin doses, as well as improvements in some cardiovascular risk factors and treatment satisfaction. SGLT-2 inhibitors and SGLT-1/2 inhibitors were associated with similar rates of hypoglycaemia but a higher incidence of genitourinary infections, compared with placebo. Diabetic ketoacidosis occurred more often with SGLT-2 inhibitors and SGLT-1/2 inhibitors vs placebo, although the incidence was generally low. Risk mitigation strategies in light of clinical trial data are also discussed. Positive data from randomized controlled trials of the SGLT-2 inhibitor dapagliflozin have led to the approval of dapagliflozin as an adjunct to insulin in adults with T1D having body mass index ≥27 kg/m2 in whom insulin does not provide adequate glycaemic control in Europe and to approval as an adjunct to insulin for adults with T1D in Japan.

Effect of a glucagon receptor antibody (REMD-477) in type 1 diabetes: A randomized controlled trial.

The aim of the current study (Clinical trial reg. no. NCT02715193, clinicaltrials.gov) was to study the efficacy and safety of REMD-477, a glucagon receptor antagonist, in type 1 diabetes. This was a randomized controlled trial in which 21 patients with type 1 diabetes were enrolled. Glycaemic control and insulin use were evaluated in outpatient and inpatient settings, before and after a single 70-mg dose of REMD-477 (half-life 7-10 days) or placebo. Inpatient insulin use was 26% (95% CI, 47%, 4%) lower 1 day after dosing with REMD-477 than with placebo (P = .02). Continuous glucose monitoring during post-treatment days 6 to 12 showed that average daily glucose was 27 mg/dL lower (P < .001), percent time-in-target-range (70-180 mg/dL) was ~25% greater (~3.5 h/d) (P = .001), and percent time-in-hyperglycaemic-range (> 180 mg/dL) was ~40% lower (~4 h/d) (P = .001) in the REMD-477 group than in the placebo group, without a difference in percent time-in-hypoglycaemic-range (<70 mg/dL). No serious adverse events were reported. Glucagon receptor antagonism decreases insulin requirements and improves glycaemic control in patients with type 1 diabetes.

New developments in the use of positive airway pressure for obstructive sleep apnea.

Obstructive sleep apnea (OSA) is a disorder which afflicts a large number of individuals around the world. OSA causes sleepiness and is a major cardiovascular risk factor. Since its inception in the early 1980's, continuous positive airway pressure (CPAP) has emerged as the major treatment of OSA, and it has been shown to improve sleepiness, hypertension, and a number of cardiovascular indices. Despite its successes, adherence with treatment remains a major limitation. Herein we will review the evidence behind the use of positive airway pressure (PAP) therapy, its various modes, and the methods employed to improve adherence. We will also discuss the future of PAP therapy in OSA and personalization of care.