To quantify and contextualize the risk for coronavirus disease 2019 (COVID-19)-related hospitalization and illness severity in type 1 diabetes.
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.
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 (HbA
), hypertension, race, recent diabetic ketoacidosis, health insurance status, and less diabetes technology use were significantly associated with illness severity.
Diabetes status, both type 1 and type 2, independently increases the adverse impacts of COVID-19. Potentially modifiable factors (e.g., HbA
) 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.
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.
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.
Identifying T1D patients with impaired awareness of hypoglycemia (IAH) is essential, as these patients are at ~10-fold risk of severe hypoglycemia. Defining IAH has relied on questionnaires such as ...Clarke score that are rarely used in clinical practice. Additional tools are needed to stratify hypoglycemia risk in patients with T1D. Here we show that CGM metrics correlate with physiologic response to hypoglycemia. We measured serum epinephrine levels in 22 subjects with T1D (ages 28-52, A1c 6.1-7.2, median Clarke score 3) during a hyperinsulinemic-hypoglycemic clamp. Baseline CGM data was collected for 2 weeks prior to clamp. These data show a novel, inverse relationship between CGM time below range (TBR, <70 mg/dL) and epinephrine response (EpiR, pg/mL/min) FIGURE. CGM TBR (ρ = -0.562, p = 0.006), Clarke score (ρ = -0.592, p = 0.03), and older age (ρ = -0.500, p = 0.015) were inversely associated with EpiR. Higher average glucose was associated with increased EpiR while time in range, coefficient of variation, BMI, and duration of T1D showed no significant association with EpiR. Our study suggests that CGM TBR predicts counterregulatory dysfunction in T1D. CGM TBR demonstrated a robust, inverse correlation with EpiR similar to the validated Clarke survey. CGM is now the gold standard for glycemic monitoring in T1D, and the percentage TBR may help identify patients at highest risk for severe hypoglycemia outcomes.
Disclosure
R.L.Thomas: None. J.M.Gregory: Advisory Panel; Eli Lilly and Company, vTv Therapeutics, Other Relationship; Medtronic. E.R.Giovannetti: None. S.C.Boeder: Consultant; Cecelia Health, Research Support; Dexcom, Inc., REMD Biotherapeutics, Eli Lilly and Company. J.Pettus: Advisory Panel; Sanofi, Novo Nordisk, Lilly, MannKind Corporation, Consultant; Carmot Therapeutics, Inc., Diasome.
Funding
JDRF (2-SRA-2018-606-M-B, 5-ECR-2020-950-A-N); National Institute of Diabetes and Digestive and Kidney Diseases (K23DK123392)
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.
To examine the effects of insulin-adjunctive therapy with a sodium-glucose cotransporter 2 (SGLT2) inhibitor and a glucagon receptor antagonist (GRA) on glycemia, insulin use, and ketogenesis during ...insulinopenia in type 1 diabetes.
In a randomized, double-blind, placebo-controlled, crossover trial we assessed the effects of adjunctive SGLT2 inhibitor therapy (dapagliflozin 10 mg daily) alone and in combination with the GRA volagidemab (70 mg weekly) in 12 adults with type 1 diabetes. Continuous glucose monitoring, insulin dosing, and insulin withdrawal tests (IWT) for measurement of glucose and ketogenesis during insulinopenia were completed during insulin-only (Baseline), SGLT2 inhibitor, and combination (SGLT2 inhibitor + GRA) therapy periods.
Average glucose and percent time with glucose in range (70-180 mg/dL) improved with combination therapy versus Baseline and SGLT2 inhibitor (131 vs. 150 and 138 mg/dL P < 0.001 and P = 0.01 and 86% vs. 70% and 78% P < 0.001 and P = 0.03, respectively) without increased hypoglycemia. Total daily insulin use decreased with combination therapy versus Baseline and SGLT2 inhibitor (0.41 vs. 0.56 and 0.52 units/kg/day P < 0.001 and P = 0.002). Peak β-hydroxybutyrate levels during IWT were lower with combination therapy than with SGLT2 inhibitor (2.0 vs. 2.4 mmol/L; P = 0.048) and similar to levels reached during the Baseline testing period (2.1 mmol/L). Participants reported enhanced treatment acceptability and satisfaction with combination therapy.
Glucagon antagonism enhances the therapeutic effects of SGLT2 inhibition in type 1 diabetes. Combination therapy improves glycemic control, reduces insulin dosing, and suggests a strategy to unlock the benefits of SGLT2 inhibitors while mitigating the risk of diabetic ketoacidosis.
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.
SGLTi treatment improves glycemic control and reduces insulin dosing but increases the risk of diabetic ketoacidosis (DKA). Combination therapy (SGLTi + GRA) could augment glycemic and insulin dosing ...benefits while mitigating DKA risk.
Subjects with T1D (n=12) received 4-week insulin-adjunctive treatments with (a) SGLTi (dapagliflozin 10 mg) + placebo and (b) SGLTi + GRA (volagidemab 70 mg) in a cross-over, double-blind design. At baseline and end of each treatment, CGM and insulin dosing were recorded, and subjects completed an 8-hr insulin withdrawal test (IWT).
Average glucose improved with both SGLTi (138 mg/dL; P < 0.01) and SGLTi + GRA (131 mg/dL; P < 0.01) compared to Baseline (150 mg/dL). Total daily insulin dose was reduced with SGLTi (0.52 U/kg/day) compared to Baseline (0.56 U/kg/day; P = 0.06) and was reduced further with SGLTi + GRA treatment (0.41 U/kg/day; P < 0.01 vs SGLTi). Peak beta-hydroxybutyrate (BHB) concentrations during IWT were lower with SGLTi + GRA treatment (2.03 mmol/L) than with SGLTi alone (2.44 mmol/L; P = 0.04); there was no significant difference in peak BHB with either treatment vs Baseline (2.14 mmol/L).
Treatment with SGLTi + GRA improved glycemic control, reduced insulin use, and mitigated ketosis during hypoinsulinemia. These data suggest that combination adjunctive therapy may be effective to address multiple metabolic abnormalities in T1D.
Disclosure
S.C.Boeder: Consultant; Cecelia Health, Research Support; Dexcom, Inc., REMD Biotherapeutics, Eli Lilly and Company. M.J.Le roux: None. E.R.Giovannetti: None. A.Armstrong: None. L.Carter: None. R.L.Thomas: None. J.M.Gregory: Advisory Panel; Eli Lilly and Company, vTv Therapeutics, Other Relationship; Medtronic. J.Pettus: Advisory Panel; Sanofi, Novo Nordisk, Lilly, MannKind Corporation, Consultant; Carmot Therapeutics, Inc., Diasome.
Funding
National Institutes of Health (P30DK063491, UL1TR001442); Diabetes Research Connection
Identification of adjunctive, oral pharmacotherapies to treat T1D has been limited by risk of DKA. TTP399, an oral hepatoselective GKA, significantly improves glycemia in individuals with T1D ...compared to placebo. This double-blind, randomized, placebo-controlled, Phase 1 mechanistic study examined whether TTP399 decreases ketogenesis during insulin withdrawal.
Individuals with T1D (n=23) using insulin pump therapy were randomized to TTP399 or placebo for 7-days after which an insulin withdrawal test (IWT) was performed. Insulin pumps were disconnected for up to hours to induce ketogenesis.
TTP399 significantly reduced fasting glucose (-27.6 vs. -4.4 mg/dL, p = 0.03) . During the treatment period, adverse events were fewer in TTP399-treated subjects. No hypoglycemic events <54mg/dL were observed in the TTP399 group compared with 2 subjects in the placebo group. Following insulin withdrawal, no significant differences in mean duration of IWT or beta-hydroxybutyrate (BOHB) at termination were observed between treatment groups (Figure 1A) . Serum bicarbonate was numerically higher and urine acetoacetate was qualitatively lower in TTP399-treated subjects (Figure 1A) . No patients on TTP399 met prespecified criteria for DKA while 43% of subjects on placebo did (Figure 1B, p = 0.03) .
These data suggest that TTP399 treatment improves glucose control with no increased risk of DKA.
Disclosure
K.Klein: None. S.C.Boeder: Consultant; Cecelia Health, Research Support; Dexcom, Inc., Lilly. J.L.Freeman: Employee; vTv Therapeutics, Stock/Shareholder; vTv Therapeutics. S.Madduri: None. E.R.Giovannetti: None. C.Valcarce: Employee; vTv Therapeutics. J.B.Buse: Consultant; Alkahest, Anji, AstraZeneca, Boehringer Ingelheim International GmbH, Cirius Therapeutics, Inc., Eli Lilly and Company, Fortress biotech, GentiBio, Glycadia, Glyscend, Janssen Pharmaceuticals, Inc., Mellitus Health, Moderna, Inc., Pendulum Therapeutics, Praetego, LLC, Stability Health, Valo, Zealand Pharma A/S, Other Relationship; Adocia, AstraZeneca, Eli Lilly and Company, Intarcia Therapeutics, Inc., MannKind Corporation, Novo Nordisk, Sanofi, Senseonics, vTv Therapeutics, Research Support; AstraZeneca, Dexcom, Inc., Eli Lilly and Company, Novo Nordisk, vTv Therapeutics, Stock/Shareholder; Glyscend, Mellitus Health, Pendulum Therapeutics, PhaseBio Pharmaceuticals, Inc., Praetego, LLC, Stability Health. J.Pettus: Advisory Panel; Lilly, MannKind Corporation, Novo Nordisk, Sanofi, Consultant; Carmot Therapeutics, Inc., Diasome.
Funding
JDRF international
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