Phase 3 Results of Fixed-Dose Combination of Remogliflozin Etabonate and Vildagliptin in Indian T2DM Patients
A clinical trial by Mohan B was presented on Friday June 25, 2021 at American Diabetes Association (ADA) 81stScientific Sessions, a Virtual Experience. The objective of this trial was to evaluate the clinical efficacy and safety of the fixed dose combination of Remogliflozin Etabonate and Vildagliptin in the management of Type 2 diabetes mellitus.
A 16-week, multi-centric, prospective, double blind, double dummy, parallel group, randomized controlled study was conducted in order to compare the safety and efficacy of fixed dose combination of Remogliflozin Etabonate (100) mg and Vildagliptin (50) mg to Empagliflozin (25) mg and Linagliptin (5) mg. The patients who were enrolled in the study had a HbA1c value between 8 – 11% and were on a stable Metformin dose of 1500 mg or more. The end – points established for efficacy were mean changes from baseline in HbA1c, fasting plasma glucose, post prandial plasma glucose, body weight and blood pressure.
Based on the results, it was found out that, amongst 182 participants, 86.3% subjects completed the study. The mean difference of -0.05% in HbA1c displayed non – inferiority of Vildagliptin 50mg (RV) to Linagliptin 5mg (EL). A noticeable reduction was observed in the fasting plasma glucose, post prandial plasma glucose, body weight and blood pressure and it was comparable across both the treatment arms. Certain drug related adverse effects were observed in 8.8% and 6.6% subjects of EL and RV respectively. Low incidence of hypoglycemia, genital and urinary tract infections were seen.
Thus, the fixed dose combination of Remogliflozin Etabonate and Vildagliptin was found to be efficacious, safe and well tolerated in the treatment and management of Type 2 diabetes mellitus patients. It additionally also displayed non – inferiority to the combination of Empagliflozin and Linagliptin.
Monotherapy in Youth-Onset Type 2 Diabetes Mellitus: A Retrospective Cohort Study
A clinical trial by Vajravelu ME was presented on Friday, June 25, 2021 at American Diabetes Association (ADA) 81st Scientific Sessions, a Virtual Experience. The aim of the trial was to determine the patterns and predictors of treatment escalation for youth with type 2 diabetes in clinical practice within 5 years of metformin monotherapy initiation.
A retrospective cohort study was conducted using data from a patient-level medical claims database from 2000 to 2019. By age at diagnosis, the frequency and order of treatment escalation to insulin and non-insulin antihyperglycemics were evaluated and classified. Age, sex, race/ethnicity, comorbidities, and metformin adherence (medication possession ratio 0.8) were all used to evaluate potential predictors of treatment escalation using Cox proportional hazards regression.
The cohort included 806 (66% female; median age at diagnosis 15 years; 19% Hispanic, 16% Black) patients, with median 3.0-year follow-up after metformin initiation. One-quarter underwent treatment escalation (n=198; 78 to insulin, 160 to non-insulin antihyperglycemic). Insulin was more likely to be prescribed as the first or only anti-hyperglycemic in younger patients. Treatment escalation was associated with age at diagnosis (HR 1.14, 95% CI 1.07-1.22), medication adherence (HR 3.77, 95% CI 2.71-5.23), and Hispanic ethnicity (HR 1.46, 95% CI 1.05-2.04), but not with comorbidities.
In clinical practice, treatment escalation for pediatric type 2 diabetes differs with age. Off-label use of non-insulin antihyperglycemics occurs, with older adolescents seems to be the most common.
Time to Consider Initiating SGLT2 Inhibitors and/or GLP-1RAs in the Inpatient Cardiovascular Care Setting—And Here’s How
Das S, presented a study in a session at the American Diabetes Association (ADA)2021 81st scientific sessions: virtual congress. The session was conducted to estimate the Key Considerations in use of sodium-glucose co-transporter-2 (SGLT2) inhibitors and/or glucagon like peptide-1 receptor agonists (GLP-1RAs) in the Inpatient Cardiovascular Care Setting.
GLP-1RAs demonstrated 13%, 26% and 12% reduction in MACE was reported in LEADER Trail, SUSTAIN-6 Trial, and REWIND respectively whereas, 14%, 18% and 10% reduction in MACE was reported by SGLT2 inhibitors in EMPA REG OUTCOME Trial, CANVAS Program and DECLARE TIMI-58. Meta-analysis of DAPA HF and Emperor-reduced Reported 13% reduction in all-cause death and 31% reduction in HF hospitalization with SGLT2 inhibitors in HFrEF patients. Hemodynamic effects on SGLT2 inhibitors show minimal effect on diuretic dose in trials.
Sotagliflozin therapy in patients with diabetes and recent worsening heart failure shows significant lower total number of deaths from cardiovascular causes and hospitalizations and urgent visits for heart failure as compared to placebo. SGLT2 inhibitors and GLP-1RAs reduce MI, stroke and CV death in patients of T2D with ASCVD. It was estimated that SGLT2 inhibitors markedly improve HFrEF and CKD outcomes, by providing 30% relative reduction in HF hospitalization and CV death, 35% reduction in CKD progression and avoids a massive burden of morbidity.GLP-1RAs are effective at reducing MACE, but require patient counseling and education. GLP-1RAs are very promising weight loss drugs but require titration to effective doses, which takes time. Weight loss can be a potent motivator for patients and help with adherence. GLP-1RAs are far less likely to be started in an outpatient cardiology setting.
SGLT2 inhibitors and GLP-1 RAs reduce MI, stroke, CV death, hospitalization for HF and CV death. These medications appear quite safe and offer some synergy in the inpatients context. Thus, it is essential Initiate SGLT2 Inhibitors and/or GLP-1RAs in the inpatient cardiovascular care setting.
Caution before Universally Recommending Initiation of SGLT2 Inhibitors and/or GLP-1RAs in the Inpatient Cardiovascular Care Setting
Green JB, presented a session at the American Diabetes Association (ADA) 2021 81st scientific sessions: virtual congress termed “Caution before Universally Recommending Initiation of sodium-glucose co-transporter-2 (SGLT2) inhibitors and/or glucagon like peptide-1 receptor agonists (GLP-1RAs) in the Inpatient Cardiovascular Care Setting.” ADA 2021 glycemic treatment clinical practice recommendations in primary care provided HER algorithm which identified one-third of primary care patients with T2D as meeting criteria for SGLT2 inhibitors and GLP-1 RA. .Underutilization and disparities in SGLT2i treatment could be partially addressed by starting guideline-based medications in the hospitals.
Cautions and concerns includes (1) mostly participants enrolled in CVOTs to date were outpatients, (2) starting SGLT2 inhibitors, GLP-1RA in acutely ill inpatients to improve CV outcomes would be an extrapolation from existing trials data, and (3) short term risk/benefit ratio may be altered in the hospitalized patient. In-hospital use of SGLT2 inhibitors and GLP-1RA provide independent outcome benefit during hospitalization remains largely unproven. DARE-19 Trials reported 2 DKA events in DAPA group as compared to none in PBO group.
SGLT2 inhibitors increase the risk of diabetic ketoacidosis developing in the community and during hospital admission. Almost 38% of DKA events, among users of SGLT2 inhibitors, developed during the course of an in-patient admission. As per ADA 2021 recommendations SGLT2 inhibitors should be avoided in cases of severe illness in patients with ketonemia or ketonuria, and during prolonged fasting and surgical procedures. Until safety and effectiveness are established, SGLT2 inhibitors are not recommended for routine in-hospital use. Use of guideline-based therapy with SGLT2 inhibitors and GLP-1RA should be an expected component of care for high risk patients with T2DM.
SGLT2 inhibitors and GLP-1RA have clear outcomes benefits in high CV risk patients with diabetes, but the drugs are currently underutilized. However the side effect profile of these medications must be carefully considered before initiation of these drugs in the hospital. Initiation at the conclusion of hospital stay or at discharge may be safest and most effective approach at this time.
Heart Failure in Diabetes—New Therapeutic Insights
Bozkurt B from Baylor College of Medicine presented her new insights on Heart failure (HF) in diabetes at American Diabetes Association (ADA) 81st Scientific Sessions, a Virtual Experience.
The author stated that diabetes patients tend to have 2 to 5 times higher risk of developing HF. Along with this she also mentioned about poor glycemic control is associated with incident HF. ACC/AHA mentions the HF stages from stage A to stage D. Stage A risk mentions about known risk factors such as hypertension, diabetes mellitus (DM) etc. with high relative risk and prevalence and population attributable risk. The author also mentions that with lifestyle modification, risk factors in Stage A and Stage B/C can be prevented. Healthy lifestyle also prevents future development of HF risk. Mediterranean and DASH diet is also found to lower the risk of heart failure. SGLT2 inhibitors (SGLT2i) in DM also show evidences in lowering the risk for Heart failure. Various study trials such as EMPA-REG, CANVAS, DECLARE and VERTIS trial have depicted reduced or prevented HF events with SGLT2i in high risk CVD. Weight was found to be reduced by ~2 kg with SGLT2i. Consistent signal for significant effect for prevention of HF in diabetes was depicted in meta-analysis of SGLT2i and heart failure hospitalizations.
Various guideline recommendations such as ADA, AACE/ACE etc. support use of SGLT2i to reduce HF risk in patients with T2D. In SGLT2i vs. GLP1RA for Heart Failure Hospitalization (HFH) meta-analysis, SGLT2i shows promising effects while GLP1RA shows neutral effect. In STOP HF trial, HF and Left Ventricular Dysfunction (LVD) were taken as the primary endpoints of study. The author also stated the treatment strategies according to stages of HF. The author mentioned about the universal definition stages of HF from stage A to stage D. The author stated that the current and proposed focus in HF guidelines for prevention of HF should range from at risk stage A to HF stage C. SGLT2i also showed positive results in Heart failure with reduced ejection fraction (HFrEF) regardless of DM.=Studies also showed significant reductions in primary and secondary endpoints in DAPA-HF and EMPEROR trials. The trials also depicted improved QOL in HFrEF. The SOLOIST trails depicted benefits for SGLT2i in patients with DM hospitalized for HF regardless of LVEF.
The author concluded the session stating DM to be a significant risk factor for HF. She also mentioned about lifestyle modification, and highlighted benefits of SGLT2i therapy to reduce risk of HF and HF events.
Diabetic Kidney Disease—What Is on the Horizon?
Spall HV presented therapies in patients with diabetic chronic kidney disease on Friday June 25, 2021 at American Diabetes Association (ADA) 81st Scientific Sessions, a Virtual Experience. About 35% of diabetic adults have chronic kidney disease (CKD) making it one of the most common comorbidities contributing towards high morbidity, mortality and healthcare resources.
High protein diet may increase glomerular filtration and ultrafiltration. A meta-analysis involving 9 small RCTs evaluated the effect of low-protein diet (defined as <0.8 g/kg/d for 4.5-6 months) in Diabetic Kidney Disease DKD patients. Results suggested a significant fall in eGFR by 22.31 ml/min/1.73m2 with low protein diet in DKD patients. A large cohort study revealed that patients undergoing bariatric surgeries had 67% reduction in the incidence of renal endpoint over an 18 year follow-up period.
Although Angiotensin-converting enzyme inhibitors (ACEi) and Angiotensin receptor blockers (ARBs) are well established therapies, they often lead to reduction in Estimated glomerular filtration rate (eGFR). A pooled analysis revealed that low dose ACEi did not reduce the all-cause mortality. However, those on target therapy or maximum tolerated ACEi therapy showed significant risk reduction. ACEi & (ARBs) reduced the risk of end-stage kidney disease (ESKD) and doubling of serum creatinine. ARBs do not reduce the risk of all-cause mortality. In the management patients with normokalemia, with <30% increase in creatinine, increase the dose of ACEI or ARBs to maximal dose. In patients with hyperkalemia, instead of stopping Renin–Angiotensin–Aldosterone System (RAAS) inhibition, include potassium binders in the therapy. In those with sustained increase of > 30% in creatinine, review the patient for possibilities of Acute kidney injury (AKI) including renal artery stenosis.
FIDELIO-DKD demonstrated a significant reduction in secondary composite outcomes & no reduction in all-cause death with fineronone. There was higher rate of adverse rate none of which led to discontinuation of therapy including hyperkalemia. Therefore, fineronone must be used with the careful monitoring and potassium binders. When compared with spironolactone, fineronone was equally or more efficient in lowering albuminuria & cardiac biomarkers (Brain natriuretic peptide (BNP), N-terminal -pro hormone BNP (NT-proBNP)).
GLP1 RA was found to improve secondary renal outcomes in DKD patients. SCORED trial demonstrated a significant reduction in primary and secondary end points with sotagliflozin 400 mg in T2D patients having CKD & CV risk factors. DAPA-CKD showed a marked decline in primary composite endpoints with the renal effects independent of glucose-lowering effect.
Overall, RAASi, SGLT2i, GLP1 RA and lifestyle modifications have all had a positive effect on the outcomes and can be used as effective strategies to improve renal outcome in DKD patients.
Combination Therapy with SGLT2i and GLP-1RA in Mitigating Cardiorenal Metabolic Risk
Vanita R. Aroda presented a session on the role of with SGLT2i and GLP-1RA combination therapy in mitigating the cardiorenal metabolic risk of diabetes patients on Friday June 25, 2021 at American Diabetes Association (ADA) 81st Scientific Sessions, a Virtual Experience. The lifetime risk of CVD in women with diabetes is 67% while in men it is 78% and increases with the increase in level of obesity. The burden of complications is increasingly driven by prevalent diabetes & changing demographics. The current world can be described as Cardiometabolic impacting lifespan and healthspan.
SGLT2i and GLP-1RA have complementary, non-overlapping clinical benefit towards mitigating cardiorenal metabolic risk as GLP-1RA significantly reduces stroke risk while SGLT2i reduce the risk of hard renal endpoints & Hospitalization due to HF. Both have the benefits in MACE, MI, CV death and broad renal endpoints. They execute physiologic or mechanistic benefits with GLP-1RA addressing atherosclerotic & inflammatory CV pathways and SGLT2i addressing myocardial energetics and cardiorenal pathways.
While treating patients with diabetes, there are multiple factors & care goals that need be considered which can be supported by the choice of therapy. ADA & ACC have recommended consideration of SGLT2i and GLP-1RA for cardiorenal risk mitigation inappropriate patients considering priorities, comorbidities, risks and benefits.
Combination therapy with SGLT2i and GLP-1RA has a significant scope with thorough clinical evidences having complementary, non-overlapping physiologic benefits. These are supported by clinical guidelines and can be achieved with patient-centric care providing model.
Personalized Diets by Prediction of Glycaemic Responses Improve Glycaemic Control in Subjects with Newly Diagnosed T2D
A clinical trial by Rein MS was presented on Friday, June 25, 2021 at American Diabetes Association (ADA) 81st Scientific Sessions, a Virtual Experience. The objective of the trial was to assess the clinical efficacy of the previously developed machine learning algorithm-based diets in subjects with newly diagnosed Type 2 Diabetes Mellitus.
A short term randomized controlled crossover trial was conducted in order to compare the effects of an algorithm based personalized postprandial targeting diet (PPT) to the routinely used Mediterranean diet in 23 patients. Based on the analysis of the results, it was found out that average post – prandial glucose responses (PPGR), glucose fluctuations and fructosamine levels witnessed a noticeable decrease during the PPT intervention as compared to the Mediterranean dietary intervention.
Additionally, long term clinical impact of the PPT diet was assessed in 16 participants and significant improvement across multiple clinical parameters were observed including the HbA1c (p<0.001), fasting glucose (p=0.02), fasting insulin (p = 0.04), triglycerides (p<0.001), body weight (p = 0.005), body fat % (p = 0.005) and waist circumference (p = 0.001). Around 61% participants demonstrated diabetes remission in the end as evaluated by the HbA1c.
The study highlighted that predicting glycaemic responses could lead to improvement in glycaemic control in subjects with newly diagnosed T2D.
ADA Presidents’ Select Abstract Presentation: Genetic Architecture and Novel Genes Implicated in Youth-OnsetType 2 Diabetes
A study conducted by Kwak SH was presented on Friday June 25, 2021 at American Diabetes Association (ADA) 81st Scientific Sessions, a Virtual Experience. The objective of this study was to evaluate the contribution of rare coding variants to the genetic basis of youth Type 2 diabetes mellitus.
In light of the same, whole exome sequences of 3005 people with youth – onset diabetes who were diagnosed before 20 years of age was analysed and 9777 ancestries matched the adult controls. Subsequently, eleven genes were discovered amongst which three genes with aggregate rare variant associations were identified and eight other genes previously linked to diabetes were identified which have also been included in the top twenty overlapping gene biologically characterised gene sets.
The eleven genes were further classified into three groups; monogenic diabetes-related genes (HNF1A, GCK, and RFX6), obesity-related genes (MC4R, ATXN2L, GHRL, and CPQ) and β-cell function related genes (SLC30A8, ABCC8, PAM, and SIX3).
A significant exome wide gene burden was observed for the ATXN2L gene and for known diabetes genes such as MC4R and HNF1A, the effect in youth onset type 2 diabetes mellitus was a lot larger than that in adult-onset type 2 diabetes mellitus. Both the common and the rare variants appeared to contribute more to youth onset Type 2 diabetes mellitus when compared to the adult – onset type 2 diabetes mellitus.
Thus youth onset type 2 diabetes mellitus appears to be a disease with intermediate severity between monogenic and type 2 diabetes which comprises of genetic variants in both, insulin secretion and insulin response pathways.
Identification of Ancestry-Specific Alleles in a Genome-Wide Association Study (GWAS) for Metformin (MET) Response in the Diabetes Prevention Program (DPP)
A study conducted by Jospehine H was presented on Friday June 25, 2021 at American Diabetes Association (ADA) 81stScientific Sessions, a Virtual Experience. The objective of this study was to evaluate whether the pharmacogenetic interactions differed in impaired glucose tolerance. In light of the same, a genome wide association study was carried out in the diabetes prevention program (DPP) to assess the Metformin response.
This response was defined by the incidence of diabetes and variation in quantitative traits such as fasting glucose, 2-hour glucose on oral glucose tolerance test, HbA1c, fasting insulin, insulin sensitivity index and weight. The samples were genotyped using the Illumina HumanCore exome array and imputed on the 1000 Genomes phase 3 panel following which the Cox proportional hazards model tested associations with the incidence of diabetes in (n = 876) of MET and (n = 887) of placebo. Additionally, a test for gene by environment interaction between MET and placebo was also carried out.
Based on the analysis, 3 Genome-wide significant (GWS) variants were found out. In case of MET, a variant near ENOSF1 was associated with an increase in % HbA1c and was fundamentally found in participants of the African ancestry. A variant near OMSR was linked with greater weight loss in MET and was established in 10% of Native Americans. Neither of the two variants had an impact in placebo nor were any GWS associations found out for diabetes incidence.
This study revealed novel associations that further require validation but once validated, it may have a positive implication in tailored therapy.
