Realizing the Benefits of SGLT2 Inhibition for Kidney Protection
Perkovic V, presented a session at the American Diabetes Association (ADA) 2021 81st scientific sessions: virtual. According to US data, there is increasing incidence and prevalence of end-stage kidney disease (ESKD) from 1990-2019 associated with major health and financial burden on community and social impact. Prognosis of patient with kidney failure requires dialysis to increase the ratio of 5-year survival. As per 2019 study, the survival probability of dialysis patients is almost 30% and not improved as compared to breast and colorectal cancer from the data of 1997-2011.
The major cause of kidney failure is type 2 diabetes mellitus (T2DM). CKD occurs in almost 40% of adults with T2DM.
RAAS inhibition (ACEi and ARB) has been the only treatment is proven to prevent kidney failure. In the RENAAL and IDNT study they have showed reduction in ESKD but despite of this there is very large risk of kidney failure in this patients. Since RENAAL and IDNT, new therapeutic strategies for patients with T2DM and CKD have failed. From the 2017 Lancet study, more intensive glucose control suggested better kidney outcomes.
Several new classes of glucose lowering treatments now widely used are DPP4i, GLP-1RAs, and SGLT2i. The CARMELINA trial showed that Linagliptin decreases ≥40% of eGFR or death due to kidney disease from baseline but no benefit of secondary outcome compared to placebo. The CANVAS 2012 trial showed that Canagliflozin significantly reduces the ratio of albumin/creatinine ratio in patients with macroalbuminuria. SGLT2i reduces intraglomerular pressure and renal damage with hyperfiltration via tubuloglomerular feedback (TGF). SGLT2i and ACEi and ARB reduce intraglomerular pressure leads to renal protection. Canagliflozin showed in 60% reduction in the rate of eGFR decline in CREDENCE trial. Dapagliflozin showed sustained ≥50% eGFR decline, ESKD, renal or CV death in DAPA-CKD trial.
The number of people with kidney failure is growing around the world. Improving outcomes for people with kidney failure is a priority, as little progress has been made. Preventing kidney failure is possible with SGLT2i in people with and without T2DM. Increasing use of these proven therapies is now the biggest challenge.
Can CGM Combined with a Smart Pen Improve Insulin Management in Primary Care?
A session by Isaacs D was presented on Monday, June 28, 2021 at American Diabetes Association (ADA) 81st Scientific Sessions, a Virtual Experience. This session was conducted to describe the insulin delivery landscape and barriers to optimal care for people with type 2 diabetes taking insulin and discuss how smart pens can combine with CGM data to facilitate interpretation and optimization of treatment. Clinical challenges with insulin therapy includes: (1) missing two doses per week can lead to an increase in A1c of up to 0.4%, (2) 2/3 of people need help calculating their insulin doses, (3) 60% of insulin doses are taken with some insulin-on-board, (4) lack of accurate dosing data is a significant barrier to optimizing glycemic control.
Insulin pen basics includes: A reusable pen or smart pen cap paired with smartphone mobile app to help people with diabetes manage their insulin regimens, can calculate and tracks insulin doses pairs with BGM and CGM, and can shared data with the clinic. Pen capabilities includes track active insulin time to prevent insulin stacking, dose reminders, insulin expiration, temperature indicator, dose calculation and record. Two U.S. products include: (1) Medtronic Inpen with Guardian Connect or Dexcom G6: this is a reusable pen that actually uses insulin cartridges; it pairs with the smartphone app. (2) Bigfoot unity with Libre 2 consists of two different types white cap is for rapid acting insulin and black cap is for long acting insulin. Use of a bolus calculator reduces fear of hypoglycemia, improves confidence in the accuracy of their insulin bolus dose and increases treatment satisfaction. Reduction in A1c from 0.7 to 1.05 was reported with the use of an automated dose calculator.
A case of 66 year old male with type 2 diabetes was presented. His HbA1c level was 9.1%, and he confirmed that he was using rtCGM. It was reported that his average glucose level dropped to 143 after he started using the smart pen, HbA1c level reduced to 6.9% after three months, and also shows 82% time in the target range.
Smart pens can help people with diabetes calculate insulin doses, remember to take their insulin, and correct high glucose without fear of insulin stacking. Data from smart pens is used by the healthcare team for more meaningful discussions which helps to optimize treatment and improve clinical outcomes.
Combination Therapies for Kidney Protection in Diabetes—Is One Plus One More than Two?
Heerspink HL from the University Medical Center Groningen presented a study “Combination Therapies for Kidney Protection in Diabetes—Is One Plus One More than Two?” at American Diabetes Association (ADA) 81st Virtual Scientific Session.
To optimize kidney protection further, new therapies like combination treatments with these new therapies can further reduce the risk of kidney failure and heart failure. Some potential combinations and the proposed algorithm to personalize treatment are as follows
- Obese individuals with HbA1c 9.1%, eGFR 45 mL/min and UACR 52 mg/mmol- SGLT1i + GLP1-RA
- NTproBNP 850pg/mL, heart failiure NYHA class III, Hba1c 7.1%, eGFR53 ml/min, UACR 109mg/mol and BMI 12kg/m2– SGLT2i + MRA
- Hba1c 8%, potassium 5.8, eGFR 46ml/min and UACR 54mg/mmol- SGLT2i +ERA
Current treatment of ACEi and ARBs are insufficient to slow CKD progression. SGLT2 inhibitors, ERA, MAR and GLP-1RA slow progression of kidney function decline. When used in combination, SGLT2 inhibitors may abrogate fluid retaining effects of ERA and hyperkalemia effects of MRA.
Yes, there is immense potential for augmentation of kidney protection and mitigation of adverse effects.
Covid 19, Diabetes and Obesity
Sattar N from University of Glasglov presented his talks on Obesity and diabetes risk factors for severe COVID 19 on Monday June 28th, 2021 at American Diabetes Association (ADA) 81st Scientific Sessions, a Virtual Experience. As per current obesity reports, the author reported – 5% excess risk Coronavirus Disease 2019 (COVID 19) per Body Mass Index (BMI) unit (higher in younger) BMI causal risk factor 14% (95% CL 7 to 21%) hospitalization per 1 kg/m2. The author depicted that diabetes/ obesity are bigger players than expected in COVID -19 severities and mentioned about controlling BP, weight, glucose levels, etc. in order to prevent the same.
Mathew Frieman presented on diabetic comorbidity effects on coronavirus pathogenesis at the session. The cause for high lethality of Middle East respiratory syndrome coronavirus (MERS-CoV) infections was diabetes severity being associated with pre-existing comorbidities such as diabetes, cardiovascular disease (CVD) pulmonary disease and end stage renal failure. The study results showed, a high fat diet induces glucose intolerance and T2D in human DPP4 (hDPP4) +/- mice.
Antonio Ceriello presented on the topic of hyperglycemia and COVID 19 prognosis at the session. The author highlighted on the topics of long term glycemic control, acute hyperglycemia, hyperglycemia and COVID-19 prognosis, and also about vaccines, role of corticosteroids and therapeutic strategy. Among 7300 cases of COVID-19 T2DM is associated with a higher death rate, wherein T2D with better glucose control level, death rates were lower in comparison to poorly controlled glucose levels.
Pedro Moraes Vieira presented on the topic of glycolysis, interferons and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections at the session. He talked about link between COVID-19 and obesity, obesity epidemics and also mentioned about SARS-CoV-2 infection inducing glycolysis in human monocytes. It was found that monocyte metabolism modulates T cell and epithelial cell response to SARS-CoV-2 infection.
The authors through various studies and evidences highlighted the link and management of COVID-19, obesity and diabetes.
Results of the Glycemia Reduction Approaches in Diabetes—A Comparative Effectiveness (GRADE) Study – Primary Outcome—Metabolic Result
John M. Lachin of The George Washington University Biostatistics Center presented a study “Results of the Glycemia Reduction Approaches in Diabetes—A Comparative Effectiveness (GRADE) Study- Primary Outcome—Metabolic Result” at the American Diabetes Association (ADA) 81st Virtual Scientific Session.
Primary Outcome (confirmation of HbA1c ≥5%)- 71% of all participants developed the primary metabolic outcome. Medication non-compliance leading to discontinuation was highest in glimepiride (20%) and lowest for glargine (13%). Use of non-study glucose-lowering medications at any time during GRADE was highest with glimepiride and sitagliptin (approx. 20%). Use of non-study glucose-lowering medication at the time of the primary outcome was low overall, ranging from 1.4% in the glimepiride-treated group to 2.3% in the glargine-treated group. The glargine and liraglutide treated groups met the primary metabolic outcome less frequently and later than the glimepiride and sitagliptin groups. The mean time to reach the primary metabolic outcome with liraglutide was 185 days longer than that for sitagliptin, 72 days longer than for glimepiride and 21 days longer for glargine.
Secondary metabolic outcome (confirmation of HbA1c>7.5%)- Glargine was significantly more effective in maintaining HbA1c in the target range than liraglutide which, in turn, was more effective than glimepiride and sitagliptin. Tertiary metabolic outcome (confirmation of HbA1c >7.5% after reaching secondary outcome)- Glimepriride and sitagliptin had more tertiary and metabolic outcomes than glargine or liraglutide, which were similar in magnitude.
There were some significant differences by baseline HbA1c. Glargine, glimepiride and liraglutide were more effective than sitagliptin and their relative benefits increased as the HbA1c increased.
Results of the Glycemia Reduction Approaches in Diabetes – A Comparative Effectiveness (GRADE) Study – Microvascular Outcomes
Deborah J. Wexler from Massachusetts General Hospital presented a study “Results of the Glycemia Reduction Approaches in Diabetes—A Comparative Effectiveness (GRADE) Study- Microvascular Outcomes” at the American Diabetes Association (ADA) 81st Virtual Scientific Session.
Albuminuria measured every 6 months by spot urine -moderately increased is ≥30mg/gm creatinine, confirmed at the successive visit and severely increased is >300mg/gm creatinine. Estimated GFR (serum creatinine with calculated CKD-EPI) annually is said to be abnormal if it is <60ml/min/1.73m2. Peripheral neuropathy with the modified Michigan Neuropathy screening instrument is performed annually, the total score is based on a questionnaire and exam (≥2.54).
Percentage of participants who developed albumin to creatinine ration ≥30mg/gm, confirmed were- 12% in glargine group, 12% in glimepiride group, 11% in the liraglutide group and 11% in sitagliptin group. The percentage of participants who developed albumin to creatinine ratio>300mg/gm was 4.7% in the glargine group, 4.9% in the glimepiride group, 5.4% in the liraglutide group and 5.3% in the sitagliptin group. Percentage of participants who developed estimated EGFR< 60ml/min/1.73m2 were 12% in the glargine group, 12% in the glimepiride group, 14% in the liraglutide group and 12% in the sitagliptin group. Percentage of participants who developed Michigan Neuropathy screening instrument ≥2.54 were 70% in the glargine group, 72% in the glimepiride group, 69% in the liraglutide group and 72% in the sitagliptin group however, no significant differences were found among treatment groups at baseline.
In a population with relatively new-onset diabetes, there were no differences among any of the treatment groups in the development of moderately or severely increased albuminuria, estimated GFR<60ml/min/1.73m2 and distal sensory polyneuropathy.
Comparing Cardiovascular Benefits between GLP-1RA and SGLT2i as an Add-On to Metformin among U.S. Adults with Type 2 Diabetes (T2D)
A study by Christina E Deremer was presented on Monday, June 28, 2021 at American Diabetes Association (ADA) 81st Scientific Sessions, a Virtual Experience. The objective of this study was to compare the cardiovascular benefits that are associated with the use of glucagon – like peptide – 1 receptor agonists (GLP – 1RA) vs. sodium – glucose co – transporter – 2 inhibitors (SGLT2i) as adjunct therapies to metformin.
The study comprised of 11911 adults with type 2 diabetes who initiated a GLP – 1RA or SGLT2i as add-on therapy to metformin. The primary endpoint of the study was a major cardiovascular composite such as acute myocardial infarction (MI), hospitalization for congestive heart failure (CHF), and stroke. The secondary endpoint included individual components of a major cardiovascular composite (MCC).
Based on the analysis, it was found out that there was no difference in the risk of MCC or any other secondary endpoints between GLP-1RA and SGLT2i users who did not have a previously established cardiovascular disease. But remarkably lower risks of MCC were observed amongst SGLT2i users when compared with GLP-1RA users, in individuals with previously established cardiovascular complications.
Thus, these findings point towards a greater cardio-protective benefit from SGLT2i as compared to GLP-1RA when used for secondary prevention among adults with Type 2 diabetes
High Glucose Level Increases Expression of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Receptors
A study by Seshagiri Rao Nandula was presented on Monday, June 28, 2021 at American Diabetes Association (ADA) 81st Scientific Sessions, a Virtual Experience. The objective of the study was to evaluate the effects of high glucose on the expression of human angiotensin converting enzyme 2 (ACE2) and transmembrane protease, serine 2 (TMPRSS2) receptors using macrophage (CD14+ve cells) as a biomarker in vivo and human endothelial cells in vitro.
The ficoll density centrifuge method was utilized to isolate mononuclear cells from whole blood and CD14 cells were isolated by the MACS kit. Following which, the migratory capacity of CD14 cells was assessed and CFU – hill colony formation essay was done on MNC’s. In vitro studies were done using HUVEC. All the COVID patients included in the study had high glucose levels (>300 mg/dl). Based on the analysis, it was found out that the migratory function of CD14 cells demonstrated increased migration when compared to non – diabetic COVID negative patients. CD14 cells displayed low expression of ACE2 and/or TMPRSS2 in all samples
In the in-vitro experiments, mRNA expression of ACE2 and/or TMPRSS2 receptors was higher in HG when compared to NG at day 7. An elevated gene expression of inflammatory marker, IL-6 and apoptosis marker, P53 were observed in HG on both, day 3 and day 7. A low incidence of SARS-CoV-2 receptors was observed on CD14 macrophage cells and this may pinpoint towards a poor recognition of the virus particle by CD14 cells. But a higher expression of the SARS-CoV-2 receptors were noted when HUVEC cells were cultured in HG for 7 days.
Thus, a longer exposure of human endothelial cells to a high glucose condition increases the SARS-CoV-2 receptor expression.
Exercise Training Improved Antilipolytic Sensitivity to Insulin in Obese Adults with Low Sensitivity to Insulin before Training
A study by Cheehoon Ahn was presented on Monday, June 28, 2021 at American Diabetes Association (ADA) 81st Scientific Sessions, a Virtual Experience. The objective of this study was to compare the adipose tissue morphology in obese adults with high- (HIGH) vs. low-sensitivity (LOW) to the antilipolytic effects of insulin and to compare the consequences of exercise training on adipose tissue from HIGH vs. LOW subjects.
Isotopic dilution methods were used, before and during a hyperinsulinemic-euglycemic clamp to assess the antilipolytic response to insulin in 36 obese adults and 13 each, sub – cohorts of LOW and HIGH were recognized. Abdominal subcutaneous adipose tissue (aSAT) samples were collected and measurements were made before and after a 12-week endurance exercise training program. Before training, the capillary densities in abdominal subcutaneous adipose tissue samples for LOW was remarkably lower than HIGH. Collagen abundance in abdominal subcutaneous adipose tissue samples’ extracellular matrix (ECM) was lower in LOW.
Based on the evaluation, it was found out that, the antilipolytic response to insulin was significantly improved in LOW but not in HIGH, in response to the training. Additionally, an increased capillary density and collagen abundance in ECM was observed along with a slight reduction in fat mass. The adipocyte size went down in both groups. Abdominal subcutaneous adipose tissue from obese adults with low antilipolytic sensitivity to insulin demonstrated lower capillarization and ECM collagen abundance compared to the obese adults with high sensitivity to the antilipolytic effects of insulin.
Thus, these findings suggest that morphological adaptations to exercise training went hand in hand with an increased antilipolytic sensitivity to insulin in subjects with low antilipolytic sensitivity before training.
Neighbourhood Walkability Is Associated with Prediabetes in a Behavioural Weight Loss Study
A study by Jacob K Kariuki was presented on Monday, June 28, 2021 at American Diabetes Association (ADA) 81st Scientific Sessions, a Virtual Experience. The objective of this study was to evaluate the co-relation of neighbourhood walkability with physical activity levels and glucose control.
Secondary analysis of a prospective observational study providing a 12-month behavioural weight loss intervention to examine lapses after intentional weight loss was carried out. The neighbourhood walkability was evaluated via Walk Score, physical activity via waist-worn ActiGraph GT3X and blood glucose via phlebotomy. The study variable comprised of car-dependent and walkable neighbourhoods, prediabetes and recommended physical activity.
Based on the results, it was found that at baseline, there were no differences between people belonging to the car-dependent vs. walkable neighbourhoods across all measures. At 12 months, the physical activity and glucose control witnessed an improvement for the entire sample. But the people belonging to walkable neighbourhoods had 17% lower odds of developing prediabetes as compared to those from car-dependent neighbourhoods.
Thus, these findings bolster previously conducted studies that demonstrated an inverse relation between neighbourhood walkability and prediabetes.
ADA Presidents’ Select Abstract: Exercise Training Promotes Mitochondrial Remodelling in Skeletal Muscle of Type 2 Diabetes Humans
A study by Lucia Mastrototaro was presented on Monday, June 28, 2021 at American Diabetes Association (ADA) 81st Scientific Sessions, a Virtual Experience. It is known that high intensity interval training can induce mitochondrial biogenesis in healthy humans but its effect on mitochondrial remodelling in insulin resistant states continues to remain indistinct.
The objective of this study was to evaluate the effect of high intensity interval training on mitochondrial function and dynamics in type 2 diabetes patients in addition to insulin resistant (IR) and insulin sensitive (IS) glucose tolerant humans to interpret the interplay between mitochondrial turnover and muscle insulin sensitivity.
The study comprised of twenty type 2 diabetes patients, eleven insulin resistant patients and twelve insulin sensitive patients who performed a 12-week high intensity interval training cycling protocol for 3 days a week. The whole-body insulin – sensitivity was measured by hyperinsulinemic-euglycemic clamps and the mitochondrial respiration and dynamics was evaluated by high resolution respirometry and immunoblotting of skeletal muscle biopsies at baseline and 72 hours after the final exercise bout.
Based on the analysis, it was found that after high intensity interval training, all participants’ demonstrated enhanced cardiorespiratory fitness and a surge in muscle maximal oxygen uptake. But the insulin sensitivity increased only in type 2 diabetes and insulin resistant patients. Additionally, high intensity interval training doubled muscle citrate synthase activity in all groups, while biomarkers of mitochondrial fission, fusion and mitophagy increased only in type 2 diabetes.
Thus, these findings indicate that mitochondrial fusion and fission, together respond to chronic exercise training and are expected to have a major role to play in the exercise training response of insulin sensitivity in type 2 diabetes patients and recognizing and targeting these mechanisms might have an instrumental role in tailoring therapies for type 2 diabetes.
Replacing Sedentary Time by Different Types of Physical Activity and the Risk of Type 2 Diabetes
A study by Xiang Li was presented on Monday, June 28, 2021 at American Diabetes Association (ADA) 81st Scientific Sessions, a Virtual Experience. The objective of the study was to figure out the types of physical activity that would act as healthy alternatives to sedentary behaviours and to evaluate the extent to which it would reduce the risk of type 2 diabetes.
The study comprised of 475,502 participants who were devoid of type 2 diabetes and an analysis regarding the association between the sedentary time and risk of type 2 diabetes was carried out. For the purpose of the study, the sedentary time was defined as the sum total of time spent on watching television, using the computer and driving.
Based on the analysis, it was found that around 18,169 incidences of type 2 diabetes were documented during the follow-up of eleven years. Sedentary time was notably associated with an increased risk of type 2 diabetes and replacing 30 minutes per day sedentary time with different types of physical activities demonstrated a 6-31% lower risk of type 2 diabetes. While strenuous sports, which are exercise leading to intense sweating and heavy breathing (30 minutes/day) displayed the strongest risk reduction, structured exercise too displayed a significant reduction in the risk of type 2 diabetes.
Thus, these findings suggest that sedentary time that is time spent in watching television, using the computer and driving are independently linked to an increased risk of developing Type 2 diabetes and replacing the sedentary time with some form of structured exercise leads to reduction of this risk.
