Results of the eValuation of ERTugliflozin EffIcacy and Safety CardioVascular Outcomes Trial (VERTIS-CV)
The sodium glucose co-transporter 2 (SGLT2) inhibitor ertugliflozin does not impact the likelihood of heart attack, stroke, or cardiac death in patients with type 2 diabetes (T2D) and established cardiovascular (CV) disease, according to data presented today. Research also showed the rate of hospitalization for heart failure was lower among study participants treated with ertugliflozin. The study was highlighted during the “Results of the eValuation of ERTugliflozin EffIcacy and Safety CardioVascular Outcomes Trial (VERTIS-CV)” symposium at the American Diabetes Association’s (ADA’s) 80th Virtual Scientific Sessions.
Ertugliflozin, a relatively new member of the SGLT2 inhibitor class of medications, is prescribed as an adjunct medication to diet and exercise to improve glycemic control in adults with T2D. The VERTIS CV Study was an international phase 3, randomized, parallel-group study to determine the CV safety of ertugliflozin compared to placebo. Beginning in 2013, the study enrolled 8,246 participants with T2D throughout the U.S. and 34 countries worldwide who were aged 40 and older and had a documented history of atherosclerosis involving the coronary, cerebral, or peripheral vascular systems. The patients were randomly assigned to take either ertugliflozin 15 mg (n= 2747), ertugliflozin 5 mg (n=2752), or a placebo (n= 2747), once daily. Participants were followed for up to 6.1 years to assess the time to the first occurrence of major adverse CV events, including CV death, non-fatal myocardial infarction, or non-fatal stroke (the primary outcome of the study).
Results of the study indicated:
- Patients treated with ertugliflozin had similar rates of CV death, heart attack, or stroke as the placebo group: the primary outcome occurred in 653 of 5,493 (11.9%) patients in the ertugliflozin groups and 327 of 2,745 (11.9%) in the placebo group (p<0.001 for non-inferiority).
- Although ertugliflozin was not shown to decrease overall risk of CV death/hospitalization for heart failure nor CV death alone, the rate of hospitalization for heart failure was lower among participants treated with ertugliflozin.
- The safety profile of ertugliflozin was consistent with known risks of the class of SGLT2 inhibitors; the rates of amputations were 0.6 and 0.5 per 100 patient years, and the confidence limit of this difference included
Microvascular and Macrovascular Complications of Diabetes Are Distinct Pathophysiologic Entities: The Endocrinologist’s Perspective: Evidence for and against
A study was presented by Deborah J. Wexler on Microvascular and Macrovascular Complications of Diabetes Are Distinct Pathophysiologic Entities? No, they are part of a continuum on Tuesday June 16, 2020 at American Diabetes Association (ADA) 80th Scientific Sessions, a Virtual Experience. The goal of diabetes treatment is reduction in long-term complications such as microvascular complications i.e. retinopathy, neuropathy, nephropathy and macrovascular complications i.e. atherosclerotic cardiovascular disease, end stage renal disease.
The reason of they are part of continuum is really because of the fundamental underline insult of hyperglycemia. Hyperglycemia is a common initiating insult. In the epidemiologic evidence, there is strong relationship glycemic levels and complications. It shows significant reduction of event rate for every one-point decrease in HbA1c in type 1 and type 2 diabetes.
In type 1 diabetes, intensive glycemic control reduces prevalence of microvascular complications after 30 years’ duration. In the evidence from the DCCT, comparing intensive to conventional treatment in the trial, moderate or severe retinopathy reduces from 50.35% to 31.2%, neuropathy reduces from 32.7% to 23.6%, microalbuminuria reduces from 7.9% to 4.3%. The rate of microvascular complications is higher than macrovascular complications in T1DM.
In type 2 diabetes, data from UKPDS shows that long term microvascular benefit in association with differences in glycemic management and some benefit of intensive glycemic control on microvascular complications was observed in ACCORD-Eye and ADVANCE trial but the effect of glycemic control is clearly weaker in T2DM.
Conclusion: Hyperglycemia is an initiating agent and contributes to both macrovascular and microvascular complications. The effect of hyperglycemia and its treatment is stronger in type 1 DM than in type 2 DM.
Microvascular and Macrovascular Complications of Diabetes Are Distinct Pathophysiologic Entities: The Endocrinologist’s Perspective: Evidence for and against
A study was presented by Deborah J. Wexler on Microvascular and Macrovascular Complications of Diabetes Are Distinct Pathophysiologic Entities? Yes, they are distinct on Tuesday June 16, 2020 at American Diabetes Association (ADA) 80th Scientific Sessions, a Virtual Experience.
Microvascular and macrovascular complications are distinct pathophysiologic entities with given different prevalence of both and differential benefit of treatment in T1DM and T2DM. Diabetes complications are complicated as hyperglycemia triggers many downstream cellular processes such as ROS, advance glycation and FFA production. Insulin, growth factors RAAS also contributes and the balance, plus genetics leads to complications. In type 2 diabetes, higher rate of obesity or insulin resistance leads to macrovascular complications and in type 1 diabetes, higher rate of insulin deficiency leads to microvascular complications. The CVD mortality is lower and glycemia is a stronger determinant of risk in T1DM than T2DM but conventional cardiac risk factors still contribute to CVD risk in T1DM. Different therapies such as intensive glycemic control, BP lowering, RAAS blockade, statins, fibrates have differential benefit for micro and macrovascular complications. In microvascular complications, it is important to target glycemic control, BP and cholesterol and in macrovascular complications, in order of priority should target cholesterol, BP and glycemic control.
Conclusion: Non-glycemic factors, and their treatment, drive macrovascular complications in both type 1 and type 2 diabetes, consistent with distinct pathophysiology.
Microvascular and Macrovascular Complications of Diabetes Are Distinct Pathophysiologic Entities: The Cardiologist’s Perspective: The case of HFpEF
A study was presented by Jasper Tromp on Microvascular and Macrovascular Complications of Diabetes Are Distinct Pathophysiologic Entities? Yes, they are distinct on Tuesday June 16, 2020 at American Diabetes Association (ADA) 80th Scientific Sessions, a Virtual Experience. The mortality risk for patients with diabetes and heart failure is 10x greater as compared to patients with diabetes alone. Diabetes traditionally considered as a consequence of macrovascular disease as diabetes generally cause coronary artery disease leads to hypoxia or cardio myocyte death end up to heart failure with reduced ejection fraction with loss of pump function and eccentric hypertrophy.
Diabetes also causes low grade inflammation leads to microvascular dysfunction causes heart failure with preserved ejection fraction (HFpEF) with reduction in filing function and concentric hypertrophy. Patients with diabetes and microvascular complications are more likely to have HFpEF. In patients with HFpEF, number of microvascular complications correlates with LV hypertrophy and in patients with HFrEF, inverse association was seen. Coronary microvascular disease relates to worse functional parameters in HFpEF and associated with a unique biomarker profile related to inflammation.
Conclusion: Microvascular complications are a risk factor for developing heart disease, independent of macrovascular complications.
Microvascular and Macrovascular Complications of Diabetes Are Distinct Pathophysiologic Entities: The Cardiologist’s Perspective: No, They Are Part of a Continuum
A study was presented by Sanjiv J. Shah on Microvascular and Macrovascular Complications of Diabetes Are Distinct Pathophysiologic Entities? No, They Are Part of a Continuum on Tuesday June 16, 2020 at American Diabetes Association (ADA) 80th Scientific Sessions, a Virtual Experience.
Macrovascular disease leads to microvascular disease via increased large artery stiffness results in increased pulsatile load (barotrauma), increased pulsatile flow (shear stress), increased reflected waves (penetration into the microvascular) and microvascular disease leads to macrovascular disease via disruption of vaso vasorum and renal dysfunction (increased artery stiffness, increased blood pressure). Clinical severity of macrovascular disease depends on presence of microvascular disease in affected organs. Tight glucose control does not improve microvascular complications in older DM patients with macrovascular disease. Mechanisms such as increased aldose reductase pathway, protein kinase activation, increased oxidative stress, protein glycation, increased hexosamine pathway; each of these mechanisms for diabetic microvascular disease are also mechanisms that result in macrovascular disease.
Conclusion: Macrovascular and microvascular complications of diabetes often co-exist, highly interrelated, shared molecular mechanisms.
New Data on Clinical Outcomes from the Diabetes Prevention Program Outcomes Study (DPPOS)
Long-term follow-up of more than 2,000 people enrolled in the Diabetes Prevention Program Outcomes Study (DPPOS) indicates a continued significant reduction in the participants’ risk of developing type 2 diabetes (T2D). Today’s “New Data on Clinical Outcomes from the Diabetes Prevention Program Outcomes Study (DPPOS)” symposium outlined the latest research results of the study at the American Diabetes Association’s® (ADA’s) 80th Virtual Scientific Sessions.
The DPPOS1 is the long-term follow-up of the Diabetes Prevention Program (DPP), a multicenter trial conducted from 1996 to 2001 that established the success of either an intensive lifestyle program or treatment with metformin to prevent or delay the development of T2D in individuals who were considered at high risk for developing the disease. The DPP demonstrated lifestyle intervention, aimed at achieving weight loss, and metformin treatment reduced the risk of T2D development by 58% and 31%, respectively, compared to placebo after an average of three years. Metformin, one of the most commonly used medications worldwide for the treatment of T2D, is currently not labeled by the FDA for prevention purposes, although it is approved in other countries.
At the conclusion of the DPP study, 88% of the original 3,234 participants enrolled in the DPPOS, including the DPP participants who had developed T2D and those who still had not developed diabetes. The DPPOS sought to evaluate the long-term effects of the DPP interventions on the further development of T2D and its complications, including retinopathy, nephropathy and cardiovascular disease.
Currently, after an average of 22 years of study, 75% of the participants who enrolled in the DPP who are still alive have continued to be evaluated. The follow-up population includes the participants who have developed diabetes and those who have not. Since metformin was continued in the original metformin treatment group over time, the current results examine whether metformin has beneficial effects on major cardiovascular disease, such as fatal and non-fatal heart attacks and stroke, or on cancer, compared with the original placebo group. In addition, since the mean age of the participants is now 72 years, DPPOS has started to investigate contributors to healthy aging and comorbidities.
The newest results indicate:
- Prevention effects in the original lifestyle group and metformin treatment group remain 22 years after the start of the study with a 25% and 18% reduced risk of diabetes development, respectively, compared with the original placebo group.
- Those participants who did not develop diabetes had a significant 57% and 37% lower risk of developing early changes of eye and kidney disease, respectively, and a 39% lower risk of major cardiovascular disease endpoints, such as heart attacks and stroke.
- Despite the benefits seen with diabetes prevention overall, there was no significant benefit seen with the individual interventions—metformin or the lifestyle intervention—with regard to heart disease or the development of kidney disease or diabetic retinopathy.
- However, there were favorable trends with metformin in stroke reduction and for cardiovascular events in the subgroup of people who started the study before age 45.
- Metformin was associated with a non-significant 12% lower risk of cancer compared with the placebo group.
- The most recent results also showed the intensive lifestyle intervention group had a long-term reduction in the development of frailty.
- The only long-term negative effect observed with any of the interventions was a modest increase in kidney disease with metformin, which appeared only in the oldest group of participants.
Which Comes First—Poor Sleep or Poor Glycemic Control?
Patton SR presented a symposium on occurrence poor sleep and glycemic control at 80th Scientific American Diabetes Association (ADA) Sessions on 16th June, 2020. Although individual variations exist, guidelines suggest that sleep requirements for teenagers is 8-10 hours and 50-70% of adolescents do not meet these. Children with T1D are three times more likely to experience insufficient sleep duration while adolescents are 6 times more likely. This is not related to BMI status. In patients with T1D, sleep dysregulation is linked to hypoglycemia, hyperinsulinemia, poor glycemic control and rapid glycemic changes affecting HbA1c levels.
Sleep is known to affect metacognition in diabetic patients. This leads to poor self-management in adolescents with T1D. There are mixed results for sleep related to T1D devices and nigh-time management. An association between sleep duration and next day frequency of SMGB and mealtime insulin use was observed.
Conclusion: Emerging data relates sleep onset latency and night time awakenings to same day and next day glycemic variability in very young children with T1D.
Overcoming Economic Barriers to Treating Obesity
Gudzune K presented a study on identifying opportunities and strategies to address economic barriers faced by patients to choose obesity treatment at American Diabetes Association (ADA) 80th Scientific Sessions on June 16, 2020. About 23% of patients do not seek obesity treatment due to lack of financial means. This can be addressed by employer support, where employers may offer access to weight management programs. They can use strategies to subsidize and promote commercial weight-loss programs by covering complete costs or cost sharing.
About 13% of population avoid therapy due to lack of insurance coverage for non-surgical medical weight management, while 11% avoid due to billing concerns. It was observed that self-pay patients had higher income, insured patients younger and had lower baseline BMI. However, weight loss outcomes were 13.4% and 13.6% in self-pay and insurance coverage patients respectively. Program dropouts were more common in insured patients and they had more clinic visits (18.4 vs 14.5). Over 11% of US population reports food insecure at some point over the course of year restricting their access to adequate and quality food. Therefore, Food insecurity (FI) should be advocated as a part of routine healthcare practices.
Conclusion: Offering services that are covered, counselling, anti-obesity medications and bariatric surgery along with good employers support may help improving obesity treatment.
