Joint ADA/EASD—Management of Hyperglycemia in Type 2 Diabetes

The 2022 draft updates to the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) consensus document provides a framework for the management of hyperglycemia in adults with type 2 diabetes.

The Rationale, Importance, and Context of Glucose-Lowering Treatment

Billy Collins and Peter Rossing

The primary goal of diabetes care is to prevent complications and improve overall health and quality of life. Preventing complications requires glucose control using glucose-lowering agents that can also provide cardiorenal protection. Weight management is a critical aspect of disease management, that can help mediate cardiovascular risk and related complications.

When considering person-centered glycemic management in type 2 diabetes, the first thing to assess is the person’s characteristics like comorbidities, age, hemoglobin A1C and body weight. Next, consider the individual goals for glycemia and weight, impact on hypoglycemia, and cardiorenal protection. Underlying physiological factors, side effect profiles, the complexity of the regimen to be prescribed, adherence and persistence, and the cost and availability are other factors to be considered. Diabetes self-management education and support (DSMES) is also important.

Therapeutic Options: Lifestyle and Healthy Behaviour, Weight Management, and Pharmacotherapy for the Treatment of Type 2 Diabetes

Vanita Aroda, Geltrude Mingrone, and Tsvetalina Tankova

Obesity has reached pandemic proportions all over the world. Very low-calorie diets and low-calorie diets can induce a meaningful weight reduction. Newly approved anti-obesity drugs such as semaglutide and tirzepatide are also effective in inducing weight reduction. Metabolic surgery is also an effective intervention with long-term results; however, surgical metabolic complications are higher than with anti-obesity medications.

When choosing a glucose-lowering medication, the drug’s ability to reduce hyperglycemia, improve glycemic control, and induce weight loss should be considered.

Dipeptidyl peptidase 4 (DPP-4) inhibitors possess intermediate glucose-lowering efficacy, have a neutral effect on body weight, and have minimal risk of hypoglycemia. The cardiovascular safety of these drugs has been demonstrated in cardiovascular outcomes trials.

SGLT2i show an intermediate to high glucose-lowering effect, have low inherent risk of hypoglycemia, intermediate weight loss effects, and excellent cardio renal effects. They have demonstrated protective effects in trials, including a demonstration of a reduction in major adverse cardiovascular events (MACE), reduction in overall cardiovascular death (with heterogeneity across the class), reduction in the risk of hospitalization for heart failure, and reduction in risk of kidney outcomes in patients with type 2 diabetes.

GLP-1RA possesses high to very high glucose-lowering efficacy, a low inherent risk of hypoglycemia, and intermediate to high weight loss. They are cardioprotective with evidence of reduction in MACE, CV death, fatal or non-fatal MI, fatal or non-fatal stroke, all-cause mortality, and composite kidney outcome driven by macroalbuminuria.

Dual combination glucose-dependent insulinotropic polypeptide receptor and GLP-1RA, tirzepatide has demonstrated very high glycemic efficacy, a low inherent risk of hypoglycemia, and a high degree of weight loss. The cardio renal effects are currently unknown, and trials are in progress.

Insulin comes with high to very high glycemic efficacy with an increased risk of hypoglycemia and weight gain and a neutral cardiorenal profile. Insulin/GLP-1RA co-formulations, IDegLira and IGlarLixi, through the combined effects of a GLP-1RA and insulin show very high glucose-lowering. They have less hypoglycemia than insulin and less nausea and gastrointestinal effects than GLP-1RA.

Combination therapy can increase the durability of glycemic effect, potentially address therapeutic inertia, and can simultaneously target multiple pathophysiologic processes characteristic of type 2 diabetes. They have a potential impact on reducing medication burden, increasing treatment adherence persistence, and have complementary clinical benefits in terms of glycemia, weight, and cardiovascular risk profile.

Personalized Approach to Treatment Based on Individual Characteristics and Comorbidities

Apostolos Tsapas and Jennifer Green

The choice of glucose-lowering therapies that confer cardiorenal protection should be a component of care offered to certain high-risk people with type 2 diabetes.

In individuals without established atherosclerotic cardiovascular disease (ASCVD), but with multiple cardiovascular risk factors, a GLP-1RA with proven benefits could be used to reduce MACE, or an SGLT2i with proven benefits could be used to reduce MACE, heart failure and improve kidney outcomes.

In people with heart failure, chronic kidney disease, established CVD, or multiple risk factors for CVD, the decision to use SGLT2i or GPL-1RA (with proven benefits) should be made independent of background metformin use or baseline HbA1C.

In people with CKD, SGLT2i and GLP-1RA reduce the risk of MACE independent of the estimated glomerular filtration rate (eGFR). SGLT2i also reduces the risk of heart failure and kidney outcomes including end-stage kidney disease.

In people with CKD and eGFR≥ 20ml/min per 1.73 m², an SGLT2i with proven benefit should be initiated to reduce the risks of MACE, heart failure, and kidney outcomes. If such treatment is not tolerated or is contraindicated, a GLP-1RA with proven cardiovascular outcome benefit could be considered.

Putting it All Together: Strategies for Implementation

Nisa Maruthur, Chantal Mathieu, & Sylvia Rosas

A holistic person-centered approach should be followed in type 2 diabetes management. Glycemic management, weight management, cardiovascular risk factor management, and cardiorenal protection should drive the choice of glucose-lowering therapies. It is important to avoid therapeutic inertia – the panel suggests promoting more aggressive, proactive treatment, including considering combinations of therapies from the beginning.

Key Knowledge Gaps and A Call to Action

John B Buse

There are key knowledge gaps in clinical studies for vulnerable populations, especially the young, old, and frail. Moreover, gender balance should be achieved, particularly in cardiovascular outcome trials. “This is a minimal first step to enhancing health justice”, says John B Buse.

Weight management is a key approach, but more comparative effectiveness studies are required to understand the optimal approaches in weight management. More comparative effectiveness regarding cardio-renal protection is also required to help choose the optimal approach. Additionally, more evidence is required for the cost-effectiveness of GLP-1RA or an SGLT2i in moderate-risk populations.

The major opportunities to improve diabetes outcomes will come from more effective implementation of best evidence through the organization of care at all levels.

Reference

Joint ADA/EASD—Management of Hyperglycemia in Type 2 Diabetes. Symposium at: American Diabetes Association 82nd Scientific Sessions; June, 2022.