Management of Diabetes Mellitus in the US: Time for the Full Court Press

There are currently an estimated 26 million US adults with diagnosed diabetes and another 9 million who are unaware of their disease¹. Even more alarming, over 90 million US adults have prediabetes and are at risk for developing diabetes in the near future¹. The costs of care for diabetes are astronomical with recent data demonstrating that, of 154 common health conditions evaluated, diabetes had the highest public insurance spending². Over 90% of cases of diabetes in the US are type 2 diabetes (T2D)¹, and It is estimated that up to half of the total direct costs of diabetes care are related to cardiovascular disease (CVD)³. There is also a lack of awareness of the CVD risk associated with diabetes leading to the “Know Diabetes by Heart” campaign, a collaborative effort between the American Heart Association (AHA) and the American Diabetes Association⁴. It is quite clear that in order to improve health and sustain our healthcare system in the US, we need an aggressive, evidence-based approach to the management of atherosclerotic CVD (ASCVD) risk in individuals with diabetes and the scientific statement from the AHA lays out an excellent framework for such an approach.

As we should with our patients, the AHA scientific statement starts with a focus on lifestyle behavior modification. For diet, an individualized nutrition plan to improve glycemic control, help facilitate weight loss if needed, and improve other CVD risk factors is recommended, ideally with the help of a medical nutrition program. Routine engagement in physical activity with goal of at least 150 minutes or more per week, with a combination aerobic exercise and resistance training, is also a key component of lifestyle management. While the evidence supporting the impact of diet and physical activity on cardiovascular health is robust, helping patients achieve lifestyle changes can be difficult and is often complicated by environmental and social factors as well as issues with access and health literacy. Data do support providing patients with detailed, individualized plans for diet and exercise. For instance, providing a structured exercise training plan to patients is more effective than simple physical activity advice only⁵. Diet and physical activity recommendations apply to all levels of BMI but for obese patients, consideration should be given to pharmacologic therapy, including the recently approved once weekly injection semaglutide, as well as metabolic surgery to facilitate weight loss. Absolute tobacco cessation is recommended for all patients and alcohol intake should be limited to light to moderate intake. Finally, depression and anxiety are known to profoundly affect the capacity for behavior modification as well as CVD outcomes so addressing psychosocial care is paramount to optimizing health outcomes and health-related quality of life⁶.

The largest shift in the approach to cardiovascular risk reduction in individuals with T2D has been the introduction of 2 novel classes of glucose lowering agents that have been shown to reduce CVD risk. Outside of metformin, prior studies testing more aggressive glucose lowering failed to show a reduction in CVD events but did show significant weight gain⁷, an obviously untoward side effect for someone with T2D. However, the advent of the sodium-glucose co-transporter-2 (SGLT2) inhibitors and the glucagon-like peptide-1 (GLP-1) receptor agonists have changed the paradigm for the treatment of T2D. The SGLT-2 inhibitors reduce reabsorption of glucose in the proximal tubule of the kidney, leading to increased excretion of glucose in the urine and lower blood sugars. This mechanism of action is also associated with a natriuretic effect with a subsequent decrease in blood pressure and weight. Several SGLT-2 inhibitors have been demonstrated to reduce MACE in individuals with established ASCVD but the most significant benefit has been a reduction in heart failure, which has been found in both those with and without established ASCVD⁸. The GLP-1 receptor agonists decrease glucose absorption by slowing gastric emptying and also inhibit glucagon production while stimulating insulin secretion. This combination of actions lowers glucose and leads to a decrease in blood pressure and weight. Several GLP-1 receptor agonists have been tested in large cardiovascular outcomes trials and were shown to decrease CVD events, largely through a reduction in MACE and CVD mortality^8,9. Along with metformin, the SGLT-2 inhibitors and the GLP-1 receptor agonists should be considered as first line therapy for T2D, especially in those with established CVD. Choice of agent should be tailored to the patient with consideration of cost, side effect profiles, and the patient’s CVD risk profile with SGLT-2 inhibitors favored in those at elevated risk for heart failure and GLP-1 receptor agonists favored for individuals more at risk for ASCVD.

Similar to prior guidelines, the AHA statement reinforces the importance of blood pressure and lipid management in individuals with diabetes. While the SPRINT trial provided support for aggressive blood pressure lowering (target blood pressure 120mmHg systolic), the trial excluded individuals with diabetes and in ACCORD, which included only individuals with T2D, more aggressive blood pressure targets were not found to improve cardiovascular outcomes^10,11. So while the exact target blood pressure goals for individuals with diabetes remains unclear, treatment of hypertension (>140/90mmHg) is clearly supported by the evidence. Atherogenic dyslipidemia is common in individuals with diabetes and aggressive treatment is warranted in the majority of cases. In addition efforts at lifestyle modification, statin therapy remains the foundation of lipid-lowering therapy for T2D. There should be a low threshold to add ezetimibe as it is inexpensive, safe, and has been shown to reduce cardiovascular event rates in addition to statin therapy, especially in those with multiple CVD risk factors¹². For individuals with T2D, established ASCVD, and suboptimal lipids despite lifestyle modification, statin therapy, and ezetimibe, consideration can be given to a PCSK9 inhibitor in those with an LDL-C >70mg/dl or icosapent ethyl, a derivative of the omega-3 fatty acid eicosapentaenoic acid, in individuals with moderate hypertriglyceridemia (triglycerides 135-499 mg/Dl).

For secondary prevention, the use of aspirin is well established to reduce ASCVD risk though it does come with a small risk of bleeding. For primary prevention, the risk/benefit ratio with aspirin is less clear. The ASCEND trial studied over 15,000 individuals with T2D but no prior ASCVD and found a small benefit over a follow-up of ~7.5 years (serious vascular event rates 8.5% vs 9.6%, p-value 0.01) but at the cost of an increase in bleeding (4.1% vs 3.2%, p-value 0.003)¹³. There was no increase in fatal bleeding and the majority of bleeding episodes were gastrointestinal in nature. For primary prevention, the decision to use aspirin should occur in the context of shared-decision making in individuals with diabetes at low bleeding risk but elevated ASCVD risk.

All patients with diabetes should be screened for chronic kidney disease as it has a significant impact on prognosis and may impact therapeutic decisions. Absolute ASCVD risk can vary significantly based on an individual’s age, sex, duration and severity of diabetes as well as the presence of other ASCVD risk factors. For individuals uncertain about their risk, a coronary artery calcium (CAC) score can be considered to help to determine the aggressiveness of therapeutic interventions. CAC has been shown to be a strong predictor of ASCVD risk in individuals with diabetes with significantly increased rates of ASCVD events in those with elevated CAC as well as low ASCVD risk in individuals with zero CAC despite the presence of diabetes^14,15. More advanced imaging with CT coronary angiography or cardiac MR has shown potential to improve risk stratification but requires further research. Given concerns for silent ischemia in individuals with diabetes, routine stress testing has been considered as a potential strategy but the overall data does not support routine ischemic evaluations in asymptomatic patients.

Improving treatment of diabetes in the US will require a collaborative effort between primary care providers, cardiologists, and endocrinologists. Given the increasing burden of diabetes and its associated costs, morbidity, and mortality, it is quite clear that we need an aggressive, multifactorial approach to its management and the AHA scientific statement provides an excellent template for such an approach. In basketball, the most aggressive defense a team can play is a full court press, where pressure is applied across the entire court. With sustained efforts at lifestyle modification, appropriate use of metformin and the 2 novel classes of glucose lowering therapies, adequate control of blood pressure and lipids, selective use of aspirin, and selective use of CAC to guide treatment decisions when ASCVD risk is uncertain, we have the ability to apply a “full court press” to diabetes to reduce its burden on our healthcare system and improve the health of our patients.