It is well established that cardiovascular risk factor control is integral to the management of diabetes, as individuals with diabetes have a higher risk of cardiovascular disease and death. Thus, over the last 1-2 decades, the concept of multiple risk factor control in diabetes has received increased attention. Yet, the effect of multiple risk factor control and the contributory effect of individual risk factors has not been well quantified in population-based studies until recently. For example, Rawshani et al.¹ showed that diabetes patients with five modifiable risk factors within target range had the same risk of acute myocardial, stroke and mortality as the general population.

The researchers explored the research question: "can the excess risk of death and cardiovascular events among patients with type 2 diabetes be reduced or eliminated?" In a large retrospective cohort study, they investigated the impact of risk factor control on cardiovascular risk among 271,274 patients with type 2 diabetes identified through the Swedish National Diabetes Register. Each patient was matched to controls (1,355,870) from the general population and followed for a median time of 5.7 years. They examined the following five risk factors: elevated hemoglobin A1C, elevated LDL cholesterol, albuminuria, smoking and elevated blood pressure. They then studied how control of these (i.e., target levels) was associated with death, myocardial infarction, stroke and hospitalization for heart failure (HF).

The main finding was that adequate control of all five risk factors renders approximately the same risk of death (HR: 1.06, CI 1.00-1.12), myocardial infarction (HR: 0.84, CI 0.75-0.93) and stroke (HR: 0.95, CI 0.84-1.07) as compared to the matched general population, and notably they observed a gradual decrease in cardiovascular risk with an incremental increase in number of risk factors controlled. An even lower risk of acute myocardial infarction and stroke was observed among those with lower than target levels of hemoglobin A1c, LDL cholesterol and systolic blood pressure. Overall, the strongest predictors of death were found to be smoking, physical activity, marital status, hemoglobin A1C and use of lipid-lowering medication.

Despite the mitigated risk observed with optimal risk factor control, there was still a markedly increased risk of HF among diabetic individuals (HR: 1.45, CI 1.34-1.57). The risk factors found to have the most prognostic impact on heart failure were atrial fibrillation, BMI, physical activity, eGFR and hemoglobin A1c. The study supports the knowledge that diabetes is an independent risk factor of HF,^2-3 and that complex cardiac and renal mechanisms are at play that extends beyond what can be modified with traditional atherosclerotic risk factor control.

A major strength of the study is the population-based scope and the detail of the baseline risk factors listed in the Swedish Diabetes Registry. Furthermore, Sweden has a tax-funded health care system that offers free and equal access to health care services, and thus socioeconomic differences should not influence the results. The study adds compelling evidence to the growing body of literature highlighting the importance of risk factor in diabetes. The Steno-2 (Intensified Multifactorial Intervention in Patients With Type 2 Diabetes and Microalbuminuria) study was the first to systematically investigate the effect of intensive multifactorial risk factor control in type 2 diabetes and found that an intensive versus standard care regimen was associated with a long-term survival benefit extending beyond the trial period.⁴ The findings by Rawshani et al., however, were observational, and it is important to note that the risk factors assessed were baseline values, hence subsequent risk factor control including pharmacotherapy during the follow-up period was not considered. Yet, as pointed out by the authors, using baseline values may safeguard the interpretation from reverse causation.

Another aspect to consider is that the associations outlined in the study represent the prognostic weight of various risk factors, but do not necessarily reflect causal effects. To that end, it is not unexpected that patients diagnosed with diabetes but with an otherwise optimal cardiovascular profile have a lower risk of future cardiovascular disease and death. Thus, clinical implications of lowering off-target risk factors cannot be drawn from this study. For example, the study shows that a lower levels (<53 mmol per mole) of hemoglobin A1c was a strong marker of all outcomes. Yet intensive lowering of hemoglobin A1c has in randomized controlled studies not been shown to have a significant effect on reducing mortality and has even been found to increase mortality.^5,6 Rather, although strict blood sugar control early in the disease course may be associated with benefits, as indicated by Rawshani et al., this may not be a favorable approach later on and could even be harmful. This represents a treatment paradox important to keep in mind when translating findings to the clinic.

The authors raise an important point that younger patients may benefit from more aggressive treatment, as they observe a monotonic relationship between younger age, number of variables not within target and cardiovascular risk. Still, this further highlights the dangers associated with reaching an unhealthy cardiometabolic profile early in life and underscores the essence of identifying people with diabetes and prediabetes early.

In summary, with the recent study by Rawshani et al., we now have strong evidence that the number of risk factors controlled at diagnosis are prognostic of later cardiovascular events. This supports the concept that a multifaceted approach directed at controlling cardiovascular risk factors is central in curbing cardiovascular complications in type 2 diabetes. Health care providers and patients should together focus on assessing and improving risk factors early on and forward; primarily through lifestyle management centered on plant based nutrition, physical activity, optimal sleep, behavioral support and smoking cessation, supplemented by concomitant individualized polypharmacotherapeutic efforts.⁷ The study by Rawshani et al. shows us that optimal risk factor control theoretically can eliminate the excess risk of atherosclerotic cardiovascular disease and death. Whether we essentially are able to abolish the increased cardiovascular risk in patients with diabetes by improving multiple off-target risk factors is not yet clear, but until then we can be cautiously optimistic and do our best to improve risk factor control and the lives of people living with diabetes.

This review was funded by an independent research grant (18-R125-A8381-22082) from the Danish Heart Foundation to cover Dr. Nørgaard's salary. The Danish Heart Foundation had no role in the conduct of any aspects of this review.

References

1. Rawshani A, Raswhani A, Franzen S, et al. Risk factors, mortality, and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med 2018;379:633-44.
2. Zarich S, Nesto R. Diabetic cardiomyopathy. Am Heart J 1989;118:1000.
3. Boudina S, Abel ED. Diabetic cardiomyopathy revisited. Circulation 2007;115:3213-23.
4. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580-91.
5. ADVANCE Collaborative Group, Patel A, MacMahon S, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560-72.
6. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545-59.
7. Garber AJ, Abrahamson MJ, Barzilay JI, et al. Consensus statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the comprehensive type 2 diabetes management algorithm – 2018 executive summary. Endocr Pract 2018;24:91-120.

Keywords: Blood Glucose, Risk Factors, Cholesterol, LDL, Diabetes Mellitus, Type 2, Diabetes Mellitus, Prediabetic State, Blood Pressure, Cardiovascular Diseases, Atrial Fibrillation, Smoking Cessation, Follow-Up Studies, Body Mass Index, Retrospective Studies, Stroke, Myocardial Infarction, Atherosclerosis, Heart Failure, Registries, Hospitalization, Life Style, Exercise, Health Personnel, Health Services Accessibility

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