New Diabetes Guidelines: 'Treat to Mitigate'

It's no secret that the number of patients with type 2 diabetes (T2D) is multiplying each day. In many countries, T2D is managed mostly in primary care and not in the offices of specialists, but it's the specialists who have written most of the guidelines. Now we have a new position statement on the management of T2D from Primary Care Diabetes Europe (PCDE) — authored by nine primary care physicians and one primary care nurse. Let's take a look at what's different.

Novel Risk Stratification

The PCDE guidelines recommend a novel risk stratification system that puts patients with a younger age at diagnosis at higher cardiovascular risk. This makes sense; when one lives for a longer time with diabetes, there are increased chances of developing micro- and macrovascular complications. Accordingly, the proposed risk stratification classifies patients as "very high cardiovascular risk" if they were younger than 40 years at diagnosis or if they have a history of cardiovascular disease, multiple uncontrolled cardiovascular risk factors (hypertension, hyperlipidemia, obesity, smoking, and/or physical inactivity), chronic kidney disease (CKD) with an estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m², or albuminuria.

All other patients with T2D, including those with obesity, are classified as "high cardiovascular risk." There is no "low risk" or "moderate risk" classification, underlining the PCDE's view that all patients with T2D have significant cardiovascular risk.

A 'Treat-to-Mitigate' Approach to Treatment

Compelling data from the VERIFY trial showed separation in cardiovascular outcomes (ie, delayed time to first adjudicated macrovascular event) with early combination therapy. Thus, the PCDE guidelines move away from the classic treat-to-failure approach (stepwise escalation of pharmacotherapy when A1c levels have risen and remained higher for a duration of time). Instead, they recommend a "treat-to-mitigate" risk approach, where dual therapy with metformin plus either a sodium-glucose cotransporter 2 (SGLT2) inhibitor or a glucagon-like peptide 1 (GLP-1) receptor agonist is started at the beginning for patients classified as high risk or very high risk to get earlier cardiovascular benefit and improve treatment durability.

For patients with very high cardiovascular risk, clinicians are encouraged to look at the disease-modifying factor that puts the patient in that very high-risk category: atherosclerotic cardiovascular disease (ASCVD), heart failure, or CKD.

For the ASCVD group, initiation of metformin plus an SGLT2 inhibitor or GLP-1 receptor agonist as dual therapy is recommended. In the heart failure group, this changes to metformin plus an SGLT2 inhibitor, along with the recommendation to avoid pioglitazone and saxagliptin and to use basal insulin therapy with caution.

Finally, for the CKD group, the guidelines recommend metformin plus an SGLT2 inhibitor, with a GLP-1 receptor agonist as third-line therapy, followed by a dipeptidyl peptidase 4 (DPP-4) inhibitor as an alternative option. They also recommend reducing the dose of glinides and reducing or discontinuing sulfonylureas if eGFR is < 45 mL/min/1.73 m², to minimize the risk for hypoglycemia.

Clinicians are encouraged to give preference to agents that do not cause hypoglycemia, especially in very high-risk patients with established cardiovascular disease. The occurrence of cardiovascular events or all-cause mortality is two to three times higher in patients with hypoglycemic events.

Use of insulin in very high-risk patients has now been relegated to a last resort option and is recommended only if all other options have failed and glycemic targets are not met. The authors also discuss access and cost of medications, recommending new-generation sulfonylureas or meglitinides for high-risk patients for whom drug costs need to be minimized.

Pioglitazone is recommended for patients with nonalcoholic fatty liver disease, particularly those with insulin resistance.

T2D With Advanced Age or Obesity

Multimorbidity modeling studies suggest that the life-years lost at a later stage owing to diabetes is not as significant as with other comorbidities, such as cardiovascular disease or cancer. As such, the PCDE recommends relaxed glycemic control with less stringent A1c goals in elderly patients.

For these patients, metformin continues to be first-line therapy, and treatment with DPP-4 inhibitors has been promoted for their safety and ease of use. The key for this group would be to reassess adherence at each visit and to avoid multiple daily injectable medications whenever possible.

Patients with T2D and obesity are classified as high risk, and the position statement categorically recommends avoiding agents that lead to weight gain, such as most sulfonylureas, glinides, pioglitazone, and insulin. If basal insulin is needed, use of fixed-ratio insulin/GLP-1 receptor agonist combinations should be considered instead of basal-only, wherever possible.

In summary, the position statement emphasizes early initiation of dual therapy and elevated risk stratification for persons whose T2D is diagnosed at an early age. In congruence with other guidelines, PCDE recommends the use of SGLT2 inhibitors for patients with T2D and heart failure or CKD, and SGLT2 inhibitors/GLP-1 receptor agonists for those with T2D and ASCVD.

Akshay B. Jain, MD, is a clinical endocrinologist who has practiced in three countries, focusing on mitigating the complications of diabetes and obesity. He is fluent in six languages and has spoken at more than 500 programs internationally.

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