Diabetes Mellitus

Treatment and management

Management of diabetes mellitus (DM)¹

DM is a chronic disease that can cause several vascular complications, including coronary artery disease, stroke, peripheral artery disease with the risk of amputation, chronic kidney disease leading to dialysis, and retinopathy with the risk of blindness, thereby having severe effects not only on the patients and their families, but also on the economy of the society.¹

Diabetic care team²

In the 1990s, studies have revealed that diabetic complications could be well controlled through diabetic team care.¹ The care team, which centers around the patient, should avoid therapeutic inertia and prioritize timely and appropriate intensification of lifestyle and/or pharmacologic therapy for patients who have not achieved the recommended metabolic targets. Strategies shown to improve care team behavior and thereby catalyze reductions in HbA1c, blood pressure, and/or low-density lipoprotein (LDL) cholesterol include:²

• Engaging in explicit and collaborative goal setting with patients.
• Identifying and addressing language, numeracy, or cultural barriers to care.
• Integrating evidence-based guidelines and clinical information tools into the process of care.
• Soliciting performance feedback, setting reminders, and providing structured care (e.g., guidelines, formal case management, and patient education resources).
• Incorporating care management teams including nurses, dietitians, pharmacists, and other providers.

Treatment goals^1,3

Overall, it is critical for the glycemic targets to be woven into the overall patient-centered strategy.³ Achieving HbA1c target of < 7% has been shown to reduce microvascular complications of type 1 and type 2 DM when instituted early in the course of disease.³ Therefore, an HbA1c goal of < 7% without significant hypoglycemia is appropriate for many nonpregnant adults. However, less stringent HbA1c goals (such as < 8%) may be appropriate for patients with limited life expectancy, or where the harms of treatment are greater than the benefits.³

Besides glycemic goals, efforts have also been directed to prevent diabetic macrovascular and microvascular complication through better blood pressure and lipid control.¹ The Diabetes Association of the Republic of China (Taiwan) has recommended blood pressure goal of < 130/80 mmHg and total cholesterol < 160 mg/dL or LDL < 100 mg/dL for patients with DM.¹

Non-pharmacologic management

Effective behavior management and psychological well-being are foundational to achieving treatment goals for people with diabetes. Essential to achieving these goals are diabetes self-management education and support (DSMES), medical nutrition therapy, routine physical activity, smoking cessation counseling when needed, and psychosocial care.⁴

• DSMES helps people with diabetes to identify and implement effective self-management strategies and cope with diabetes at diagnosis, when not meeting treatment targets, when complicating factors develop and when transitions in life and care occur.⁴
• Medical nutrition therapy can help patients to promote and support healthful eating patterns in order to achieve and maintain body weight goals, to attain individualized glycemic, blood pressure, and lipid goals, and to delay or prevent the complications of diabetes.⁴
• Physical activity is a general term that includes all movement that increases energy use; and exercise is a more specific form of physical activity that is structured and designed to improve physical fitness. Most adults with diabetes should engage in 150 min or more of moderate- to vigorous-intensity aerobic activity per week.⁴
• People with diabetes who smoke have a heightened risk of cardiovascular diseases, premature death, microvascular complications, and worse glycemic control when compared with those who do not smoke. Therefore, all patients should be advised not to use cigarettes and other tobacco products or e-cigarettes.⁴
• Psychosocial screening and follow-up may include, but are not limited to, attitudes about diabetes, expectations for medical management and outcomes, affect or mood, general and diabetes-related quality of life, available resources (financial, social, and emotional), and psychiatric history.⁴

Pharmacologic approaches to glycemic control

Type 1 DM⁵

Because the hallmark of type 1 DM is absent or near-absent β-cell function, insulin treatment is essential for individuals with type 1 DM.⁵ Over the past three decades, evidence has accumulated supporting more intensive insulin replacement, using multiple daily injections of insulin or continuous subcutaneous administration through an insulin pump, as providing the best combination of effectiveness and safety for people with type 1 DM.⁵ The DCCT demonstrated that intensive therapy with multiple daily injections or continuous subcutaneous insulin infusion (CSII) reduced HbA1c and was associated with improved long-term outcomes.⁵

The central precept in the management of type 1 DM is that some form of insulin be given in a planned regimen tailored to the individual patient to keep them safe and out of diabetic ketoacidosis and to avoid significant hypoglycemia, with every effort made to reach the patient’s glycemic targets.⁵ Typical multidose regimens for patients with type 1 DM combine premeal use of shorter-acting insulins with a longer-acting formulation, usually at night.⁵ Over the last 25 years, rapid-acting and long-acting insulin analogs have been developed that have distinct pharmacokinetics compared with recombinant human insulins: basal insulin analogs have longer duration of action with flatter, more constant plasma concentrations and activity profiles; and rapid-acting analogs have a quicker onset and peak and shorter duration of action.⁵ Treatment with analog insulin in people with type 1 DM is associated with less hypoglycemia and weight gain as well as lower HbA1c compared with human insulins. Patients with type 1 DM should receive education on how to match prandial insulin doses to carbohydrate intake, premeal blood glucose, and anticipated physical activity.⁵

Type 2 DM

The American Diabetes Association/ European Association for the Study of Diabetes recommend a patient-centered approach to choosing appropriate pharmacologic treatment of blood glucose. This includes consideration of efficacy and key patient factors: 1) important comorbidities such as atherosclerotic cardiovascular disease (ASCVD) and indicators of high ASCVD risk, chronic kidney disease (CKD), and heart failure, 2) hypoglycemia risk, 3) effects on body weight, 4) side effects, 5) cost, and 6) patient preferences. Lifestyle modifications that improve health should be emphasized along with any pharmacologic therapy.⁵

Figure 2. Glucose-lowering medications in type 2 DM by 2021 American Diabetes Association guideline.

• Metformin

Metformin should be started at the time type 2 DM is diagnosed unless there are contraindications.⁵ Metformin is effective and safe, is inexpensive, and may reduce risk of cardiovascular events and death.⁵ Additional and/or alternative agents may be considered in special circumstances, such as in individuals with established or increased risk of cardiovascular or renal complications⁵ Because type 2 DM is a progressive disease in many patients, maintenance of glycemic targets with monotherapy is often possible for only a few years, after which combination therapy is necessary.⁵

• For type 2 DM patients with established ASCVD or high risks

Among patients with type 2 DM who have established ASCVD or indicators of high risk (such as patients ≥ 55 years of age with coronary, carotid, or lower-extremity artery stenosis > 50% or left ventricular hypertrophy), a sodium-glucose cotransporter 2 (SGLT2) inhibitor or Glucagon-like peptide-1 receptor agonist (GLP-1 RA) with demonstrated cardiovascular disease benefit is recommended as part of the glucose-lowering regimen independent of HbA1c and in consideration of patient-specific factors.⁵ The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 DM Mellitus Patients (EMPA-REG OUTCOME) was a randomized, double-blind trial that assessed the effect of empagliflozin, an SGLT2 inhibitor, versus placebo on cardiovascular outcomes in 7,020 patients with type 2 DM and existing cardiovascular disease.⁶ EMPA-REG OUTCOME showed that over a median follow-up of 3.1 years, treatment reduced the composite outcome of MI, stroke, and cardiovascular death by 14% (P = 0.04 for superiority) and cardiovascular death by 38% (P < 0.001). Furthermore, the addition of empagliflozin to standard care led to a significant 35% reduction in hospitalization for heart failure compared with placebo, regardless history of heart failure at baseline.⁶ Therefore, SGLT2 inhibitors are recommended in patients with heart failure, particularly those with left ventricular ejection fraction of < 45%.⁵ As for patients with type 2 DM and chronic kidney disease, SGLT2 inhibitors and GLP-1 RAs should be considered after metformin to attain target HbA1c or those who cannot tolerate metformin.⁷ Specifically, empagliflozin reduced the risk of incident or worsening nephropathy (a composite of progression to urinary albumin-to-creatinine ratio [UACR] > 300 mg/g Cr, doubling of serum creatinine, ESRD, or death from ESRD) by 39% and the risk of doubling of serum creatinine accompanied by eGFR ≤ 45 mL/min/1.73 m² by 44% when compared with placebo.⁷

• For patients without established ASCVD or high risks

For patients without established ASCVD, indicators of high ASCVD risk, heart failure, or CKD, the choice of a second agent to add to metformin is not yet guided by empiric evidence comparing across multiple classes. Rather, drug choice is based on efficacy, avoidance of side effects (particularly hypoglycemia and weight gain), cost, and patient preferences.⁵

For patients who have compelling needs to minimize risk of hypoglycemia, dipeptidyl peptidase-4 (DPP-4) inhibitors, SGLT-2 inhibitors, GLP-1 RA or thiazolidinediones are recommended.⁵ The Cardiovascular Outcome Study of Linagliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA) trial randomized adults at high cardiovascular risk to receive the DPP-4 inhibitor linagliptin or to receive the sulfonylurea glimepiride to evaluate the primary end point of major adverse cardiovascular events (MACE). No between-group difference was found in the occurrence of MACE (HR 0.98; 95% CI 0.84, 1.14). At the end of CAROLINA trial, linagliptin, as compared with glimepiride, resulted in a 1.5-kg weight loss benefit, no difference in HbA1c or introduction of glucose-lowering medications postbaseline, and substantial benefits in terms of reductions in hypoglycemia.⁸

For patients who have compelling needs to minimize weight gain or promote weight loss, SGLT2 inhibitors or some GLP-1 RA are recommended.⁵

• Insulin therapy

Many patients with type 2 DM eventually require and benefit from insulin therapy.⁵ Educating and involving patients in insulin management is beneficial.⁵ Comprehensive education regarding self-monitoring of blood glucose, diet, and the avoidance and appropriate treatment of hypoglycemia are critically important in any patient using insulin.⁵ Basal insulin alone is the most convenient initial insulin regimen and can be added to metformin and other oral agents.⁵ Many individuals with type 2 DM require doses of insulin before meals, in addition to basal insulin, to reach glycemic targets. The prandial insulin regimen can then be intensified based on patient needs. Combination injectable therapy be also be used with GLP-1 RA added to basal insulin or multiple doses of insulin when HbA1c remains above target.⁵