A patient-centred or individualised approach should include promoting healthy lifestyle behaviours, diabetes self-management education and support, avoiding clinical inertia, and taking social determinants of health into consideration. Pharmacologic therapy should be guided by patient-centred treatment factors.¹ 

Patient-centred factors that affect the choice of treatment include individualised glycaemic and weight goals, impact on weight, risk of hypoglycaemia, and cardiorenal protection.¹ 

Other important factors that need to be considered include cardiovascular and renal comorbidities, efficacy, cost, access to treatment, risk of side effects, and individual preferences. First-line therapy generally includes metformin or other agents as well as comprehensive lifestyle modification.¹

One of the challenges in the effective management of T2DM is that the majority of patients are unable to maintain recommended HbA_1c targets due to the progressive nature of the disease. Progression is associated with the  gradual loss of endogenous insulin secretion due to deterioration of beta-cell function and associated insulin resistance.³

As a result, most patients treated with oral anti-diabetic drugs (OADs) will eventually need insulin therapy to achieve long-term glycaemic control, in order to minimise the risk of micro- and macrovascular complications and all-cause mortality.³ 

When to intensify treatment

The ADA guidelines recommend an HbA_1c goal of <7% for many non-pregnant adults without significant hypoglycaemia. If using ambulatory glucose profile/glucose management indicator to assess glycaemia, a parallel goal for many non-pregnant adults is time in range of >70% with time below range <4% and time <3mmol/L <1%.⁴

The ADA also recommends that treatment intensification for patients not meeting treatment goals should not be delayed and should be based on shared decision-making.¹

According to guidelines published by the East African Diabetes Study Group (EADSG) in 2018, patients with HbA_1c ≥7.5% can be considered for treatment with insulin monotherapy or in combination with OADs.⁵

However, in patients with  HbA_1c ≥10%, initiation of insulin therapy is essential – especially when diet, physical activity, and other anti-hyperglycaemic agents have been optimally used.⁵

The ADA recommends early introduction of insulin if there is evidence of ongoing catabolism (weight loss), if symptoms of hyperglycaemia are present, or when HbA_1c levels (>10%) or blood glucose levels (16.7mmol/L) are very high.¹

How to intensify treatment

In the past, the ADA recommended a stepwise approach to treatment intensification but now states that it is not necessary to follow a ‘pure’ sequential approach. Instead treatment should be tailored to the individual goals or needs of a patient – the essence of individualised care.¹

The authors of the EADSG guidelines concur, stating that: An insulin regimen should be adopted and individualised. They caution that regimens should closely resemble a natural physiologic state and avoid wide fluctuating glucose levels it possible.⁵

Insulin initiation should start by adding a long-acting (basal) insulin or once-daily premixed/co-formulation insulin or twice-daily premixed insulin, alone or in combination with glucagon-like peptide-1 receptor agonist or in combination with other OADs. If patients still do not achieve targets, rapid- or short-acting (bolus or prandial) insulin can be added at mealtime to control PPG excursions.⁵

The advantage of premixed insulins, when given before meals, is that they target both fasting and postprandial glucose (PPG) levels with a single injection.⁶

Selecting the most appropriate premixed analogue for your patient 

The most commonly used premixed insulin analogues are low-mix formulations with a low rapid- to a long-acting analogue ratio (eg 25/75). However, for some patients (those with high carbohydrate diets and patients with large PPG excursions – especially after lunch), premixed 50/50 formulations may be more appropriate.⁶

Deed et al (2017) conducted a systematic literature review to assess the efficacy and safety of a premixed 50/50 formulation, compared with low-mix, basal, or basal-bolus therapy, for insulin initiation and intensification. Their review included 35 studies.⁶

The findings of their review show that for patients initiating insulin treatment, a premixed 50/50 formulation may result in better glycaemic control than either low-mix insulin analogues or basal therapy.⁶

Furthermore, in patients at risk of nocturnal hypoglycaemia, a premixed 50/50 formulation at dinner may be a better choice than basal or low-mix insulins. Similarly, a premixed 50/50 formulation could be used during Ramadan to reduce the risk of PPG excursions after the evening meal, which often contains a large caloric load. A premixed 50/50 formulation may also be an appropriate choice for patients at high risk of micro- and macrovascular complications caused by high glycaemic variability.⁶

Watada et al (2017) compared premixed 25/75 and 50/50 formulations as initial intensification therapy. Participants received either 25/75 (n=207) or 50/50 (n=196) formulations twice a day for 26 weeks. The primary outcome was HbA_1c change from baseline.⁷

The researchers found that 59.7% of participants in the 50/50 formulation group, compared to 45.9% in the 25/75 formulation group achieved HbA_1c targets of <7%. The 50/50 formulation was also more effective than the 25/75 formulation in reducing PPG excursions after the morning (mean difference in change from baseline, 0.56mmol/L) and evening (1.11mmol/L) meals.⁷

The reduction in fasting blood glucose was significantly greater in the 25/75 formulation group (-2.37mmol/L) compared to the 50/50 formulation group (-1.99mmol/L). However, the 50/50 formulation was more effective than the 25/75 formulation in reducing HbA_1c in participants with baseline HbA_1c, PPG excursions, or carbohydrate intake levels greater than the median levels. Hypoglycaemia rates and weight gain were similar between groups.⁷

Conclusion

According to Britto et al suboptimal glycaemic control continues, with many patients remaining on unmodified treatment regimens for too long. Guidelines emphasise the importance of modifying treatment regimens when HbA_1c goals have not been attained.³

Modifications should be implemented before loss of glycaemic control occurs and should be individually tailored to patient needs. When treatment is actively titrated, assessed and intensified, patients are more likely to achieve glycaemic targets, they concluded.³

REFERENCES

1. El Sayed NA, Aleppo G, Aroda VR, et al. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes – 2023. Diabetes Care, 2023.
2. Ruissen MM, Rodriquez-Gutierrez R, Montori VM, and Kunneman M. Making Diabetes Care Fit – Are We Making Progress? Front  Clin Diabetes Healthc, 2021.
3. Brito M, Lighthelm RJ, et al. Intensifying existing premix therapy (BIAsp 30) with BIAsp 50 and BIASP 70: A consensus statement. Indian Journal of Endocrinology and Metabolisms, 2011.
4. El Sayed NA, Aleppo G, Aroda VR, et al. Glycemic Targets: Standards of Care in Diabetes – 2023, Diabetes Care 2023
5. Silver B, Ramaiya K, et al. EADSG Guidelines: Insulin Therapy in Diabetes. Diabetes Ther, 2018.
6. Deed G, et al. Use of 50/50 Premixed Insulin Analogs in Type 2 Diabetes: Systematic Review and Clinical Recommendation. Diabetes Ther, 2017
7. Watada H, Su Q, Li PF, et al. Comparison of insulin lispro mix 25 with insulin lispro mix 50 as an insulin starter in Asian patients with type 2 diabetes: a phase 4, open-label, randomized trial (CLASSIFY studyl). Diabetes Metab Res Rev, 2017.
8. Edelman SV, Wood R, Roberts M and Shubrook JH. Patients With Type 2 Diabetes Are Willing to Do More to Overcome Therapeutic Inertia: Results From a Double-Blind Survey. Clin Diabetes, 2020