This article is based on a presentation by Dr Julien Trokis, a diabetologist based in the Western Cape.  Dr Trokis was one of the keynote speakers at the recent South African launch of iGlarLixi, a once-daily titratable fixed-ratio formulation that combines basal insulin glargine 100 units/mL and the glucagon-like peptide-1 receptor agonist (GLP-1RA), lixisenatide. The combination offers a once-weekly, single-injection option for treatment intensification. 

In South Africa, the International Diabetes Management Practices Study survey showed that only 36% of patients achieve recommended glycaemic targets

T2DM accounts for the vast majority (around 90%) of cases (416 million). About 65 million people with T2DM need insulin, but only 50% are able to access treatment. Apart from limited access to treatment, Dr Trokis discussed some of the other challenges that complicate the effective management of patients with T2DM.1,2,3

The problem of clinical inertia

Khunti et al (2013) showed that in people with HbA1c ≥7%, ≥7.5%, or ≥8%, the median time from above HbA1c cut-off to intensification with an additional oral antidiabetic (OAD) agent was 2.9, 1.9, or 1.6 years, respectively, for those taking one oral antidiabetic agent (OAD) and >7.2, >7.2, and >6.9 years for those taking two OADs. Median time to intensification with insulin was >7.1, >6.1, or 6 years for those taking one, two, or three OADs.13

Mean HbA1c at intensification with an OAD or insulin for people taking one, two, or three OADs was 8.7%, 9.1%, and 9.7%. In patients taking one, two, or three OADs, the median time from treatment initiation to intensification with an OAD or insulin exceeded the maximum follow-up time of 7.2 years. The probability of patients with poor glycaemic control taking one, two, or three OADs, intensifying at end of follow-up with an OAD, was 21.1%–43.6% and with insulin 5.1%–12.0%.13

In a follow-up study (2016), Khunti et al found that 36.5% of patients had their treatment intensified during the study period (three years). Of these, the treatment of 50%, 42.5% and 7.4% were intensified with bolus or premix insulin or GLP-1RAs, respectively. The median time from initiation of basal insulin to treatment intensification was 4.3 years. Among patients clinically eligible for treatment intensification (HbA1c ≥7.5%), 30.9% had their treatment regimen intensified. The median time to intensification in this group was 3.7 years.14

In a cohort of 105 477 patients, Paul et al showed that mean HbA1c was 8.1% at diagnosis, 11% had a history of cardiovascular disease, and 7.1% experienced at least one macrovascular event during 5.3 years of median follow-up. In patients with HbA1c consistently >7% and 7.5% two years post-diagnosis, 26% and 22% never received any treatment intensification.15

Compared to patients with HbA1c <7%, in patients with HbA1c ≥7%, a one year delay in receiving treatment intensification was associated with a significantly increased risk of MI, stroke, heart failure and composite macrovascular events by 67%, 64% and 62% respectively. One year delay in treatment intensification in interaction with HbA1c above 7.5% was also associated with a similar increased risk of macrovascular events.15

According to Khuni et al, clinicians’ inertia may be driven by:14

  • Lack of knowledge about the current opinion that aggressive control early on the following diagnosis leads to significant benefit in appropriate patients
  • The assumption that the management of patients with T2DM and multiple comorbidities is challenging and require specialist training
  • Worries about potential adverse side effects such as hypoglycaemia
  • Concerns about patient adherence (patients might be unable or unwilling to adapt to the increasingly complex regimen)
  • Lack of time available to primary care physicians to adequately tackle concerns.

Patient-level inertia may be the result of:

Misperceptions about insulin therapy such as:

  • The belief that insulin therapy is not efficacious
  • Their quality of life will drop considerably
  • They will not be able to adhere to increasingly complex regimens
  • Fears of unwanted side effects such as weight gain, hypoglycaemia, and injection pain.

Intervening earlier

Unfortunately, many patients do not achieve recommended glycaemic targets. In Canada 49.9%, in the United States 44% and in Europe only 37.4%, and in South Africa, the International Diabetes Management Practices Study survey showed that 36% of patients achieve their recommended targets.8,9,10,23

Guidelines support individualised glycaemic targets based on patient preference, as well as treatment efficacy, and safety profiles. Although individualised targets are advocated, guidelines recommend a target HbA1c of <7% for most non-pregnant adults with T2DM. In patients who do not achieve individualised targets, a stepwise introduction of pharmacotherapy is recommended. 5,6

The 2020 American Association of Clinical Endocrinologists and American College of Endocrinology and ADA guidelines recommend early combination therapy in patients with HbA1c >9% or 1.5%-2% above target, respectively, as the effectiveness of most OADs rarely exceeds a 1% HbA1c reduction.5,22

The importance of early initiation of pharmacotherapy was shown in the landmark United Kingdom Prospective Diabetes Study (UKPDS). The study showed that by the time HbA1c levels reach >7.5%, the risk of microvascular complications increases 2.5-5-fold.4,5,6

Every 1% reduction of HbA1c was associated with reductions in the risk of:

  • 21% of any endpoint related to diabetes
  • 21% for deaths related to diabetes
  • 14% for myocardial infarction
  • 37% for microvascular complications.

Weight gain: A consequence of the intensification

According to Dr Trokis, studies show that the majority of patients with T2DM are already overweight or obese by the time they are diagnosed. In addition, a sub-study of UKPDS showed that patients started on OADs gain an average of eight kilogrammes over a ten-year period.3,12

The fear of gaining further weight is physiologically and psychologically undesirable for patients who already struggle with their weight – a concern shared by clinicians added Dr Trokis. These concerns negatively impact treatment adherence and treatment intensification, he added.3

Hyperglycaemia

According to guidelines, the primary purpose of treating glycaemia in patients with T2DM is to reduce blood glucose sufficiently to relieve any symptoms of hyperglycaemia to prevent or delay the onset of microvascular and macrovascular complications.5,6

However, many patients still have HbA1c levels above target despite fasting hyperglycaemia (FPG) being at target. This is known as residual hyperglycaemia’ (HbA1c ≥7%).3

Monnier et al showed that HbA1c levels are determined by a combination of both FPG and postprandial hyperglycaemia (PPG) and Riddle et al demonstrated that PPG accounted for 66% of total hyperglycaemia in patients taking basal insulin. Thus, both PPG and FPG need to be addressed to achieve sustained glycaemic control.16,17

Raccah et al found that between 24% to 54% of patients with T2DM globally had residual hyperglycaemia with HbA1c not at target, despite achieving FPG control on basal insulin, indicating a significant unmet need for PPG control.18

Options after basal failure

There are various options for intensification after basal failure:7

1. Adding rapid-acting insulin progressively to an existing basal insulin regimen

2. Switching to multiple daily premix insulin doses (basal and prandial insulin co-formulation)

3. Adding a daily or weekly GLP-1RA to an existing basal insulin regimen

4. Switching to a once-daily fixed-ratio combination (FRC) of basal insulin and GLP-1RA.

Fixed-ratio combinations

According to Blonde et al, adding a GLP-1RA to basal insulin has been associated with improved overall glycaemic control, addressing the need for PPG control. The newer titratable FRCs combine basal insulin with GLP-1RA in one combination, offering less complex dosing schedules leading to improved treatment adherence.20

The clinical trial programme of iGlarLixi showed that:24,25,26

  • LixiLan O: Evaluated the efficacy and safety of iGlarLixi compared with both components, iGlar and Lixi, given separately in T2DM patients inadequately controlled on metformin, with or without a second oral glucose-lowering drug. Greater reductions in HbA1c from baseline (8.1%) were achieved with iGlarLixi compared with iGlar and Lixi (−1.6%, −1.3%, −0.9%, respectively), reaching mean final HbA1c levels of 6.5% for iGlarLixi versus 6.8% and 7.3% for iGlar and Lixi, respectively. More patients reached target HbA1c <7% with iGlarLixi (74%) versus iGlar (59%) or Lixi (33%). Mean body weight decreased with iGlarLixi (−0.3 kg) and Lixi (−2.3 kg) and increased with iGlar (+1.1 kg, difference 1.4 kg). Documented symptomatic hypoglycaemia (≤70mg/dL) was similar with iGlarLixi and iGlar (1.4 and 1.2 events/patient-year) and lower with Lixi (0.3 events/patient-year). iGlarLixi improved PGG control versus iGlar and demonstrated considerably fewer nausea (9.6%) and vomiting (3.2%) events than Lixi (24% and 6.4%, respectively).24
  • LixiLan L: Evaluated the efficacy and safety of iGlarLixi, and lixisenatide, compared with iGlar in patients with T2DM inadequately controlled on basal insulin with or without up to two oral glucose-lowering agents. HbA1c decreased from 8.5% to 8.1% during the run-in period. After randomisation, iGlarLixi showed greater reductions in HbA1c from baseline compared with iGlar (–1.1% vs. –0.6%), reaching a mean final HbA1c of 6.9% compared with 7.5% for iGlar. HbA1c <7.0% was achieved in 55% of iGlarLixi patients compared with 30% on iGlar. Mean body weight decreased by 0.7kg with iGlarLixi and increased by 0.7kg with iGlar (1.4 kg difference). Documented symptomatic hypoglycaemia (≤3.9 mmol/L) was comparable between groups. Mild gastrointestinal (GI) side effects were very low but more frequent with iGlarLixi. Slow titration of FRCs has been shown to reduce the occurrence and severity of GI side effects.25
  • Solimix: The first head-to-head clinical trial comparing the safety and efficacy of iGlarLixi versus premix insulin in adults with insufficiently controlled T2DM on basal insulin plus one or two OAD agents. The SoliMix trial found that when managing T2DM, the once-daily iGlarLixi edged out the twice-daily premix insulin analogue BIAsp 30. The key results of the SoliMix study are that in comparison with the fixed mixture, BIAsp 30, the fixed-ratio combination iGlarLixi demonstrated non-inferiority and, in fact, superiority in terms of HbA1c reduction importantly, it did so without causing significant body weight change – this was increased with the BIAsp 30 but reduced with iGlarLixi. The number of patients who achieved HbA1c target without weight gain and without significant hypoglycaemia was increased with the iGlarLixi.26

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4. UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet, 1998.

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10. De Pablos-Velasco, Parhofer KG, Bradley C, et al. Current level of glycaemic control and its associated factors in patients with type 2 diabetes across Europe: data from the PANORAMA study. Clin Endocrinol, 2014.

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13. Khunti K, Wolden ML, Thorsted BL, et al. Clinical Inertia in People With Type 2 Diabetes: A retrospective cohort study of more than 80,000 people. Diabetes Care, 2013.

14. Khunti K, Nokolajsen A, Thorsted BL, et al. Clinical inertia with regard to intensifying therapy in people with type 2 diabetes treated with basal insulin. Diabetes Obes Metab, 2016.

15. Paul SK, Klein K, Thorsted BL, et al. Delay in treatment intensification increases the risks of cardiovascular events in patients with type 2 diabetes. Cardiovasc Diabetol, 2015.

16. Monnier L, Lapinski H and Colette C. Contributions of Fasting and Postprandial Plasma Glucose Increments to the Overall Diurnal Hyperglycemia of Type 2 Diabetic Patients. Diabetes Care, 2003.

17. Riddle M, Umpierrez G, DiGenio A, et al. Contributions of Basal and Postprandial Hyperglycemia Over a Wide Range of A1C Levels Before and After Treatment Intensification in Type 2 Diabetes. Diabetes Care, 2011.

18. Raccah D, Chou E, Colaquiri S, et al. A global study of the unmet need for glycemic control and predictor factors among patients with type 2 diabetes mellitus who have achieved optimal fasting plasma glucose control on basal insulin. Diabetes Metab Res Rev, 2017.

19. Dalal MR, Kazemi M, Ye F, et al. Hypoglycemia After Initiation of Basal Insulin in Patients with Type 2 Diabetes in the United States: Implications for Treatment Discontinuation and Healthcare Costs and Utilization. Adv Ther, 2017.

20. Blonde L, Anderson JE, Chava P and Dendy JA. Rationale for a titratable fixed-ratio co-formulation of a basal insulin analog and a glucagon-like peptide 1 receptor agonist in patients with type 2 diabetes. Curr Med Res Opin, 2019.

21. Davies MJ, D’Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care, 2018.

22. Garber AJ, Handelsman Y, Grunberger G, et al. Consensus Statement by the American Association of Clinical Endocrinologists and American College of Endocrinology on the Comprehensive Type 2 Diabetes Management Algorithm – 2020 Executive Summary. Endocrine Practice, 2020.

23. Aschner P, Gagliardino JJ, Ilkova H, et al. Persistent poor glycaemic control in individuals with type 2 diabetes in developing countries: 12 years of real-world evidence of the International Diabetes Management Practices Study (IDMPS). Diabetologia, 2020.

24. Rosenstock J, Aronson R, Grunberger G, et al. Benefits of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide, Versus Insulin Glargine and Lixisenatide Monocomponents in Type 2 Diabetes Inadequately Controlled on Oral Agents: The LixiLan-O Randomized Trial. Diabetes Care, 2013.

25. Aroda VR, Rosenstock J, Wysham C, et al. Efficacy and Safety of LixiLan, a Titratable Fixed-Ratio Combination of Insulin Glargine Plus Lixisenatide in Type 2 Diabetes Inadequately Controlled on Basal Insulin and Metformin: The LixiLan-L Randomized Trial. Diabetes Care, 2016.

26. Rosenstock J, Emral R, Sauque-Reyna L, et al. Advancing therapy in suboptimally controlled basal insulin-treated type 2 diabetes: Clinical outcomes with iGlarLixi versus premix BIAsp 30 in the SoliMix randomized controlled trial. Diabetes Care, 2021.