The efficacy and benefits of GLP-1 and basal insulin

According to the International Diabetes Federation, it is estimated that an average of 387 million people worldwide live with diabetes, with an average of 21 million people from Africa suffering from the disease. Further, it is estimated that 77% of people with diabetes live in low- to middle-income countries. Type 2 diabetes is a progressive disease requiring treatment intensification to maintain glycaemic control.

Key facts of people living with diabetes are undiagnosed

Factors that influence treatment

Even despite advances in therapy, glycaemic control is not optimal. Research indicates the following factors as influential:

  • Failure to attain and sustain optimal long-term glycaemic control
  • Adherence: issues associated with weight gain and hypoglycaemia
  • Inadequate postprandial plasma glucose (PPG) control
  • Unpredictable glucose fluctuations
  • Excess CVD.

Many patients with diabetes do not adhere to their treatment due to the following reasons:

  • Retrospective studies in people with Type 2 diabetes reported adherence rates of 36%-93%, for oral agents and 62%-64% for insulin
  • Therapy persistence has been shown to decrease with time, and with polytherapy compared with monotherapy.

According to a study, Diabetes Care 2015, by Kirman SM et al, several patient demographics and clinical factors influence adherence to non-insulin antidiabetic medications, including: older age, male sex, higher education levels, higher income and the presence of comorbidities. According to the study, “patients who were new to therapy were 61% less likely to be adherent.”

Patients with Type 2 diabetes, often have multiple comorbidities that contribute to increase cardiovascular (CV) risk 71% have high blood pressure (BP)

  • 65% have dyslipidaemia
  • 85% are overweight

Tight BP control helps to avoid CV complications

Tight BP control helps to avoid CV complications

The SEMDSA (Society for Endocrinology, Metabolism and Diabetes of South Africa), guidelines will be published in May 2017.

What is the ideal treatment approach?

  • Early, more aggressive treatments should be initiated in patients failing to reach goals
  • Preference should be given to drugs that have a low risk of hypoglycaemia and are well tolerated
  • Treatments should go beyond HbA1c control to address comorbidities such as weight gain and high blood pressure in support of CV risk factor reduction.
  • Data from the Steno-2 study, suggests that more important than BP control, for reducing CV risk factors and death, in regression analysis, is lipid control.
  • Patient preference should be taken into account when deciding on treatment.

 

2016 AACE/ACE guideline recommendations suggest a number of options for early combination therapy table

Basal insulin and GLP-1

For patients unable to achieve individualised glycaemic targets with oral glucose-lowering agents, basal insulin is usually initiated and uptitrated to a fasting glucose (FG) target, but postprandial glucose may remain elevated.

The primary role of basal insulin is to keep blood glucose levels stable during periods of fasting, such as while you’re sleeping. While fasting, the liver continuously secretes glucose into the bloodstream. Basal insulin is needed to keep these glucose levels under control. Without this insulin, glucose levels would rise at an alarming rate. Basal insulin ensures that the cells are fed with a constant stream of glucose throughout the day.

There are two main types of basal insulin:

Intermediate-acting insulin: This insulin is administered once or twice daily, usually mixed with mealtime insulin either in the morning, before the evening meal, or both. It works hardest in the four to eight hours after injection, and starts waning after about 16 hours.

Long-acting insulin. This basal insulin begins working 90 minutes to four hours after injection and remains in the bloodstream for up to 24 hours. It may start weakening a few hours earlier for some patients, or last a few hours longer for others. There isn’t a peak time for this type of insulin. It covers at a steady rate throughout the day.

Although mealtime insulin may control postprandial glucose, weight gain, increased hypoglycaemia risk, and poor patient acceptance may result. Recent studies suggest that adding a short-acting glucagon-like peptide 1 (GLP-1) receptor agonist to target postprandial glucose may be a viable option.

A study: GLP-1 and basal insulin for glucose control

A study, Adding GLP-1 Receptor Agonist Therapy to Basal Insulin for Postprandial Glucose Control, by Andrew S. Rhinehart, summarises three recent articles, demonstrating the glycemic control efficacy and other benefits of adding a GLP-1 receptor agonist to basal insulin and describes a strategy to implement this therapy in busy primary care settings.

“Even with current guidelines, treatment algorithms, and recommendations available regarding diabetes management, providers struggle with adding therapies to manage postprandial hyperglycaemia after basal insulin therapy in combination with oral antidiabetic medications (OADs) has failed to control a patient’s hyperglycaemia,” Rhinehart said.

Historically, after titration of basal insulin to achieve morning glucose control, adding a bolus, or prandial, rapid-acting insulin analogue has been recommended either in a stepwise approach or as a full basal-bolus insulin regimen.

“However, recent research has shown that adding a GLP-1 receptor agonist to basal insulin may be as effective as adding prandial insulin therapy. These results have given providers and patients a potentially easier option when glycaemic control is not achieved with basal insulin in combination with OADs. Three recent articles, have been studied, to demonstrate the glycaemic control efficacy and other benefits of adding a GLP-1 receptor agonist to basal insulin and describes a strategy to implement this therapy in busy primary care settings,” Rhinehart said.

The study, Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro, reported on a randomised, open-label, active-controlled trial testing once-weekly albiglutide versus thrice-daily prandial insulin lispro as an add-on to titrated insulin glargine.

The primary endpoint of the study was A1C change from baseline to 26 weeks. Albiglutide was found to be noninferior based on predefined endpoints but numerically superior to lispro as part of a basal-bolus insulin regimen, with A1C reductions of 0.82 and 0.66%, respectively.

The albiglutide treatment group had a mean weight loss of 0.73 kg with no severe hypoglycaemia and 15.8% rate of documented hypoglycaemia. The lispro group had a mean 0.81 kg weight gain, two episodes of severe hypoglycaemia, and a 29.9% rate of documented hypoglycaemia. However, gastrointestinal side effects such as nausea, vomiting, and diarrhoea were more common in the albiglutide group.

In a further study, Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis, the authors reviewed studies comparing GLP-1 receptor agonist and basal insulin combination therapy to other antidiabetic therapy regimens.

The main endpoints evaluated were glycaemic control, hypoglycaemia, and changes in weight. In all three endpoints, GLP-1 receptor agonist therapy was found to be superior to the other therapies studied, demonstrating robust glycaemic control with no increases in the rate of hypoglycaemia or weight gain.

However, GLP-1 receptor agonist therapy was again associated with more gastrointestinal side effects than prandial insulin therapy.

The research, Glucagon-like peptide 1 receptor agonist or bolus insulin with optimized basal insulin in type 2 diabetes, reported on a 30-week, open-label, multicentre, randomised, noninferiority trial comparing exenatide to thrice-daily lispro added to a background of glargine and metformin. The primary endpoint was A1C change from baseline to 30 weeks. Exenatide was found to be noninferior to lispro based on predefined endpoints as part of a basal-bolus insulin regimen.

A1C reductions were 1.13% with exenatide and 1.10% with lispro. The exenatide treatment group had a mean weight loss of 2.5 kg, two episodes of severe hypoglycaemia, and a 30% incidence of minor hypoglycaemia, whereas the lispro group had a mean weight gain of 2.1 kg, seven episodes of severe hypoglycaemia, and a 41% incidence of minor hypoglycaemia. Gastrointestinal side effects were more common in the exenatide group.

“These three articles help to reinforce the potential benefits of GLP-1 receptor agonist therapy,” Rhinehart said.

Further, a study, Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years, by David C et al, “Exenatide therapy for ≥ 3 years demonstrated sustained and clinically-relevant improvements in glycemic control, pancreatic β‑cell function, cardiovascular risk factors, and hepatic injury biomarkers, coupled with progressive weight reduction. Therefore, exenatide represents an option for adjunctive therapy for patients with type 2 diabetes not achieving adequate glycemic control.”

Courtesy of Julio Rosenstock, MD a. Liebl A. Curr Med Res Opin. 2007;23:129-13232; b. Rosetti P. Arch Physiol Biochem. 2008;114:3-1033; c. Holst JJ, et al. Mol Cell Endocrinol. 2009;297:127-1361; d. Calabrese D. Am. Managed Care. 2011;S52-S582.

Courtesy of Julio Rosenstock, MD
a. Liebl A. Curr Med Res Opin. 2007;23:129-13232; b. Rosetti P. Arch Physiol Biochem. 2008;114:3-1033; c. Holst JJ,
et al. Mol Cell Endocrinol. 2009;297:127-1361; d. Calabrese D. Am. Managed Care. 2011;S52-S582.

These benefits include:

  • Glucose-dependent insulin secretion
  • Glucose-dependent glucagon secretion
  • Low risk of hypoglycaemia
  • Possible weight loss
  • Postprandial glucose control
  • Less energy intake
  • Increased satiety
  • Delayed gastric emptying.

Beyond these potential pharmacological benefits are two additional advantages:

  1. Less of a treatment burden for patients resulting from fewer required injections compared to a basal-bolus insulin regimen.
  2. Easier patient education and simplified dose titration for providers initiating GLP-1 receptor agonist treatment compared to rapid-acting prandial insulin.

Important indications, warnings, and contraindications regarding GLP-1 receptor agonist therapy include:

  • Contraindicated (with the exception of exenatide) in patients with a personal or family history of medullary thyroid carcinoma
  • Contraindicated (with the exception of exenatide) in those with a history of multiple endocrine neoplasia syndrome type 2
  • To be used with caution in patients with a history of pancreatitis or gastroparesis
  • Not to be used (with the exception of dulaglutide) in patients using prandial insulin
  • Not for use in patients with Type 1 diabetes. However, as an exception, insulin degludec is now available which has a basal profile of up to 36 hours, and has been combined with liraglutide for the study of Type 1 diabetes, although it is not officially registered in SA  for this indication.
  • Not for use in patients with diabetic ketoacidosis
  • May cause hypersensitivity reactions.

Treatment

  • Rhinehart identified the following steps in implementing this treatment option as a simple process:
  • Identify as possible candidates patients who are not at their A1C target despite taking OAD(s) and >0.5–0.7 units/kg of basal insulin or taking basal insulin appropriately titrated to morning glucose control
  • Be sure the patient is within 1–1.5 percentage points of his or her A1C target for the best chance of success. HbA1c on GLP1 is dependant on starting HbA1c, duration of diabetes, and Beta cell reserve. Reductions of up to five percent have been documented. For the purpose of a RCT trail the data is pooled, hence the recommendation of 1 to 1.5%.
  • Discuss the proposed therapy with the patient to be sure none of the warnings, precautions, or contraindications listed above preclude its initiation
  • Find out which of the available GLP-1 receptor agonists are covered by the patient’s insurance plan
  • Discuss with the patient the most common potential side effects such as nausea, vomiting, and allergic reactions
  • Encourage the patient to regularly self-monitor his or her blood glucose and log the results
  • Teach the patient proper injection technique and proper dosing; this should be carried out by the provider, a nurse or medical assistant in the provider’s office, or the patient’s pharmacist
  • Arrange a follow-up visit in one month to evaluate treatment efficacy and assess the patient for possible side effects.

Conclusion

This recent important research, will give providers and their patients with Type 2 diabetes an alternative when prandial insulin is thought to be an excessive treatment burden for the patient, an educational burden for the provider, or a regimen beyond the provider’s level of comfort or expertise. These articles provide evidence in support of the hypothesis that the benefits of GLP-1 receptor agonist therapy outweigh the associated risks.

“The most efficacious use of a GLP-1 receptor agonist would be in patients whose A1C level is within 1–1.5 percentage points from their individualised target. Patients whose A1C is >1.5 percentage points above target likely will gain more benefit from aggressive insulin management strategies when oral therapies and basal insulin have failed to provide adequate glycaemic control,” Rhinehart states.

References:
  • Andrew S. Rhinehart. Adding GLP-1 Receptor Agonist Therapy to Basal Insulin for Postprandial Glucose Control
  • Rosenstock J, Fonseca VA, Gross JL, et al.; Harmony 6 Study Group. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care 2014;37:2317–2325
  • Eng C, Kramer CK, Zinman B, Retnakaran R. Glucagon-like peptide-1 receptor agonist and basal insulin combination treatment for the management of type 2 diabetes: a systematic review and meta-analysis. Lancet 2014;384:2228–2234
  • Diamont M, Nauck MA, Shaginian R, et al.; 4B Study Group. Glucagon-like peptide 1 receptor agonist or bolus insulin with optimised basal insulin in type 2 diabetes. Diabetes Care 2014;37:2763–2773
  • Diabetes Care 2014; 37:2763–2773 | DOI: 10.2337/dc14-0876; Glucagon-Like Peptide 1 Receptor Agonist or Bolus Insulin With Optimised Basal Insulin in Type 2 Diabetes.
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