Beyond Insulin
Patients with Type 1 diabetes rely on insulin, but other medications are increasingly prescribed to help stabilize blood sugar levels, as well as secondary symptoms such as hypoglycemia. This journal scan will discuss the most recent literature on the efficacy and administration of supplemental treatments for Type 1 and 2 diabetes.
May 2021
Volume 10, Issue 2

Chapter 1: Non-Insulin Injectable Medications

Non-insulin injectable agents have revolutionized the long-term management of this chronic disease.

Diabetes Care. 2020;43:(9):2303-2312

Stated simply, type 2 diabetes is a disease of insulin resistance and beta-cell dysfunction, and treatments often focus on increasing insulin sensitivity and overall availability, in addition to glucose secretion and decreased carbohydrate absorption. However, we now know that diabetes is not simply beta-cell failure or a disease only involving the deficiency of insulin. Treatment of type 1 diabetes requires replacement of insulin due to insulin deficiency. Patients with type 2 diabetes, however, may require insulin therapy in the setting of increased insulin resistance and decreased beta-cell function, but current therapies aiming to improve insulin sensitivity actually decrease the need for higher doses of insulin. Additionally, increasing insulin dosing is weight-promoting, which in turn increases insulin resistance, propagating the need for even more insulin and elevating the risks of developing metabolic syndrome. Our current available therapies aid in breaking this cycle.

Glucagon-like Peptide 1 (GLP-1) Receptor Agonists and Amylin Analogs

Glucagon-like peptide 1 (GLP-1) receptor agonists and amylin analogs are two forms of non-insulin injectable agents that mitigate the need for increased insulin.

Amylin is a 37-amino-acid peptide that is released from pancreatic beta cells, along with insulin. Amylin and insulin levels synchronously rise and fall, and they have complimentary actions. In type 2 diabetes, there is a relative deficiency of insulin and amylin.

Glucagon-like peptide 1 (GLP-1) is produced by the L cells of the small intestine and is released in response to nutrient intake. GLP-1 binds to GLP-1 receptors, which are located in pancreatic beta cells and ducts, gastric mucosa and organs such as the kidney, lungs and heart, in addition to the hypothalamus.

Both GLP-1 and amylin affect glucose control via several mechanisms:

  • Delayed gastric emptying
  • Regulation of glucagon after meal intake
  • Energy expenditure
  • Reduction of caloric intake via appetite suppression

GLP-1 additionally stimulates glucose-dependent insulin synthesis and release from the pancreas following meal intake. In the setting of diabetes, the release and regulation of GLP-1 and amylin are impaired.

Synthetic GLP-1 Agonists

Synthetic GLP-1 agonists are resistant to degradation by the enzyme dipeptidyl peptidase 4 (DPP-4), and have a much longer half life than endogenously produced GLP-1. Amylin and GLP-1 agonists have unique effects on the satiety pathways, as they bind to different receptors in the hypothalamus. Amylin agonists also regulate post-meal glucagon release more so than GLP-1 agonists.


Pramlintide is an amylin analog that is administered subcutaneously prior to mealtimes, and is used in the treatment of both type 1 and type 2 diabetes. Pramlintide controls post-meal blood sugar levels by slowing gastric emptying and increasing satiety, in addition to suppressing the rise of glucagon after meals. Pramlintide used alone does not cause hypoglycemia.

In type 2 diabetes, pramlintide (at a dose of 120mcg twice daily, not 60 or 90mcg twice daily) has shown the following:

  • Hemoglobin A1C reduction of an average of 0.62-1%age points
  • Weight loss, average 1.4kg
  • Reduction of post-prandial glucose spikes in comparison to insulin therapy alone
  • Improvement of overall glycemic control

Side effects of Pramlintide include:

  • Mild to moderate nausea, which can be minimized by slow dose titration

Hypoglycemia may arise if insulin doses are not decreased accordingly. This occurs less frequently in type 2 diabetes than type 1 diabetes.

Pramlintide is only approved for use in patients who also require mealtime and short-acting insulin. Pre-meal insulin doses should be decreased by 50% when pramlintide is initiated, to avoid hypoglycemia post-prandially. Additionally, pramlintide should be avoided in patients with a history of gastroparesis.


The first GLP-1 agonist, exenatide, was approved in 2005 for the treatment of type 2 diabetes, and in 2009 it was approved as monotherapy for patients with type 2 diabetes who could not reach glycemic goals with lifestyle changes alone. There are now 6 GLP-1 agonists approved for treatment of type 2 diabetes, one of which now comes in an oral formulation. GLP-1 agonists may be added to insulin or oral hypoglycemic therapy, save for DDPIV-inhibitors, and with additional caution when added to sulfonylureas and short-acting insulin due to risk for hypoglycemia.

GLP-1 agonists have shown the following benefits:

  • Significant reductions in blood sugars and hemoglobin A1C levels (on average 0.55-1.38% points)
  • Weight loss via increased satiety and slowed gastric emptying
  • Reduction in cardiovascular disease outcomes, particularly with use of liraglutide, semaglutide, dulaglutide and albiglutide (no longer on the market)

Adding GLP-1 analog therapy to basal insulin therapy results in greater reductions in Hemoglobin A1C, fasting plasma glucose and body weight

A 2019 meta-analysis of cardiovascular, mortality and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes revealed the following:

  • Reduction of the risk of MACE by 12% (HR 0.88; 95% CI 0.82-0.94; p=0.001) and its individual factors
  • Reduction in risk of death from cardiovascular causes ((HR 0.88; 95% CI 0.81-0.96; p=0.001)
  • Reduction in fatal or non-fatal stroke (HR 0.84; 95% CI 0.76-0.93; p=0.001)
  • Reduction in fatal or non-fatal myocardial infarction (HR 0.91; 95% CI 0.84-1.00; p=0.043)
  • Reduction in all-cause mortality by 12% (HR 0.88; 95% CI 0.83-0.95; p=0.001)
  • Reduction in hospital admission for heart failure by 9% (HR 0.0.91; 95% CI 0.83-0.99; p=0.028)
  • Reduction in new-onset microalbuminuria, decline in estimated glomerular filtration rate (or rise in creatinine), progression to end-stage kidney disease or death due to renal disease by 17% (HR 0.83; 95% CI 0.78-0.89; p=0.001)

There was no increased risk of development of severe hypoglycemia, thyroid carcinoma, pancreatitis or pancreatic cancer with use of GLP-1 receptor agonist treatment.

Injectable GLP-1 receptor agonists come in twice daily (exenatide), once daily (liraglutide and lixisenatide), and weekly (dulaglutide, semaglutide) formulations.

Precautions and side effects of GLP-1 receptor agonists include:

  • Avoidance in patients with a history of pancreatitis
  • Caution in patients with history of gastroparesis
  • Caution in patients with renal impairment (particularly with eGFR < 30mL/min/1.73m2)
  • Avoidance in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B

Most common side effects include nausea, vomiting and diarrhea, but these can improve with slow up-titration of dosing.

These benefits of therapy show cardioprotective benefit and clearly set GLP-1 receptor agonists apart, providing an opportunity to truly reduce morbidity and mortality.


Next Article:
Chapter 2: Pursuing Non-Insulin Oral Medications for Type 1 Diabetes
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