The Role of the Pharmacist in Managing Type 2 Diabetes with Glucagon-Like Peptide-1 Receptor Agonists as Add-On Therapy

The prevalence and associated clinical burden of type 2 diabetes (T2D) is increasing in the USA and other countries. As a consequence, the role of the pharmacist in managing T2D is expanding, and it is becoming increasingly important for pharmacists to have a complete understanding of the disease course and treatment options. Pharmacists have a key role in the use of injectable therapies, including incretin-based treatment with glucagon-like peptide-1 receptor agonists (GLP-1RAs). This article discusses the role of the pharmacist in the management of patients with T2D, particularly with respect to the use of GLP-1RAs to achieve glycemic control. GLP-1RAs are a class of injectable agents used as an adjunct to diet and exercise to improve glycemic control in adults with T2D. GLP-1RAs have been shown to lower glucose levels, slow gastric emptying, enhance satiety, and reduce body weight without increasing the risk of hypoglycemia. GLP-1RAs currently approved in the USA include exenatide twice daily, liraglutide once daily, and albiglutide, dulaglutide, and exenatide once weekly. Pharmacists can work with physicians to help identify patients for whom GLP-1RA therapy is appropriate. In addition, pharmacists can educate patients regarding medication storage, preparation, and injection techniques, glycated hemoglobin (HbA_1c) targets, pre- and post-meal blood glucose goals, adverse events and management strategies, and the long-term benefits of reducing HbA_1c. As members of the diabetes care team, pharmacists play an important role in improving patient outcomes. Funding: AstraZeneca.     

Incorporating Incretin-Based Therapies into Clinical Practice for Patients with Type 2 Diabetes

Background

Effective, evidence-based management of type 2 diabetes (T2D) requires the integration of the best available evidence with clinical experience and patient preferences.

Methods

Studies published from 2000 to 2012 evaluating glucagon-like peptide-1 receptor agonists (GLP-1RAs) or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors) were identified using PubMed. The author contextualized the study findings with his clinical experience.

Results

Incretin-based therapy targets multiple dysfunctional organs in T2D. Injectable GLP-1RAs provide substantial glycemic control and weight reduction; while oral DPP-4 inhibitors provide moderate glycemic control and weight neutrality. Both classes are effective, well tolerated, and associated with a low incidence of hypoglycemia when used alone or in combination with other antidiabetes agents. GLP-1RAs are associated with transient nausea and, like DPP-4 inhibitors, rare pancreatitis.

Conclusion

Data indicate and clinical experience confirms that incretins are well tolerated in appropriate patients and provide sustained glycemic control and weight loss or weight neutrality throughout T2D progression.     

User’s guide to mechanism of action and clinical use of GLP-1 receptor agonists

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are injectable glucose-lowering medications approved for the treatment of adult patients with type 2 diabetes mellitus (T2DM). This article provides practical information to guide primary care physicians on the use of GLP-1RAs in patients with T2DM. Two short-acting (once- or twice-daily administration; exenatide and liraglutide) and three long-acting (weekly administration; albiglutide, dulaglutide and exenatide) GLP-1RAs are currently approved in the US. These drugs provide levels of GLP-1 receptor agonism many times that of endogenous GLP-1. The GLP-1RAs have been shown to significantly improve glycemic parameters and reduce body weight. These agents work by activating GLP-1 receptors in the pancreas, which leads to enhanced insulin release and reduced glucagon release—responses that are both glucose-dependent—with a consequent low risk for hypoglycemia. Effects on GLP-1 receptors in the CNS and the gastrointestinal tract cause reduced appetite and delayed glucose absorption due to slower gastric emptying. The most common adverse effects are gastrointestinal, which are transient and less common with the long-acting drugs. GLP-1RAs are recommended as second-line therapy in combination with metformin, sulfonylureas, thiazolidinediones or basal insulin, providing a means of enhancing glucose control while offsetting the weight gain associated with insulin and some oral agents. GLP-1RAs represent a useful tool that the primary care physician can use to help patients with T2DM achieve their therapeutic goals.     

Fixed-ratio combination therapy for type 2 diabetes: the top ten things you should know about insulin and glucagon-like peptide-1 receptor agonist combinations

Many individuals with type 2 diabetes (T2D) will eventually require insulin therapy to help achieve and maintain adequate glycemic control. However, the use of insulin can be associated with adverse effects such as hypoglycemia and weight gain, and in some patients the addition of insulin to treatment regimens is often still insufficient to achieve target glycemic control. Combining basal insulin with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) for the treatment of patients with T2D has been demonstrated to be effective and well tolerated, while mitigating many of the adverse events associated with giving either of these drug classes alone. Two titratable, fixed-ratio combination therapies, iGlarLixi and IDegLira, that combine basal insulin and a GLP-1 RA in a once-daily subcutaneous injection are currently approved by the US Food and Drug Administration (FDA) for the treatment of patients with T2D. The fixed-ratio combination iGlarLixi combines insulin glargine 100 Units/mL with lixisenatide, while IDegLira combines insulin degludec 100 Units/mL with liraglutide. While these new fixed-ratio combinations contain antihyperglycemic medications that are familiar to most health care providers, there are many questions relating to their use when formulated as a fixed-ratio combination therapy. This article discusses the ‘top 10’ considerations that health care providers should know about these novel combination therapies as these agents begin to gain an increasing presence in clinical practice.     

Safety and efficacy of a glucagon-like peptide-1 receptor agonist added to basal insulin therapy versus basal insulin with or without a rapid-acting insulin in patients with type 2 diabetes: results of a meta-analysis

Objective: To consolidate the evidence from randomized controlled trials evaluating the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) as add-on to basal insulin therapy in type 2 diabetes (T2D) patients.

Research design and methods: We searched the EMBASE® and NCBI PubMed (Medline) databases and relevant congress abstracts for randomized controlled trials evaluating the efficacy and safety of GLP-1 RAs as add-on to basal insulin compared with basal insulin with or without rapid-acting insulin (RAI) through 23 May 2016. The pooled data were analyzed using a random-effects meta-analysis model. A subanalysis was performed for trials investigating basal insulin plus GLP-1 RAs versus basal insulin plus RAI.

Results: Of the 2617 retrieved records, 19 randomized controlled trials enrolling 7,053 patients with T2D were included. Compared with basal insulin ± RAI, reduction in glycated hemoglobin (HbA1c) from baseline (difference in means: –0.48% [95% confidence interval (CI), –0.67 to –0.30]; p < 0.0001) and weight loss (–2.60 kg [95% CI, –3.32 to –1.89]; p < 0.0001) were significantly greater with basal insulin plus GLP-1 RA. The subanalysis similarly showed significant results for change in HbA1c from baseline and for weight loss, as well as a significantly lower risk of symptomatic hypoglycemia in patients treated with basal insulin plus GLP-1 RA versus basal insulin plus RAI (odds ratio, 0.52 [95% CI, 0.42 to 0.64]; p < 0.0001).

Conclusions: Addition of GLP-1 RA to basal insulin provided improved glycemic control, led to weight reduction and similar hypoglycemia rates versus an intensified insulin strategy; however, symptomatic hypoglycemia rates were significantly lower when compared with a basal insulin plus RAI.     

Current treatments and strategies for type 2 diabetes: Can we do better with GLP-1 receptor agonists?

Abstract

Diet, lifestyle modification, and pharmacotherapy with metformin are appropriate initial treatments for many patients with type 2 diabetes (T2DM). However, most individuals do not maintain glycemic control with metformin alone. Addition of other oral antidiabetes drugs (OADs), including sulfonylurea, meglitinide, or thiazolidinedione, is often the next step. Newer options, including incretin-based glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, offer important benefits as monotherapies or in combination with OADs, with low risk for hypoglycemia. Reductions in glycated hemoglobin (A1C) have been reported among patients treated with GLP-1 RAs (exenatide, ?0.8 to ?1.1%; liraglutide, ?0.8 to ?1.6%), as has weight loss (exenatide, ?1.6 to ?3.1 kg; liraglutide, ?1.6 to ?3.2 kg). GLP-1 RAs also stimulate β-cell responses and have positive effects on cardiovascular risk factors often present in patients with T2DM. The most common adverse events associated with GLP-1 RAs are nausea, which diminishes over time, and hypoglycemia (when used in combination with a sulfonylurea). A large number of trials demonstrated benefits of GLP-1 RAs, suggesting they could provide suitable treatment options for patients with T2DM.     

Postprandial plasma glucose effects of once-weekly albiglutide for the treatment of type 2 diabetes

Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) vary in their structure, duration of action, efficacy, and safety. In order to optimize glycemic control, it is important to target both fasting (FPG) and postprandial plasma (PPG) glucose. Although phase 3 trials document the effect of GLP-1 RAs on glycated hemoglobin, few data are available to assess their effect on PPG. Albiglutide is a once-weekly GLP-1 RA with a half-life of ≈ 5 days. The goal of this review is to summarize the effects of albiglutide on PPG in four phase 2 trials and to describe the PPG-lowering effects of the GLP-1 RAs. At clinically relevant doses (30-64 mg), albiglutide consistently lowered PPG after each meal in addition to its effect on lowering FPG. Multiple weekly subcutaneous injections of albiglutide led to improvements in a variety of glycemic measures, including maximal reductions in PPG from baseline, postmeal glucose excursions, and FPG. Albiglutide, a longer-acting GLP-1 RAs, provides reductions in FPG, PPG following meals, and glucose over 24 hours.     

Current treatments and strategies for type 2 diabetes: can we do better with GLP-1 receptor agonists?

Abstract Diet, lifestyle modification, and pharmacotherapy with metformin are appropriate initial treatments for many patients with type 2 diabetes (T2DM). However, most individuals do not maintain glycemic control with metformin alone. Addition of other oral antidiabetes drugs (OADs), including sulfonylurea, meglitinide, or thiazolidinedione, is often the next step. Newer options, including incretin-based glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, offer important benefits as monotherapies or in combination with OADs, with low risk for hypoglycemia. Reductions in glycated hemoglobin (A1C) have been reported among patients treated with GLP-1 RAs (exenatide, -0.8 to -1.1%; liraglutide, -0.8 to -1.6%), as has weight loss (exenatide, -1.6 to -3.1 kg; liraglutide, -1.6 to -3.2 kg). GLP-1 RAs also stimulate β-cell responses and have positive effects on cardiovascular risk factors often present in patients with T2DM. The most common adverse events associated with GLP-1 RAs are nausea, which diminishes over time, and hypoglycemia (when used in combination with a sulfonylurea). A large number of trials demonstrated benefits of GLP-1 RAs, suggesting they could provide suitable treatment options for patients with T2DM.     

Differential effects of prandial and non-prandial GLP-1 receptor agonists in type 2 diabetes therapy

In type 2 diabetes mellitus (T2DM), decreased pancreatic beta-cell function and increased insulin resistance contribute to a steady decline in glucose homeostasis. Maintaining levels of glycated hemoglobin ≤7.0% is thought to reduce the microvascular and possibly macrovascular complications that result if T2DM is not properly managed. Recent guidelines have recognized the importance of postprandial glucose (PPG) control in reducing cardiovascular risks, and have recommended a more patient-centered approach. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) mimic the action of the endogenous gastrointestinal hormone GLP-1 to activate the insulin response in pancreatic beta cells in a glucose-dependent manner. Prandial GLP-1 RAs have a short plasma half-life and are particularly effective at targeting PPG elevations, whereas long-acting non-prandial GLP-1 RAs are more effective at reducing fasting plasma glucose. These differences highlight the potential for treatment with these agents to be tailored to the need of individual patients and their glycemic imbalance. All GLP-1 RAs are being evaluated in long-term cardiovascular outcome trials. To date, the only cardiovascular trial that has been completed is the ELIXA trial for lixisenatide, which was found to meet the pre-specified criterion of non-inferiority versus placebo in terms of cardiovascular outcomes.     

Renal effects of sodium–glucose cotransporter-2 inhibitors in patients with type 2 diabetes and renal impairment

In patients with type 2 diabetes (T2D), microvascular changes in the kidney often result in diabetic kidney disease (DKD), the progression of which is associated with an increased risk of cardiovascular (CV) and all-cause mortality. Sodium-glucose cotransporter-2 inhibitors (SGLT-2is) are a newer class of oral glucose-lowering therapies that were associated with significant reductions in the risk of major adverse CV events, CV death, and hospitalization for heart failure compared with placebo in CV outcomes trials (CVOTs) of patients with T2D and established CV disease or varying levels of CV risk. In addition, SGLT-2is reduced the risks of clinically relevant renal outcomes in these large randomized studies, indicating the potential for renoprotective effects in patients with T2D and DKD. This review discussed the non-glycemic effects of SGLT-2is in patients with T2D and renal impairment, including reductions in systolic and diastolic blood pressure, decreases in albuminuria and plasma uric acid, changes in estimated glomerular filtration rate, and minimal changes in electrolytes. Potential mechanisms for the renoprotective effects of SGLT-2is observed in CVOTs were considered, including the likely incremental benefits of SGLT-2is when added to renin-aldosterone-angiotensin system inhibitors (RAASis). The possibility of extending the use of SGLT-2is to patients with non-DKD was also discussed. Although the exact mechanisms by which SGLT-2is improve renal outcomes are not fully understood, they are likely to be multifactorial and additive when these drugs are used in combination with RAASis in patients with DKD.     

Albiglutide: a unique GLP-1 receptor agonist

ABSTRACT

Introduction: Albiglutide is a long acting GLP-1 receptor agonist (GLP-1 RA) administered by weekly injection.

Area covered: The pharmacokinetic and pharmacodynamic properties of albiglutide and its clinical effects are discussed. The review encompassed a search of PubMed and a thorough analysis of the European Union and US Food and Drug Administration approval documents.

Expert opinion: Albiglutide has a chemical structure quite distinct from that of other marketed GLP-1 RAs. The agent has less gastrointestinal side effects than other comparable GLP-1 RAs and is safe in patients with renal failure. As a sole treatment for diabetes and used with other hypoglycemic agents, it achieves a lowering of HbA1c of up to 1%, less than several competitor GLP-1 RAs. The benefit on weight reduction is minimal compared to other GLP-1 RAs. There exists concern about an imbalance of pancreatitis cases in the approval program as well as injection site reactions which led to discontinuance of therapy in up to 2% of participants. A large long term study now underway will determine if albiglutide, with its lower level of GI intolerance, has a place in the treatment of patients with increased risk of cardiovascular events.     

The importance of postprandial glycemic control: optimizing add-on therapy to basal insulin

Diabetes, mainly type 2 diabetes mellitus (T2DM), is associated with a growing clinical and economic burden in the United States, which is expected to increase in association with an aging population. Sufficient glycemic control in patients with T2DM, in order to reduce the risk of micro- and macrovascular complications associated with diabetes, is mediated by lifestyle modifications and a regimen of increasingly intensive antidiabetes drugs. Several treatments and strategies are available for primary care physicians to select from when choosing the most appropriate therapy for their individual patients with T2DM, but, ultimately, due to the progressive nature of the disease, most of these patients will require insulin therapy to maintain glycemic control. Regimens containing basal and postprandial insulins are widely used, but there is still widespread reluctance to initiate insulin treatment due to fear of weight gain and hypoglycemia. Furthermore, as patients approach recommended glycated hemoglobin targets, postprandial hyperglycemia becomes the main contributor to hyperglycemic exposure, necessitating the timely initiation of prandial treatment. Finally, insulin treatment can be limited by factors like the number of injections, mealtime restrictions, complex titration algorithms and patient adherence. Recent developments in antidiabetes drug research have brought more convenient basal and postprandial regimens closer. Clinical evaluation of the efficacy and safety of basal insulins plus add-on glucagon-like peptide-1 receptor agonists (GLP-1 RAs) has yielded promising results. Primary care physicians are continually challenged to optimize insulin treatment strategies to maximize patient outcomes. Emerging strategies such as long-acting basal insulin analogs and short-acting GLP-1 RAs are particularly appealing to address this challenge.     

Rationale for treatment options for mealtime glucose control in patients with type 2 diabetes

While glycemic control is routinely assessed using HbA1c and fasting glucose measures, postprandial glucose (PPG) is also an important contributor of overall glycemia. Furthermore, PPG excursions have been linked to complications of diabetes. This review examines the effects of glucose-lowering therapies (including treatments administered at mealtime) on postprandial hyperglycemia in patients with type 2 diabetes. A PubMed search was conducted to identify clinical studies of treatments for mealtime glucose control in type 2 diabetes. Different treatments may have comparable effects on HbA1c but varying effects on PPG control and glucose fluctuations. Older classes of oral glucose-lowering treatments administered at mealtime to lower PPG include meglitinides and α-glucosidase inhibitors. Injectable therapies, including prandial insulin analogs, glucagon-like peptide-1 receptor agonists (GLP-1RAs), and the amylin analog pramlintide, all effectively target postprandial hyperglycemia. Compared with longer-acting GLP-1RAs, short-acting GLP-1RAs, such as exenatide twice daily and lixisenatide once daily, have a greater effect on PPG control, which is primarily mediated by a more pronounced effect on delayed gastric emptying. Dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter 2 inhibitors also reduce postprandial hyperglycemia. To achieve more physiologically normal glycemic control, choice of therapy should ideally aim to address daily glucose fluctuations, including hyperglycemic peaks and hypoglycemic troughs, and long-term glycemic control.     

全面评估，合理决策:基于胰高血糖素样肽1受体激动剂用药风险的最新发现

胰高血糖素样肽1受体激动剂(glucagon-like peptide-1 receptor agonists, GLP-1RAs)作为一种新型降糖药物,被广泛应用于2型糖尿病的治疗。GLP-1RAs能够有效降低血糖且低血糖风险小,此外,GLP-1RAs减重效果显著,兼具一定的心血管及肾脏保护作用; 轻中度胃肠道症状是GLP-1RAs最常见的不良反应,一般随时间延长可逐渐减轻。最新研究显示,GLP-1RAs的使用与胆囊或胆道疾病发生风险相关,尤其在高剂量、长时间使用以及用于减重治疗时,风险显著增加,但胆囊或胆道疾病的绝对风险不高。临床医生需全面权衡GLP-1RAs使用的获益与风险,并与患者共同作出合理决策。     

Differentiating among incretin therapies: a multiple-target approach to type 2 diabetes

What is known and Objective: Incretin-based glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitor therapies provide glycaemic control with reduced risks associated with weight gain or hypoglycaemia. Incretin therapies are compared with their mechanisms of action, effects on haemoglobin A(1C) (HbA(1C) ), fasting plasma glucose (FPG), post-prandial glucose (PPG), body weight, β-cell function, cardiovascular biomarkers and in their safety profiles to aid clinicians in the selection of individualized pharmacotherapy for patients with type 2 diabetes. Methods: Relevant articles for a systematic review were identified through PubMed. Randomized, head-to-head comparison studies among incretin therapies were identified and included in the review. Additionally, randomized, controlled monotherapy and combination therapy studies examining glycaemic and extraglycaemic effects of individual incretin therapies from 2007 to 2011 were reviewed. Results and Discussion: Glucagon-like peptide-1 receptor agonists are generally preferred over DPP-4 inhibitors because of their greater effectiveness in reducing HbA(1C) , FPG and PPG excursions, and greater weight loss potentiation. As a monotherapy option, longer-acting GLP-1 RAs, including liraglutide and exenatide once-weekly, may be preferred at higher HbA(1C) because of their more pronounced effects on FPG. At lower/near normal HbA(1C) , a short-acting GLP-1 RA, such as exenatide twice-daily, may be a better choice as its effects are more pronounced with PPG. Ideal patients or patient situations for DPP-4 inhibitors include patients who need minimal reduction in HbA(1C,) elderly patients, patients who are unwilling or unable to take an injectable agent, when GLP-1 RAs are contraindicated or when the patient will not benefit from weight loss. Treatment benefits common to all incretin-based therapies include minimal hypoglycaemia risk, potential preservation of β-cell function and effective targeting of multiple organs underlying type 2 diabetes and of comorbidities commonly associated with type 2 diabetes, such as obesity and hypertension. What is new and Conclusion: Key differences in mechanisms of action and in glycaemic and extra-glycaemic treatment outcomes exist among incretin therapies, both within the GLP-1 RA class, and between GLP-1 RAs and DPP-4 inhibitors. Clinical judgment acknowledging important differences among incretin therapies and treatment-related patient characteristics will aid in the selection of the appropriate incretin agent for individualized pharmacotherapy.     

Application of 2021 American Diabetes Association Glycemic Treatment Clinical Practice Recommendations in Primary Care

OBJECTIVEWe aimed to identify the proportion of primary care patients meeting criteria for sodium–glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP-1 RAs) for cardiorenal comorbidities per 2021 American Diabetes Association (ADA) Standards of Care recommendations using readily available electronic health record (EHR) characteristics.RESEARCH DESIGN AND METHODSWe applied 2021 ADA recommendations to a primary care cohort of 13,350 adults with type 2 diabetes (T2D).RESULTSWe found that 33% of patients with diabetes would be eligible for an SGLT2i or GLP-1 RA based on cardiorenal comorbidities, 13% of patients met criteria for an SGLT2i based on heart failure or albuminuric chronic kidney disease (CKD), and 18% of patients met criteria for either agent based on atherosclerotic cardiovascular disease or CKD with an albumin-to-creatinine ratio of ≤300 mg/g.CONCLUSIONSThis EHR algorithm identified one-third of primary care patients with T2D as meeting criteria for SGLT2i and GLP-1 RA based on strict comorbidity definitions according to 2021 ADA recommendations.     

Liraglutide for type 2 diabetes mellitus

Introduction: Prevalence of type 2 diabetes mellitus (T2DM) is increasing. Management of this condition and minimizing the cardiovascular risks associated with it poses a significant burden on healthcare resources across the world. Currently available therapeutic agents are effective in glycemic management; however, the majority of these are associated with undesirable effects such as hypoglycemia and weight gain. Incretin-based therapies have been introduced over the last few years and are associated with less risk of hypoglycemia and weight gain.

Areas covered: This review includes current challenges in the management of T2DM, and an overview of glucagon-like peptide-1 (GLP-1)-based therapies, in particular the results of Phase III clinical studies of recently approved liraglutide. Apart from glycemic control, multifactorial interventions are needed to minimize the cardiovascular risks associated with T2DM. Liraglutide is effective in improving glycemic control measured by HbA1c and it is also shown to improve weight. Recently, the National Institute of Health and Clinical Excellence in the UK has approved liraglutide 1.2 mg dose in dual and triple therapy for T2DM.

Expert opinion: Liraglutide, a once-daily GLP-1 analog, has a definite role in selected patients with T2DM and the long-term cardiovascular safety is currently being ascertained in ongoing trials.     

Complementing Insulin Therapy to Achieve Glycemic Control

Introduction

Most patients with type 2 diabetes mellitus (T2DM) will need incrementally more complex therapeutic regimens to control hyperglycemia as the disease progresses. Insulin is very effective in reducing hyperglycemia and may improve β-cell function in patients with T2DM. However, insulin therapy is associated with weight gain and increased risk of hypoglycemia. Adding other antidiabetes medications to insulin can improve glycemic control and potentially lower the required insulin dose, resulting in less weight gain and lower risk for hypoglycemia. This article summarizes the advantages and disadvantages of different classes of commonly used antidiabetes agents, with emphasis on newer classes, for use as add-on therapy to insulin in patients with T2DM inadequately controlled on insulin therapy.

Methods

A PubMed search from July 1, 2003 to April 15, 2013 for peer-reviewed clinical and review articles relevant to insulin combination or add-on therapy in T2DM was conducted. Search terms included “insulin combination therapy,” “add-on therapy diabetes,” “dipeptidyl peptidase-4 (DPP-4) inhibitors,” “glucagon-like peptide-1 (GLP-1) receptor agonist,” “sodium-glucose cotransporter 2 (SGLT2) inhibitors”, “insulin metformin,” “insulin sulfonylurea,” and “insulin thiazolidinedione.” Bibliographies from retrieved articles were also searched for relevant articles. Study design, clinical relevance, and effect on insulin combination therapy were analyzed.

Results

Therapies used as add-on to insulin include agents associated with weight gain (thiazolidinediones and sulfonylureas) and/or hypoglycemia (sulfonylureas), which, therefore, may exacerbate risks already present with insulin. GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when added to insulin and have a low propensity for hypoglycemia and cause no change (DPP-4 inhibitors) or a reduction (GLP-1 receptor agonists, SGLT2 inhibitors) in body weight.

Conclusion

GLP-1 receptor agonists, DPP-4 inhibitors, and SGLT2 inhibitors improve glycemic control when combined with insulin. They also have low propensity for weight gain and hypoglycemia and so may be preferred treatment options for insulin combination when compared with traditional therapies.