New Pharmacologic Agents for Diabetes Treatment

Abstract

Therapeutic options for diabetes management have expanded dramatically in the last five years. While there continues to be consensus that lifestyle modification aimed at 5–7% weight loss and metformin are the appropriate first line therapies for type 2 diabetes, there are many options for intensification of diabetes management. The American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) have released recent guidelines that prioritize use of the newer classes of medications.^1,2 There are a number of considerations in selecting medications, including risk of hypoglycemia, effect on body weight, adverse event profile, renal function, and cost/insurance coverage. The objective of this article is to discuss mechanism, efficacy, and safety for each new class of medications. We conclude with a quick reference for the use of these medications in primary and specialty care, based on their various attributes and patient and provider preferences.

New Oral Medications and Non-Insulin Injectables

SGLT2 Inhibitors

Mechanism

The sodium-glucose co-transporter 2 (SGLT2) is expressed in the proximal tubule of the kidney and is responsible for 90% of renal glucose reabsorption. Inhibitors of SGLT2 promote urinary excretion of glucose and lower elevated blood glucose levels. SGLT2 inhibitors rarely cause hypoglycemia since their effect is not mediated through beta cell function or increased insulin sensitivity. In addition, SGLT2 inhibitors are reported to decrease blood pressure and weight. ^3,4

Efficacy

SGLT2 inhibitors were first approved by the U.S. Food and Drug Administration (FDA) in 2013 (canaglifozin followed by dapagliflozin and empagliflozin) for patients with type 2 diabetes.

SGLT2 inhibitors compared to placebo have a modest effect on HbA1c ranging from 0.5 to 0.7% reductions.^{3, 4}

Empagliflozin recently demonstrated a significant 38% relative risk reduction (RRR) in death from cardiovascular causes (3.7% for treatment vs. 5.9% for placebo), and a 35% RRR in hospitalization for heart failure (2.7% and 4.1%, respectively) in addition to a 32% RRR of death from any cause (5.7% and 8.3%, respectively). No difference was seen in non-fatal MI and non-fatal stroke.⁵ These benefits were significant despite a minimal difference in glycemic control between treatment groups. Ongoing outcome trials are underway to determine if these findings represent a class effect. The Canagliflozin cardiovascular assessment study, CANVAS, completed recruitment in March 2011 and is expected to report in 2017.⁶ This study is being reviewed due to a possible increase in amputations, mostly of the toe. DECLARE-TIMI58 is a multicenter randomized double blind, placebo controlled trial that will evaluate the effect of dapagliflozin on the incidence of cardiovascular death, myocardial infarction and ischemic strokes in patients with type 2 diabetes. It is also expected to address safety related questions and will report in 2019. ⁷

In addition to the reported cardiovascular benefit, SGLT2 inhibitors decrease weight. Trials with dapagliflozin, canagliflozin and empagliflozin reported a sustained 2 to 3 kg weight loss over 24–52 weeks.^{3, 4}

Safety

In December 2015, the FDA issued a warning about SGLT2 inhibitors and ketoacidosis based on 73 cases of ketoacidosis and euglycemic ketoacidosis in patients with type 1 or type 2 diabetes treated with SGLT2 inhibitors between March 2013 to May 2015.⁸ Serum ketones should be obtained in any patient with nausea, vomiting, or malaise while taking SGLT2 inhibitors, and SGLT2 inhibitors should be discontinued if acidosis is confirmed.⁹ These agents have also been associated with genital mycotic infections and urinary tract infections. Vulvovaginal candidiasis was reported in 10 to 15 % of women taking SGLT2 inhibitors.¹⁰ In addition, 19 cases of life-threatening urosepsis and pyelonephritis were reported from March 2013 through October 2014.⁸

Given that these drugs work by inducing an osmotic diuresis, there is concern for dehydration and acute kidney injury. A basic metabolic panel, lipid panel, and blood pressure should be checked at baseline and periodically thereafter. Dosing and adjustments with renal and hepatic impairment are presented in Table 1.

Table 1.

Summary of new oral agents and non-insulin injectables

Drug Class	Drug Name	Recommended Dose	Renal/Hepatic Adjustment	Benefits	Adverse Effects
SGLT2 inhibitors	Canagliflozin	100 – 300 mg PO once daily	Do not exceed 100 mg in moderate renal impairment. Do not use with eGFR < 45 ml/min (100mg) or < 60 ml/min (300 mg) No adjustment for hepatic impairment	No hypoglycemia Weight loss ↓ Blood pressure ↓ CVD events (Empagliflozin)	Genitourinary infections Hypotension Euglycemic DKA
	Dapagliflozin	5–10 mg PO once daily	Do not use with eGFR < 60 ml/min No adjustment for hepatic impairment
	Empagliflozin	10–25 mg PO once daily	Do not use with eGFR < 45 ml/min No adjustment for hepatic impairment
GLP-1 agonists	Exenatide	5–10 mcg SC twice daily	Do not use with eGFR < 30 ml/min or end stage renal disease.	No hypoglycemia Weight loss	Acute pancreatitis? Caution with gastroparesis Nausea/vomiting, diarrhea Thyroid C-cell tumor risk in rodents (contraindicated in patients with medullary thyroid carcinoma or MEN2 for all except twice daily exenatide)
	Liraglutide	0.6–1.8 mg SC once daily	No renal or hepatic adjustment but use with caution
	Exenatide ER	2 mg SC once weekly	Caution: eGFR 30–50 ml/min Avoid use: eGFR < 30ml/min
	Albiglutide	30–50 mg SC once weekly	No renal or hepatic adjustment but use with caution
	Dulaglutide	0.75–1.5 mg SC once weekly	No renal or hepatic adjustment but use with caution
DPP-4 Inhibitors	Sitagliptin	25mg–100mg PO daily	Use 50 mg eGFR 30–49 ml/min Use 25 mg eGFR < 30 ml /min Dose not defined in Child-Pugh class C.	No hypoglycemia No weight gain	Possible increase in heart failure hospitalizations (saxagliptin, alogliptin) Slight increase in nasopharyngitis Joint pain
	Saxagliptin	2.5–5 mg PO daily	Use 2.5 mg eGFR ≤50 ml/min Hemodialysis: give dose after HD. Not defined dose in peritoneal dialysis. No hepatic adjustment
	Linagliptin	5 mg PO daily	No renal or hepatic adjustment
	Alogliptin	6.25–25mg PO daily	12.5mg eGFR 30–59 ml/min 6.25mg eGFR < 30ml/min Child-Pugh Class C: not defined; post- marketing reports of hepatic failure
Dopamine receptor Agonist	Bromocriptine quick release	0.8–4.8 mg PO daily	No renal or hepatic adjustment but use with caution	Oral administration Well tolerated	Nausea/vomiting, headache, syncope, hypotension

Glucagon-Like Peptide-1 (GLP-1)

Receptor Agonists

Mechanism

GLP-1 is an endogenous incretin peptide that is released from intestinal L cells in response to meals. GLP-1 is rapidly inactivated by the enzyme dipeptidyl-peptidase-4 (DPP-4) and cleared by the kidneys. GLP-1 stimulates post meal pancreatic insulin synthesis and insulin secretion in a glucose dependent manner. It also slows gastric emptying,¹¹ inhibits glucagon release and promotes satiety. GLP-1 receptor agonists are structurally similar to GLP-1 but resist DDP-4 degradation. There are three formulations of these agents that are available as once weekly preparations (exenatide extended release, dulaglutide, albiglutide) and two immediate release preparations (exenatide, liraglutide).

Efficacy

Exenatide was the first GLP-1 receptor agonist to be approved by the FDA and has been available since 2005. GLP-1 receptor agonists reduce HbA1c by around 1% ¹² and usually do not cause hypoglycemia in the absence of other therapies that cause hypoglycemia. GLP-1 receptor agonists can also improve satiety and result in weight loss.¹³ A systematic review of 17 randomized trials comparing GLP-1 receptor agonists with placebo or insulin glargine, DPP-4 inhibitors, thiazolidinedione or a sulfonylurea demonstrated a 1.5 to 2.5 kg weight loss over 30 weeks with the former. ¹² Another systematic review and meta-analysis of 25 trials demonstrated a mean weight loss of 2.8 kg (95% CI −3.4 to −2.3 kg) in patients with diabetes.¹³

In diabetes trials, liraglutide (0.6–1.8 mg daily) was associated with a significant 1.8 to 2.8 kg weight reduction compared to placebo.¹⁴ Conflicting results are reported for weight loss with immediate and extended release exenatide.^15,16,17 Other head-to-head trials with GLP-1 receptor agonists revealed significantly greater reductions in weight with liraglutide than the once-weekly exenatide (0.9 kg difference), albiglutide (1.6 kg difference) or dulaglutide (0.7 kg difference).^18,19,20 Liraglutide 3.0 mg per day was approved for weight management in December 2014.²¹

Safety

Side effects of GLP-1 receptor agonists include nausea, vomiting, and diarrhea.¹² Nausea improves with duration of therapy and dose titration. There is insufficient data to confirm an increased risk of pancreatitis with GLP-1 receptor agonists, but it is prudent not to initiate GLP-1 receptor agonists in patients with history of pancreatitis and to discontinue therapy in patients who develop acute pancreatitis.²² This class of medications also includes a black box warning regarding C-cell tumors of the thyroid because this complication was seen in rodents, but has not been confirmed in human studies. However, these medications should not be used in those with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 (MEN2).

Dose titration for these medications is described below and summarized in Table 1.

Short Acting Preparations

Short acting exenatide is packaged in prefilled syringes of either 5 or 10 mcg doses administered subcutaneously (SC) twice daily within one hour before meals. Liraglutide’s initial dose is 0.6 mg once daily for one week then 1.2 mg once daily for one week. If blood glucoses remain above target, the dose can be increased to 1.8 mg once daily.

Once Weekly Preparations

Exenatide extended release is dosed at 2 mg SC once weekly, at any time of day and with or without meals. Albiglutide’s initial dose is 30 mg once weekly, which can be increased to 50 mg once weekly after six to 8 weeks if glycemic control remains suboptimal. Dulaglutide’s initial dose is 0.75 mg once weekly that can be increased to 1.5 mg after six to eight weeks if blood glucose remains above goal. Exenatide extended release and albiglutide require additional preparation before administration. There is no defined laboratory monitoring recommended.

DPP-4 Inhibitors

Mechanism

DPP-4 inhibitors block the DPP-4 enzyme that deactivates multiple incretin peptides including glucose-dependent insulinotropic polypeptide (GIP) and GLP-1. DPP-4 inhibitors thus increase GLP-1 and reduce blood glucose by inhibiting glucagon release and stimulating insulin secretion.

Efficacy

Sitagliptin was first approved in 2006 followed by linagliptin, saxagliptin and alogliptin.

DPP-4 inhibitors reduce HbA1c ~0.5–1%.^23,24 DPP-4 inhibitor monotherapy is well tolerated with no reported effects on body weight or hypoglycemia. These agents are useful in patients with reduced renal function and mild diabetes, a group particularly susceptible to hypoglycemia with other therapies. Dosing and monitoring is reviewed in Table 1.

Safety

These drugs should be avoided in patients with pancreatitis. ^25,22 DPP-4 enzyme substrates are ubiquitous, and include mediators of immune function, but adverse effects on immunity were not apparent in short-term clinical trials.²⁴ A meta-analysis of 18 trials demonstrated no overall increase in infection risk compared with placebo (RR 0.98 95% CI 0.93, 1.05). ²⁶

A number of trials evaluated the cardiovascular effects of DPP-4 inhibitors, demonstrating no increased risk of adverse cardiovascular events.²⁷ In 2013, a saxaglitpin cardiovascular outcome randomized controlled trial with a median follow up of two years did not detect an increase or decrease in the rate of ischemic events. There was an increase in the rate of hospitalization for heart failure (3.5% versus 2.8%, hazard ratio 1.27, 95% CI, 1.07 to 1.51; P=0.007), and the FDA has issued a warning.²⁸ A more recent FDA warning issued April 2016 included saxagliptin and alogliptin with recommendation to discontinue these medications in patients who develop heart failure. Results from the multicenter, randomized, double-blind, placebo-controlled EXAMINE trial, cited by the FDA, found that more patients randomized to the alogliptin group (106/2701, 3.9%) experienced at least one hospitalization for heart failure compared to patients randomized to placebo (89/2679, 3.3%).²⁹ Another analysis of EXAMINE data in 2015 revealed no increase in hospitalization for heart failure as a first event in the alogliptin group compared with placebo (85/2701 or 3·1% v. 79/2679 or 2·9% taking placebo with a hazard ratio of 1.07, 95% CI 0·79–1·46).³⁰ The clinical significance of this finding and whether it extends to other DDP-4 inhibitors remains unclear.

Bromocriptine

Bromocriptine is a dopamine agonist used for hyperprolactinemia and treatment of Parkinson’s disease. A quick release formulation of bromocriptine is approved for treatment of type 2 diabetes, but the mechanism of action is unclear. Bromocriptine is well tolerated in patients with type 2 diabetes. Common side effects include nausea, vomiting, dizziness and headaches.³¹ Bromocriptine has a small effect on glycemic control with a 0.4 to 0.5 % point reduction in HbA1c.³² Dosing is reviewed in Table 1.

New Insulin Preparations

A rapid acting inhaled insulin and a new ultra-long acting basal insulin are now available. Some insulins are now available in pens in concentrated formulations, allowing the injection of high doses of insulin in smaller volumes to improve absorption. Because of the risk of hypoglycemia, concentrated insulin should be used with extreme caution and preferably in consultation with a diabetes specialist.

Inhaled Technosphere Insulin

In 2014, the FDA approved an inhaled technosphere insulin preparation. Technosphere insulin (TI) is a rapid acting inhaled insulin that provides mealtime coverage, representing an alternative to bolus insulin injections. It is approved for use in both type 1 and type 2 diabetics and used with injected basal insulin.

The peak action is estimated to be 15 minutes, faster than currently available SC rapid acting insulin. For patients requiring mealtime insulin who are averse to injections, this provides a possible alternative; however, there is not a practical method for administering large doses because it comes in cartridges of 4 and 8 units, and is administered via a specialized inhaler.

Major adverse effects include cough and a small reversible decrease in the forced expiratory volume in 1s (FEV1). TI is contraindicated, and carries a black box warning, in patients with chronic lung disease. Treated patients must receive periodic pulmonary function tests. ^33,34 There is little clinical experience converting from SC to inhaled insulin, and dosing is approximate (e.g. patients on 5–8 units of rapid acting SC insulin would receive 8 units inhaled insulin), so close monitoring for hypoglycemia is essential.

Insulin Degludec

Insulin degludec is an ultra-long acting insulin that forms a subcutaneous depot of soluble multihexamers from which insulin is slowly and continuously absorbed into the circulation allowing a stable steady state.³⁵ Insulin degludec has a terminal half-life of more than 25 hours and a duration of action of more than 40 hours.^{36, 37}

This may be a good basal insulin choice for patients at higher risk of nocturnal hypoglycemia. In a treat to target non-inferiority trial, insulin degludec was found to be non-inferior to glargine in HbA1c reduction at one year (0.4% point reduction versus 0.39% point reduction, respectively). Though overall rates of confirmed hypoglycemia were similar between groups, the rate of confirmed nocturnal hypoglycemia was 25% lower with degludec than with glargine (4.41 versus 5.86 episode per patient-year of exposure, p= 0.021).³⁸ In addition, because of its longer duration of action, insulin degludec can be administered daily at any time of the day with variable injection timing without compromising glycemic control or safety.^{39, 40} This characteristic allows for a more flexible schedule that can accommodate individual patient needs. It comes in prefilled pens with two different concentrations: 100 units/mL and 200 units/mL, and the adverse events profile is similar to insulin glargine. The 200 unit/mL pen allows for administration of up to 160 units of insulin in a single injection.

U300 Insulin Glargine

U300 insulin glargine is a basal insulin that is concentrated at 300 units/mL. The prefilled pen contains 450 units and allows for delivery of the same number of insulin units as U100 insulin glargine but in a smaller volume. However, U300 insulin glargine appears to have a smaller glucose-lowering effect per unit of insulin than U100 glargine.

Efficacy is similar in both glargine preparations. There is conflicting data regarding the incidence of hypoglycemia, with one trial reporting a significantly lower incidence in the U300 insulin glargine group.⁴¹

Conversion from once-daily U100 insulin glargine to once-daily U300 insulin glargine can be 1:1. However, a higher daily dosage of U300 insulin glargine will usually be required to achieve the same level of glycemic control as with U100 insulin glargine. When converting from U300 insulin glargine to U100 insulin glargine, a 20% reduction is advised.⁴²

U500 Regular Insulin

New Delivery Mechanism in Pens

The FDA recently approved a pre-filled device containing the highly concentrated formulation of U500 regular insulin (500 units/ml). This insulin is used to more conveniently treat patients requiring more than 200 units of insulin per day, by using smaller volumes to deliver more insulin. It is dosed with meals two to three times per day and covers mealtime and basal insulin needs. Prior to this approval, U500 regular insulin was only available in vials, administered with either a U100 insulin syringe or a tuberculin syringe. The pen formulation increases convenience and safety for the patient, eliminating the need for dose conversion. A pen contains 1500 units of insulin, allowing the delivery of up to 300 units in a single injection. Consultation with a specialist is recommended when prescribing concentrated insulin to avoid dosing errors because inadvertent overdose may result in a serious adverse reaction or life-threatening hypoglycemia. ⁴³

Conclusions

Given the properties of newly available medications for diabetes, there are a number of considerations when choosing an agent for those patients who require therapy in addition to metformin, diet and lifestyle modification to achieve glycemic goals. Table 2 highlights agents that may be considered for certain clinical priorities. For further detail, both ADA and AACE guidelines provide detailed algorithms for making these selections.

Table 2.

Quick Reference for choosing agents for glycemic control intensification

Priority	Drugs to Consider
Weight loss	GLP-1 receptor agonists (Liraglutide>others) SGLT-2 inhibitors
Avoiding weight gain	DPP-IV inhibitors
Avoiding injections	DPP-IV inhibitors SGLT-2 inhibitors Bromocriptine quick release Inhaled insulin
Avoiding hypoglycemia	GLP-1 analogues DPP-IV inhibitors SGLT-2 inhibitors
Avoiding renal adjustment	Linagliptin
CVD risk reduction	Empagliflozin
Maximizing insulin absorption in individuals with high total daily dose	Concentrated insulins (U200, U300, U500)
Minimize cost	This will depend upon insurer formulary Most (including MO Medicaid) cover at least one GLP-1 receptor agonist and DPP-IV inhibitor; SGLT-2 inhibitors covered with additional authorization on MO Medicaid

Biography

Sarah Bou Malham, MD, (left), is a Clinical Fellow, and Cynthia J. Herrick, MD, (right), is an Assistant Professor, Division of Endocrinology, Metabolism, and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis.

Contact: cherrick@dom.wustl.edu