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Recent Advances in the Management of Diabetes
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Diabetes mellitus is a chronic disease that poses a significant burden to patients. According to the CDC, an estimated 30.3 million people in the United States received a diagnosis of diabetes in 2015.1 Although the majority of patients affected by diabetes receive a proper diagnosis, 23.8% of affected adults remain undiagnosed.1 Along with the estimated 84.1 million adults with prediabetes who are at an increased risk for diabetes and cardiovascular disease, the prevalence of diabetes and associated health issues may continue to rise.1,2
The treatment spectrum for the management of diabetes has rapidly advanced in recent years, with new approvals, expanded indications, and technological innovations helping to shape new approaches to care.
GUIDELINE-DIRECTED THERAPEUTIC MANAGEMENT
In addition to lifestyle modifications, the American Diabetes Association recommends the initiation of drug therapy based on glycated hemoglobin (A1C).2 Typically, initiation of monotherapy with metformin is considered upon diagnosis of type 2 diabetes (T2D) with an A1C of less than 9%, unless contraindications are present.2 If A1C is 9% or greater, dual therapy should be considered. Drug selection should be individualized for each patient based on patient preference and drug characteristics to optimize reduction in blood glucose levels and minimize risk of adverse events.2 Drug classes that may be considered for combination therapy include sodium-glucose cotransporter 2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, dipeptidyl-peptidase-4 (DPP-4) inhibitors, thiazoli- dinediones, sulfonylureas, and insulins.
Combination therapy with injectables should be reserved for patients with an A1C of 10% or greater, blood glucose level of 300 mg/dL or greater, an uncontrolled A1C.2
ADDITIONAL CARDIOVASCULAR INDICATIONS
Despite the current availability of multiple treatment options, guideline-recommended lifestyle modifications, and pharmacologic interventions, diabetes was the seventh-leading cause of death in the United States in 2015.3 In patients with diabetes, atherosclerotic cardiovascular disease (ASCVD) is the leading cause of morbidity and mortality.2 Moreover, ASCVD is the greatest contributor to the direct and indirect costs associated with diabetes, which were estimated at $245 billion in 2012.2,3 For patients with T2D and ASCVD, treatment with a second agent that has evidence of cardiovascular risk reduction is recommended.2
Two medications on the market for T2D have recently received approval for additional indications for reducing the risk of cardiovascular death. Empagliflozin (Jardiance), an SGLT2 inhibitor, was originally approved in 2014 as an adjunct to diet and exercise to improve glycemic control in adults with T2D mellitus. Treatment with empagliflozin has been shown to lower the risk of death from cardiovascular cause, or any cause, and hospitalization for heart failure. Based on results from the EMPAREG OUTCOME study, the FDA approved an additional indication for empagliflozin (Jardiance) in 2016 to reduce the risk of cardiovascular death in adult patients with T2D mellitus and established cardiovascular disease.4-6
Liraglutide (Victoza), a GLP-1 receptor agonist, first received approval in 2010 as an adjunct to diet and exercise to improve glycemic control in adults with T2D mellitus. After demonstrating significant reductions in cardiovascular death in the LEADER study, liraglutide was approved in 2017 for an additional indication to reduce the risk of major adverse cardiovascular events in adults with T2D mellitus and established cardiovascular disease.6-8
Other medications in these classes are also under investigation for their effect on cardiovascular outcomes. Canagliflozin (Invokana), an SGLT2 inhibitor, is seeking an indication to reduce the risk of death from cardio- vascular disease, as well as an indication for diabetic nephropathy.9
RECENTLY APPROVED TREATMENT OPTIONS
The treatment spectrum for T2D expanded significantly in 2017 with the approval of 3 new agents. The combination dapagliflozin and saxagliptin (Qtern), an SGLT2 and DPP-4 inhibitor approved in February 2017, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with T2D mellitus who have inadequate control with dapagliflozin or who are already treated with dapagliflozin and saxagliptin. The dapagliflozin and saxagliptin combination therapy is contraindicated in patients with severe renal impairment, end-stage renal disease, or who are on dialysis.10
Semaglutide (Ozempic) a once-weekly subcutaneous injection, gained approval in December 2017 as an adjunct to diet and exercise to improve glycemic control in adults with T2D mellitus.11 Similar to most GLP-1 analogues, semaglutide carries a boxed warning for the risk of thyroid C-cell tumors.11 Therefore, semaglutide is not recommended as first-line therapy. Alternative treatment options should also be considered for patients with a history of pancreatitis because of the insufficient number of studies performed in this population.11
Ertugliflozin (Steglatro), an SGLT2 inhibitor, was also approved in December 2017 as an adjunct to diet and exercise to improve glycemic control in adults with T2D mellitus. Ertugliflozin is contraindicated in patients with severe renal impairment, end-stage renal disease, or who are on dialysis.12 In a phase 3 clinical trial, ertugliflozin demonstrated improvements in glycemic control and reductions in body weight.13
In addition to recent approvals, the emergence of biosimilars has changed the landscape of insulin therapy for patients with diabetes. In December 2015, insulin glargine (Basaglar) was the first biosimilar insulin to be approved by the FDA.14 Fiasp, a rapid-acting insulin aspart injection approved in September 2017, is now currently available as a multiple-dose vial and a convenient prefilled pen.15 As a fast-acting mealtime insulin, Fiasp® allows flexible scheduling and gives the patient the option to administer subcutaneously at the beginning of a meal or within 20 minutes of starting a meal.15 See the table for a list of new FDA approvals and indications since 2010.4,6,7,10-12
MEDICATIONS IN THE PIPELINE FOR T2D
Despite the variety of available treatment options, many patients with diabetes fail to achieve glycemic control. Several agents currently in phase 3 trials may eventually provide additional treatment options for patients with diabetes.
A long-acting GLP-1 agonist, efpeglenatide, is currently being investigated in a phase 3 study in patients with T2D mellitus inadequately controlled with diet and exercise. Efpeglenatide is also being evaluated for potential effects on cardiovascular outcomes.16,17
Insulin lispro (Admelog), approved in September 2017, was the first follow-on biologic for insulin lispro.18 Currently, phase 3 clinical trials evaluating two rapid-acting biosimilars of insulin lispro are in progress. In the first trial, comparisons of SAR341402 with other rapid-acting insulins are ongoing in patients with type 1 diabetes (T1D) and T2D who are also treated with a basal insulin.19 In the second trial, LY900014, an ultra rapid formulation of insulin lispro, is currently in recruitment.20
Currently, all approved GLP-1 receptor agonists are available only as a subcutaneous injection in order to evade the proteolytic degradation of protein-based drugs in the gastrointestinal tract. Semaglutide is the first once-daily oral GLP-1 receptor agonist to demonstrate promising results in reduction of hemoglobin A1C and body weight in patients with T2D.21
ADVANCES IN TECHNOLOGY
Technological innovations play an important role in diabetes management. For instance, advances in continuous glucose monitoring (CGM) now allow systems to record glucose readings throughout the day and detect trends in glucose levels. Additionally, new features enable better glycemic control and prevent severe hypoglycemic and hyperglycemic episodes.
In 2016, the FDA approved the MiniMed 670G, the first hybrid closed-loop CGM system. The MiniMed 670G mimics the role of the pancreas with the ability to automatically adjust basal insulin based on glucose readings. Other features of the MiniMed 670G include the ability to calculate mealtime insulin requirements based on intended carb consumption and to suspend insulin administration 30 minutes prior to reaching preset low limits. The MiniMed 630G, also approved in 2016, is a closed loop system with similar features designed to aid in glycemic control.22
FreeStyle Libre Flash glucose monitoring system, approved in September 2017, was the first CGM system not requiring fingerstick calibration to reach the market. In patients with T1D, clinical trials of the Libre Flash demonstrated a reduction in time spent in hypoglycemia.23
In March 2018, the FDA approved the Guardian Connect system as the first standalone CGM that is specifically intended for patients who use multiple daily injections. By connecting to a smartphone via Bluetooth, the Guardian Connect does not require a separate receiver commonly used with other CGM systems.24
CONCLUSIONS
Many therapeutic and technological advances have affected and continue to shape diabetes management. The availability of new treatment options enables individualized patient care with consideration of patient preference, cost, disease state, and medication profile. Moreover, improvements in technology have demonstrated increased glycemic control in patients with diabetes. Successful integration of lifestyle modifications, pharmacologic treatment, and technology can contribute significantly to improvements in diabetes management and patient outcomes.
REFERENCES
1. CDC. National diabetes statistics report, 2017. cdc.gov/diabetes/pdfs/data/sta- tistics/national-diabetes-statistics-report.pdf. Published 2017. Updated February 24, 2018. Accessed June 18, 2018.
2. American Diabetes Association. Standards of medical care in diabetes - 2018.Diabetes Care. 2018;41(suppl 1):S1-S159.
3. CDC. About Underlying Cause of Death 1999-2016. CDC WONDER Database. wonder.cdc.gov/ucd-icd10.html. Updated December 2017. Accessed June 15, 2018.
4. Jardiance [prescribing information]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2017. www.docs.boehringer-ingelheim.com/Prescribing%20 Information/PIs/Jardiance/jardiance.pdf. Accessed June 15, 2018.
5. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in type 2 diabetes.N Engl J Med. 2015;373(22):2117-2128. doi:10.1056/NEJMoa1504720.
6. Drugs@FDA: FDA approved drug products. FDA website. www.accessdata. fda.gov/scripts/cder/daf/index.cfm. Accessed June 18, 2018.
7. Victoza [package insert]. Plainsboro, NJ: Novo Nordisk; 2017. www. novo-pi.com/victoza.pdf. Accessed June 15, 2018.
8. Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and Cardiovascular Outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311-322. doi: 10.1056/ NEJMoa1603827.
9. Invokana [package insert]. Titusville, NJ: Janssen Pharmaceuticals, Inc; 2017. http://www.janssenlabels.com/package-insert/product-monograph/prescribing-in- formation/INVOKANA-pi.pdf. Accessed June 15, 2018.
10. Qtern [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2017. http://www.azpicentral.com/qtern/qtern.pdf. Accessed June 15, 2018.
11. Ozempic [package insert]. Plainsboro, NJ: Novo Nordisk; 2017. www.novo-pi.com/ozempic.pdf. Accessed June 15, 2018.
12. Steglatro [package insert]. Whitehouse Station, NJ: Meck & Co., Inc; 2017. http://www.merck.com/product/usa/pi_circulars/s/steglatro/steglatro_pi.pdf. Accessed June 15, 2018.
13. Terra SG, Focht K, Davies M, et al. Phase III, efficacy and safety study of ertugliflozin monotherapy in people with type 2 diabetes mellitus inadequately controlled with diet and exercise alone. Diabetes Obes Metab. 2017;19(5):721- 728. doi: 10.1111/dom.12888.
14. Basaglar [package insert]. Indianapolis,IN: Lilly USA, LLC; 2017. http://uspl. lilly.com/basaglar/basaglar.html#pi. Accessed June 15, 2018.
15. Fiasp [package insert]. Plainsboro, NJ: Novo Nordisk; 2017. www.novo-pi.com/fiasp.pdf. Accessed June 15, 2018.
16. Efficacy and safety of efpeglenatide versus placebo in patients with type 2 diabetes mellitus inadequately controlled with diet and exercise. clinicaltrials.gov/ ct2/show/NCT03353350. Updated June 1, 2018. Accessed June 18, 2018.
17. Effect of efpeglenatide on cardiovascular outcomes in high cardiovascular risk in type 2 diabetes patients. clinicaltrials.gov/ct2/show/NCT03496298. Updated June 18, 2018. Accessed June 18, 2018.
18. Admelog [package insert]. Bridgewater, NJ: Sanofi-Aventis; 2017.
