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New Developments in Diabetes Management: Medications of the 21st Century

  • Vivian A. Fonseca
    Correspondence
    Address correspondence to: Vivian A. Fonseca, MD, Section of Endocrinology, Tulane University Medical Center, 1439 Tulane Avenue, SL 53, New Orleans, LA 70112
    Affiliations
    Section of Endocrinology, Tulane University Medical Center, New Orleans, Louisiana
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      Abstract

      Background

      Suboptimal blood glucose control among patients with type 2 diabetes continues to support the need for new pharmacologic approaches.

      Objective

      The purpose of this commentary was to highlight newly available and soon-to-be available agents that are promising tools for targeting specific pathophysiologic pathways in the management of diabetes.

      Methods

      Published evidence to support the application of novel incretin-based therapies, dipeptidyl peptidase (DPP)-4 inhibitors, sodium-glucose cotransporter (SGLT)-2 inhibitors, other oral agents and insulins for managing specific aspects of type 2 diabetes, as well as disadvantages associated with those novel medications, are discussed.

      Results

      Several new glucagon-like peptide (GLP)-1 receptor agonists with different time frames of action, although each has unique advantages and disadvantages, have been through clinical trials. Examples of these are lixisenatide and albiglutide. Currently available DPP-4 inhibitor agents, important for inhibiting the breakdown of endogenous GLP-1, have not been associated with weight gain or hypoglycemia. SGLT-2 inhibitors, which do not depend on insulin secretion or insulin action, may be advantageous in that they appear to be broadly efficacious at all stages of diabetes. New insulin analogues, such as degludec and U-500, improve glycemic control without contributing to hypoglycemia.

      Conclusions

      Advances in pharmacologic options offer the promise of improving glycemic control for longer periods, with limited glycemic fluctuations, hypoglycemia, and weight gain. However, the effectiveness of these agents ultimately depends on their availability to providers managing the health care of patients at high risk for poor diabetes outcomes and patients’ use of them as directed. Long-term effectiveness and safety trials are ongoing.

      Key words

      Introduction

      Despite considerable advances in the therapy for type 2 diabetes, blood glucose control remains suboptimal.

      Ali MK, Bullard KM, Saaddine JB, et al. Achievement of goals in U.S. diabetes care, 1999–2010. N Engl J Med. 2013;368:1613–1624

      Physicians and others who are struggling to prevent and minimize diabetes complications among their patients continue to face a number of challenges. A significant component of diabetes management lies with the person with diabetes.
      • Rodriguez K.M.
      Intrinsic and extrinsic factors affecting patient engagement in diabetes self-management. Perspectives of a certified diabetes educator.
      Diabetes self-management includes using prescribed medications as recommended by the diabetes clinician; however, medication nonadherence may be caused, in part, by the medications themselves, including weight gain, unpredictable glucose fluctuations in the postprandial period, and plunges in glucose levels causing hypoglycemic events. Although multifactorial in nature,
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      Barriers to diabetes management. Patient and provider factors.
      medication nonadherence may also be caused by comorbidities of diabetes, including cognitive impairment and depression, as well as financial constraints. Providers managing type 2 diabetes are challenged in their efforts to sustain blood glucose at goal for the long term while also reducing or eliminating the residual risk for cardiovascular events,
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      Long-term effects of intensive glucose lowering on cardiovascular outcomes.
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      Glucose control and vascular complications in veterans with type 2 diabetes.
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      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      despite important advances in preventive cardiology. Health care systems contribute to the challenges of mitigating the long-term societal costs of an increasing proportion of the population that is living with diabetes and its complications. Systems struggling to manage increasing volumes of patients with diabetes and their multi-morbidities have inadequately invested in diabetes self-management resources
      • Kirsh S.
      • Hein M.
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      Improving outpatient diabetes care.
      and inadequately adopted next-generation diabetes medications by integrating them into their formularies.
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      • Asch S.M.
      A bitter pill. Formulary variability and the challenge to prescribing physicians.
      Several abnormalities have been identified in the pathophysiology of type 2 diabetes, and at least 8 of them (Table I) are amenable to treatment, serving as pharmacologic targets.
      • Defronzo R.A.
      Banting lecture. From the triumvirate to the ominous octet. A new paradigm for the treatment of type 2 diabetes mellitus.
      The purpose of this review is to highlight some recent therapies that have become available for the treatment of type 2 diabetes or that are expected to become available in the near future, while placing them within the diabetes treatment algorithm, targeting pathophysiology appropriately. The medication classes that are addressed here include glucagon-like peptide (GLP)-1 agents, dipeptidyl peptidase (DPP)-4 inhibitors, sodium-glucose cotransporter (SGLT)-2 inhibitors, insulins, and other agents still under investigation.
      Table IThe Ominous Octet—pathophysiologic abnormalities (and treatment targets) contributing to hyperglycemia in type 2 diabetes.
      • Defronzo R.A.
      Banting lecture. From the triumvirate to the ominous octet. A new paradigm for the treatment of type 2 diabetes mellitus.
      1.Decreased insulin secretion
      2.Decreased glucose uptake in tissues due to insulin resistance
      3.Increased hepatic glucose production
      4.Decreased incretin effect
      5.Increased glucagon secretion (and lack of suppression during hyperglycemia
      6.Increased lipolysis and free fatty acids in circulation
      7.Neurotransmitter dysfunction
      8.Increased glucose reabsorption in the renal tubule

      Incretin-Based Therapies

      In the past 3 decades, several studies have demonstrated that insulin secretion is greater following an oral glucose load compared with intravenously administered glucose.
      • Mudaliar S.
      • Henry R.R.
      The incretin hormones. From scientific discovery to practical therapeutics.
      This incremental increase in insulin secretion from glucose or food is mediated through signals from the gut. This process has been termed the incretin effect. Several incretins have been identified, with GLP-1 most likely the most important. GLP-1 is a natural hormone secreted in the gut that has been used in physiologic studies.
      • Mudaliar S.
      • Henry R.R.
      The incretin hormones. From scientific discovery to practical therapeutics.
      The incretin effect is attenuated in people with diabetes and has been considered an important abnormality that can now be corrected with drug therapy. An infusion of GLP-1 leads to a reduction in glucose with a stimulation of insulin secretion and suppression of plasma glucagon in a glucose-dependent manner, suggesting that insulin secretion is no longer stimulated and that glucagon secretion increases when blood glucose is reduced to the normal range. This process represents an important defense mechanism against hypoglycemia and is an advantage of GLP-1–related therapies in the treatment of diabetes. In contrast, sulfonylureas continue to stimulate insulin secretion even when in the presence of hypoglycemia. This important difference between treatments has been confirmed in several clinical trials.
      • DeFronzo R.A.
      • Ratner R.E.
      • Han J.
      • et al.
      Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes.
      • Drucker D.J.
      • Nauck M.A.
      The incretin system. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.
      GLP-1 has a very short half-life, as a result of the enzyme dipeptidyl peptidase (DPP)-4, a naturally occurring enzyme that is present in most tissues of the body and that naturally breaks down GLP-1.
      • Drucker D.J.
      • Nauck M.A.
      The incretin system. Glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes.
      • Ahren B.
      • Schmitz O.
      GLP-1 receptor agonists and DPP-4 inhibitors in the treatment of type 2 diabetes.
      Due to the short half-life, natural GLP-1 would need to be administered by continuous infusion. Because this is generally impractical, the pharmacologic approach to replace GLP-1 consists of either using an analogue that is resistant to DPP-4, leading to a longer half-life, or administering pharmacologic agents that inhibit the activity of the enzyme DPP-4.
      The first GLP-1 analogue or receptor agonist to become available was exenatide, which is actually an analogue of exendin-4 (with others in development).
      • DeFronzo R.A.
      • Ratner R.E.
      • Han J.
      • et al.
      Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes.
      • Kendall D.M.
      • Riddle M.C.
      • Rosenstock J.
      • et al.
      Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea.
      • Buse J.B.
      • Henry R.R.
      • Han J.
      • et al.
      for the Exenatide-113 Clinical Study Group
      Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes.
      A long-acting version of this compound, consisting of microspheres within a biodegradable polymer, is available for once-weekly dosing. An alternative approach is an analogue of human GLP-1, which has been slightly modified to add on the fatty acid that binds to albumin. The albumin analogue complexes are resistant to DPP-4, and free GLP-1 is gradually released from this complex. Liraglutide (which is effective for 24 hours) is an example of this approach,
      • Zinman B.
      • Schmidt W.E.
      • Moses A.
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      Achieving a clinically relevant composite outcome of an HbA1c of <7% without weight gain or hypoglycaemia in type 2 diabetes. A meta-analysis of the liraglutide clinical trial programme. Diabetes.
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      for the LEAD-6 Study Group
      Liraglutide once a day versus exenatide twice a day for type 2 diabetes. A 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6).
      and others are in development.
      GLP-1 receptor agonists have several clinical effects, listed in Table II. They increase insulin secretion and decrease glucagon production, leading to improved glucose control. In addition, they decrease gastric emptying, which delays food absorption and may have an effect on appetite, leading to weight loss. The GLP-1 agonist is not associated with hypoglycemia and weight loss, suggesting important clinical advantages to using this agent.
      • Zinman B.
      • Schmidt W.E.
      • Moses A.
      • et al.
      Achieving a clinically relevant composite outcome of an HbA1c of <7% without weight gain or hypoglycaemia in type 2 diabetes. A meta-analysis of the liraglutide clinical trial programme. Diabetes.
      Further, data suggest a potential to improve β-cell function over the long term and prevent the decline of natural progression of β-cell loss. On the other hand, they have several disadvantages, including the need for injections that require training, frequent gastrointestinal side effects, and a high cost. Other GLP-1 receptor agonists are in development, both short acting, such as lixisenatide, and long acting, such as albiglutide. Differences between agents are related to their pharmacokinetic properties (short- vs long-acting agents given weekly) or to plasma levels of free drug able to stimulate the receptor, which may determine side effects. For example, once-weekly preparations of exenatide cause less nausea and vomiting than do shorter-acting agents such as exenatide or liraglutide. Understanding such differences may help a clinician to individualize therapy for the patient.
      Table IIPotential clinical effects of GLP-1 receptor agonists.
      Physiologic effects
      • Increased GLP-1 activity
        • Decreased glucagon production
        • Increased insulin synthesis and secretion
      • Glycemic control
        • Decreased A1c
        • Decreased FPG and PPG
      • Weight effects
        • Decreased gastric emptying
        • Decreased caloric intake
        • Weight loss
      Potential clinical advantages
      • Low to no hypoglycemia
      • Weight reduction
      • Potential for improved β-cell mass/function?
      • Potential cardiovascular protective actions?
      Potential clinical disadvantages
      • Gastrointestinal side effects
      • Injectable
      • Training requirements
      • High cost
      A1c = hemoglobin A1c; FPG = fasting plasma glucose; GLP-1 = glucagon-like peptide-1; PPG = postprandial plasma glucose.
      The American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) Position Statement recommends a GLP-1 receptor agonist as an initial drug therapy in patients in whom metformin is contraindicated (eg, in patients with moderate renal impairment) or cannot be tolerated and in whom weight loss is essential.
      • Inzucchi S.E.
      • Bergenstal R.M.
      • Buse J.B.
      • et al.
      for the American Diabetes Association, European Association for the Study of Diabetes
      Management of hyperglycemia in type 2 diabetes. A patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).
      Alternatively, it can be used as second- or third-line therapy in combination with metformin or other agents.
      Table III
      • Meier J.J.
      GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.
      compares short- and long-acting GLP-1 receptor agonists, which may have differences beyond the duration of action that may be clinically relevant. For example, the short-acting agonists have a powerful effect on postprandial hypoglycemia compared with the long-acting ones, mainly through an effect on gastric emptying. This has potential advantages if these drugs are combined with basal insulin.
      Table IIIComparison of short- and long-acting GLP-1 receptor agonists.
      • Meier J.J.
      GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus.
      ParameterShort ActingLong Acting
      CompoundsExenatide, lixisenatideAlbiglutide, dulaglutide, exenatide-LAR, liraglutide
      Half-life2–5 h12 h to several days
      Effects
       FBG reductionModestStrong
       PP hyperglycemia reductionStrongModest
       Fasting insulin secretion stimulationModestStrong
       PP insulin secretionReductionModest stimulation
       Glucagon secretionReductionReduction
       Gastric emptying rateDecelerationNo effect
       Weight reduction, kg1–52–5
       Induction of nausea, %20–50, attenuates over weeks to months20–40, attenuates over 4-8 wks
      FBG = fasting blood glucose; GLP-1 = glucagon-like peptide-1; LAR = long-acting release; PP = postprandial. Adapted by permission from Macmillan Publishers Ltd: Nature Reviews Endocrinology, GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus, copyright 2012.
      A number of clinical trials have tested GLP-1 receptor agonists, including exenatide,
      • Buse J.B.
      • Bergenstal R.M.
      • Glass L.C.
      • et al.
      Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes. A randomized, controlled trial.
      liraglutide,
      • DeVries J.H.
      • Bain S.C.
      • Rodbard H.W.
      • et al.
      Liraglutide-Detemir Study Group. Sequential intensification of metformin treatment in type 2 diabetes with liraglutide followed by randomized addition of basal insulin prompted by A1C targets.
      and lixisenatide,
      • Kendall D.M.
      • Riddle M.C.
      • Rosenstock J.
      • et al.
      Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes treated with metformin and a sulfonylurea.
      in combination with basal insulin. Ongoing clinical trials are evaluating the potential for combining a GLP-1 receptor agonist with basal insulin in the same injection device.

      Novo Nordisk. Dual Action of Liraglutide and Insulin Degludec in Type 2 Diabetes: A Trial Comparing the Efficacy and Safety of Insulin Degludec/Liraglutide, Insulin Degludec and Liraglutide in Subjects With Type 2 Diabetes (DUAL™ I). http://clinicaltrials.gov/show/NCT01336023. Accessed January 31, 2014.

      Sanofi. Efficacy and Safety of Insulin Glargine/Lixisenatide Fixed Combination Versus Insulin Glargine Alone on Top of Metformin in Type 2 Diabetic Patients. http://clinicaltrials.gov/show/NCT01476475. Accessed January 31, 2014.

      The major advantage of GLP-1 receptor agonists is lowering body weight, which can be substantial in some patients, although it is unpredictable. The weight appears to be mainly visceral fat, and there are other benefits, including reductions in blood pressure.
      A number of concerns have been raised about GLP-1 receptor agonists, including an increased risk for pancreatitis, and the US Food and Drug Administration (FDA) recommends that the drug not be used in patients who have a history of pancreatitis. However, the true propensity to cause pancreatitis is unclear. Drugs may also induce antibody formation (particularly with exendin-based drugs), although the clinical significance of this activity is unclear.

      DPP-4 Inhibitors

      As incretin agents, DPP-4 inhibitors enhance the duration of action of endogenous GLP-1 by blocking its breakdown. Studies have suggested that even in the long term they continue to suppress glucagon.

      Novo Nordisk. Dual Action of Liraglutide and Insulin Degludec in Type 2 Diabetes: A Trial Comparing the Efficacy and Safety of Insulin Degludec/Liraglutide, Insulin Degludec and Liraglutide in Subjects With Type 2 Diabetes (DUAL™ I). http://clinicaltrials.gov/show/NCT01336023. Accessed January 31, 2014.

      • Ahern B.
      • Foley J.E.
      • Ferrannini E.
      • et al.
      Changes in prandial glucagon levels after 2-year treatment with vildagliptin or glimepiride in patients with type 2 diabetes mellitus inadequately controlled with metformin monotherapy.
      Several DPP-4 inhibitors are currently available (eg, sitagliptin, saxagliptin, alogliptin, linagliptin), all of which apparently are similar with regard to efficacy and tolerability, although they have different sites of breakdown and metabolism. Linagliptin is different from other DPP-4 inhibitors in that it is not excreted through the kidney and therefore may be used in patients with renal impairment without lowering the dose.
      Overall, this class of drugs has modest effects on glycemia; however, there are still advantages to using them, including ease of administration using the oral route, good tolerability, and a lack of association with weight gain or hypoglycemia. They are therefore preferentially used over sulfonylureas in patients who fail on metformin monotherapy, who have modest elevations in A1c, and in whom it is important to avoid side effects, especially hypoglycemia.
      A number of cardiovascular outcomes trials have been conducted with incretin agents, 2 of which have recently completed.
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • et al.
      for the SAVOR-TIMI 53 Steering Committee and Investigators
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      • White W.B.
      • Cannon C.P.
      • Heller S.R.
      • et al.
      for the EXAMINE Investigators
      Alogliptin after acute coronary syndrome in patients with type 2 diabetes.
      Contrary to study expectations based on a reduction in events from meta-analysis of short-term clinical trials, neither study demonstrated a reduction in events. The outcomes from these studies serve to reiterate the importance of engaging in specific cardiovascular outcomes trials rather than relying on short-term trial data. Furthermore, data from the SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus) trial
      • Scirica B.M.
      • Bhatt D.L.
      • Braunwald E.
      • et al.
      for the SAVOR-TIMI 53 Steering Committee and Investigators
      Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus.
      suggest an increase in hospitalization for heart failure with saxagliptin compared with placebo. This intriguing finding may have occurred by chance but requires additional study. Several other trials are ongoing, with an incretin drug or placebo added on to usual therapy. The latter may differ between groups and lead to the confounding of differences in glycemic control or hypoglycemia. Indeed, in a study of linagliptin compared with sulfonylurea in combination with metformin over 1 year, glycemic control was similar but cardiovascular events were fewer in the linagliptin-treated group.
      • Gallwitz B.
      • Rosenstock J.
      • Rauch T.
      • et al.
      2-year efficacy and safety of linagliptin compared with glimepiride in patients with type 2 diabetes inadequately controlled on metformin. A randomised, double-blind, non-inferiority trial.
      This result needs to be confirmed in a larger and longer trial.

      Sodium-Glucose Cotransporter 2 Inhibitors

      The sodium-glucose cotransporter (SGLT)-2 is involved in reabsorbing 90% of glucose that is filtered in the glomerulus of the kidney.
      • Bakris G.L.
      • Fonseca V.A.
      • Sharma K.
      • Wright E.M.
      Renal sodium-glucose transport. Role in diabetes mellitus and potential clinical implications.
      Most of this resorption occurs in the proximal renal tubule, resulting in a minimal amount of glucose—if any—excreted in the urine. However, in diabetes, this transporter is saturated and glycosuria occurs, although it may occur at a higher level of blood glucose than in healthy individuals, perhaps due to a maladaptive process.
      • Bakris G.L.
      • Fonseca V.A.
      • Sharma K.
      • Wright E.M.
      Renal sodium-glucose transport. Role in diabetes mellitus and potential clinical implications.
      By blocking this transporter, a number of drugs have been shown to increase glycosuria and have been developed for the treatment of type 2 diabetes.
      • Bakris G.L.
      • Fonseca V.A.
      • Sharma K.
      • Wright E.M.
      Renal sodium-glucose transport. Role in diabetes mellitus and potential clinical implications.
      • Sha S.
      • Devineni D.
      • Ghosh A.
      • et al.
      Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects.
      They cause loss of glucose in the urine, thereby contributing to falling blood glucose levels. Canagliflozin and dapagliflozin have been shown to lower A1c by ~0.8%.
      • Bailey C.J.
      • Gross J.L.
      • Pieters A.
      • et al.
      Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin. A randomised, double-blind, placebo-controlled trial.
      • Wilding J.P.
      • Norwood P.
      • Tʼjoen C.
      • et al.
      A study of dapagliflozin in patients with type 2 diabetes receiving high doses of insulin plus insulin sensitizers. Applicability of a novel insulin–independent treatment.
      • Cefalu W.T.
      • Leiter L.A.
      • Yoon K.H.
      • et al.
      Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU). 52 week results from a randomised, double-blind, phase 3 non-inferiority trial.
      • Schernthaner G.
      • Gross J.L.
      • Rosenstock J.
      • et al.
      Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea. A 52-week randomized trial.
      Table IV illustrates the potential advantages and disadvantages of SGLT-2 inhibition. They are easy to use and have the advantage of working on all phases of glucose metabolism, with no risk for hypoglycemia. They also cause modest blood pressure lowering and weight loss and work in combination with all other treatments for diabetes. However, by increasing the amount of glucose in the genitourinary tract, fungal genital infections may occur in some individuals.
      Table IVPotential advantages of and concerns about SGLT-2 inhibitors.
      Potential AdvantagesConcerns
      Once-daily administrationBacterial urinary tract infections
      Decreases FPG, PPG, A1cFungal genital infections
      Weight loss (60 g urine glucose = 240 kcal/d = 0.5 lb/wk)May not be as effective in patients with renal impairment
      No/low risk for hypoglycemiaRise in LDL-C
      Modest blood pressure loweringCancer in dapagliflozin trials
      Effect independent of insulin secretion or insulin resistanceTransient initial period of dehydration, polyuria, thirst
      Use complementary with other type 2 diabetes treatmentsNo known long-term effects on kidney or on CV outcomes
      Potential for use in type 1 diabetesAdded cost to diabetes therapy
      A1c = hemoglobin A1c; CV = cardiovascular; FPG = fasting plasma glucose; LDL-C = low-density lipoprotein cholesterol; PPG = postprandial glucose; SGLT-2 = sodium-glucose cotransporter 2.
      The exact role of SGLT-2 inhibitors in the diabetes treatment algorithm remains to be determined. The drugs became available only after the publication of the ADA/EASD guidelines and were therefore not discussed therein. Nonetheless, clinical trials have demonstrated their efficacy at all stages of diabetes, including the late stage of patients treated with insulin in combination with oral agents.
      • Wilding J.P.
      • Woo V.
      • Soler N.G.
      • et al.
      for the Dapagliflozin 006 Study Group
      Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin. A randomized trial.
      This broad efficacy and synergy perhaps relate to the unique mechanism of action that is different from that of all other agents and is not dependent on insulin secretion or activity.

      Investigative Agents in Type 2 Diabetes

      Several new therapies have been developed for the treatment of type 2 diabetes and are summarized in Table V. Closest to the market are several long-acting GLP-1 receptor agonists, several SGLT-2 inhibitors, as well as some dual inhibitors, and activators of G-protein–coupled receptor (GPR)-40, a receptor that is present on the surface of β cells.
      • Burant C.F.
      • Viswanathan P.
      • Marcinak J.
      • et al.
      TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus. A phase 2, randomised, double-blind, placebo-controlled trial.
      In addition, inflammation has been identified as a target for the treatment of diabetes, and several anti-inflammatory agents have been shown to improve glucose control.
      • Goldfine A.B.
      • Fonseca V.
      • Jablonski K.A.
      • et al.
      for the TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes) Study Team
      The effects of salsalate on glycemic control in patients with type 2 diabetes. A randomized trial.
      • Goldfine A.B.
      • Fonseca V.
      • Jablonski K.A.
      • et al.
      for the Targeting Inflammation Using Salsalate in Type 2 Diabetes Study Team*
      Salicylate (salsalate) in patients with type 2 diabetes. A randomized trial.
      • Goldfine A.B.
      • Fonseca V.
      • Shoelson S.E.
      Therapeutic approaches to target inflammation in type 2 diabetes.
      Table VInvestigational agents being developed for the treatment of type 2 diabetes mellitus.
      Long-acting glucagon-like peptide-1 (GLP-1) receptor agonists
      Sodium-glucose cotransporter (SGLT) -1 and -2 inhibitors
      Ranolazine
      Dual (α/Γ) & Pan (α/Γ/Δ) peroxisome proliferator-activated receptor (PPAR) agonists
      11b hydroxysteroid dehydrogenase (HSD)-1 inhibitors
      Fructose 1,6-bisphosphatase inhibitors
      Glucokinase activators
      G protein-coupled receptor (GPR)-40 and -119 agonists
      Protein tyrosine phosphatase (PTB)-1b inhibitors
      Carnitine palmitoyltransferase (CPT)-1 inhibitors
      Acetyl coenzyme A carboxylase (ACC)-1 and -2 inhibitors
      Glucagon receptor antagonists
      Salicylate derivatives
      Immunomodulatory drugs
      Salsalate, a treatment of rheumatoid arthritis, was shown to be modestly effective in patients with type 2 diabetes in a 12-month randomized trial. However, there were small increases in both albuminuria and low-density lipoprotein cholesterol. The mechanism for these increases was unclear. Antibodies to interleukin-1 have also been shown to have glucose-lowering properties and may be developed for the treatment of type 2 diabetes.
      • Larsen C.M.
      • Faulenbach M.
      • Vaag A.
      • et al.
      Interleukin-1-receptor antagonist in type 2 diabetes mellitus.
      Finally, the GPR-40 agonist TAK-875 has been shown to be as effective as glimepiride in lowering glucose, but caused less hypoglycemia, in a head-to-head trial.
      • Burant C.F.
      • Viswanathan P.
      • Marcinak J.
      • et al.
      TAK-875 versus placebo or glimepiride in type 2 diabetes mellitus. A phase 2, randomised, double-blind, placebo-controlled trial.
      However, development of this compound was recently discontinued due to hepatic toxicity. Finally, an inhibitor of the enzyme 11β-hydroxysteroid dehydrogenase has also been shown to reduce A1c significantly,
      • Rosenstock J.
      • Banarer S.
      • Fonseca V.A.
      • et al.
      for the INCB13739-202 Principal Investigators
      The 11-beta-hydroxysteroid dehydrogenase type 1 inhibitor INCB13739 improves hyperglycemia in patients with type 2 diabetes inadequately controlled by metformin monotherapy.
      but concerns remain about interference with the pituitary-adrenal axis.

      Insulin

      There have been several developments in insulin therapy in the past few decades with the development of insulin analogues. These analogues have been shown to improve glycemic control, with less hypoglycemia, in several studies.
      • Rosenstock J.
      Basal insulin supplementation in type 2 diabetes; refining the tactics.
      New basal insulin analogues have been developed, with several of them, such as degludec, having been approved in countries other than the United States. Degludec has been shown to be longer acting than insulin glargine.
      • Garber A.J.
      • King A.B.
      • Del Prato S.
      • et al.
      for the NN1250-3582 (BEGIN BB T2D) Trial Investigators
      Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN basal-bolus type 2). A phase 3, randomised, open-label, treat-to-target non-inferiority trial.
      Studies of degludec suggest that it may cause less nocturnal hypoglycemia than glargine.
      • Zinman B.
      • Philis-Tsimikas A.
      • Cariou B.
      • et al.
      for the NN1250-3579 (BEGIN Once Long) Trial Investigators
      Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes. A 1-year, randomized, treat-to-target trial (BEGIN once long).
      The US FDA has asked the manufacturer to complete a long-term study of cardiovascular outcomes with insulin degludec before making a safety determination. Another basal insulin analogue, pegylated insulin lispro, has specific activity on the liver, with theoretical potential for less weight gain than with other basal insulins - that needs to be confirmed in clinical trials. Patients in clinical trials of pegylated insulin lispro experienced less weight gain than with other basal insulins. In a clinical trial of degludec plus aspart insulin as basal bolus therapy compared with glargine plus aspart in patients with both type 1 and type 2 diabetes, efficacy was similar, but nocturnal hypoglycemia was less with degludec.
      • Garber A.J.
      • King A.B.
      • Del Prato S.
      • et al.
      for the NN1250-3582 (BEGIN BB T2D) Trial Investigators
      Insulin degludec, an ultra-long-acting basal insulin, versus insulin glargine in basal-bolus treatment with mealtime insulin aspart in type 2 diabetes (BEGIN basal-bolus type 2). A phase 3, randomised, open-label, treat-to-target non-inferiority trial.
      • Zinman B.
      • Philis-Tsimikas A.
      • Cariou B.
      • et al.
      for the NN1250-3579 (BEGIN Once Long) Trial Investigators
      Insulin degludec versus insulin glargine in insulin-naive patients with type 2 diabetes. A 1-year, randomized, treat-to-target trial (BEGIN once long).
      Several very rapid–acting insulin analogues are in development, including insulin mixed with hyaluronidase to enhance its absorption.
      Finally, there has been an increase in the use of more concentrated insulins, such as U-500 insulin, which has a pharmacokinetic profile different from that of regular insulin U-100. The reason for the change of pharmacodynamic properties is not clear. Nonetheless, concentrated insulins, such as U-200 degludec and U-300 glargine, continue to be developed because some patients have very high insulin requirements.

      Mesoblast, Ltd. Safety study of mesenchymal precursor cells in type 2 diabetes. http://clinicaltrials.gov/show/NCT01576328. Accessed February 3, 2014.

      Coupled with advances in insulin therapy, there have been developments in continuous glucose-monitoring systems, which, when used together with pump therapy, have been shown to reduce the risk for hypoglycemia, particularly when a signal to a pump to switch off for a short period of time when the blood glucose is dropping may be very useful in treating type 1 diabetes.
      • Bergenstal R.M.
      • Tamborlane W.V.
      • Ahmann A.
      • et al.
      for the STAR 3 Study Group
      Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes.
      Such a pump coupled with continuous glucose-monitoring systems has been approved by the FDA for clinical use.
      Although islet-cell transplants are effective in the short term, other treatments for type 1 diabetes have been somewhat disappointing. A number of immunotherapies for type 1 diabetes have been tried but so far have been shown to have a transient effect. There remains interest in stem cell therapy for type 1 diabetes; stem cell therapy has been explored for type 2 diabetes as well.

      Mesoblast, Ltd. Safety study of mesenchymal precursor cells in type 2 diabetes. http://clinicaltrials.gov/show/NCT01576328. Accessed February 3, 2014.

      Conclusions

      We have made tremendous progress with the management of diabetes. However, the disease remains a challenge because of its very high prevalence as well as disease progression and associated comorbidities. Several novel approaches have been tried to help overcome the burden of diabetes, targeting novel pathways that promise to improve diabetes control and eliminate long-term complications.

      Conflicts in Interest

      Dr. Fonseca has received research grant support (to Tulane) from Eli Lilly and Co, The sanofi-aventis Group, Eli Lilly and Co, and Abbott Laboratories; and honoraria for consulting and lectures from AstraZeneca Pharmaceuticals LP, Abbott Laboratories, Bristol-Myers Squibb Co, GlaxoSmithKline, Takeda Pharmaceuticals North America, Inc, The sanofi-aventis Group, Eli Lilly and Co, and Pamlab. The author has indicated that she has no other conflicts of interest with regard to the content of this article.

      Acknowledgments

      Dr. Fonseca was the sole author responsible for the literature search, data interpretation, figure creation, and writing of the manuscript.

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