INTRODUCTIONDiabetes has reached global epidemic proportions,with projections for very rapid increases across theworld that would seriously affect the health economicsof many countries. Over the past 2 decades, there hasbeen a rapid increase in the number of drugs availableto treat hyperglycemia, as illustrated in Slide 1, alongwith developments of evidenced-based guidelines fromorganizations such as the American Diabetes Associa-tion, which has helped to improve overall diabetes careand control. As a result, as shown in Slide 2, the aver-age hemoglobin A1c (A1c) concentration in the UnitedStates has dropped almost 0.5% over a 5-year periodbut still does not represent normal glycemia. Fortu-nately, this improvement in glycemic control is nowbeing translated into better clinical outcomes, with re-ductions in rates of a variety of complications as well asmortality in people with diabetes.1,2
A number of important challenges remain to optimallymanage and control diabetes. Some of these challengesare shown in Slide 3. First, the large number of patients
ith diabetes makes it very challenging in practice to giveatients the time that is needed to provide optimal care.herefore, the prevention of diabetes through lifestyle
hanges remains crucial in the future of diabetes control.
714
ven with successful preventive measures, some otherroblems include the failure to attain and sustain optimalong-term glycemic control, and better approaches tohanging the natural history of the disease are needed.urthermore, we currently have inadequate tools to ad-ress unpredictable glucose fluctuations, particularlyostprandial glucose excursions, and strategies and tech-ologies to monitor and control these fluctuations areeeded. However, the biggest problem related to mortal-ty in diabetes remains cardiovascular disease (CVD), andlthough rates for CVD have declined, there still remainsn excess residual risk in people with diabetes comparedo those without the disease. Management of hyperglyce-ia in the past has been plagued with problems of hypogly-
emia as well as weight gain, both of which contribute notnly to patients’ discomfort but also worsening cardiovas-ular risk.3,4 The purpose of this review was to highlightome of the novel approaches that are being developed tomprove glucose control in patients with diabetes.
PATHOPHYSIOLOGY OF DIABETESThere have been tremendous advances in our under-standing of the pathophysiology recognized by De-Fronzo in his Banting lecture of 2009,5 at which timehe described at least eight defects in the pathophysiol-ogy of diabetes, all of which are now well-recognizedbut also provide appropriate treatment targets. De-Fronzo’s “Ominous Octet” is illustrated in Slide 4.
Novel approaches to type 2 diabetes mellitus in-clude a wide range of new drugs, summarized in Slide5. Some of these represent new versions of drugs thathave been available for some time, whereas others rep-resent a completely new approach to management.This is not a comprehensive list of therapeutic strate-
This paper represents a summary of a presentation at the JeffersonDiabetes Symposium in Philadelphia in September 2012.
Accepted for publication April 19, 2013.http://dx.doi.org/10.1016/j.clinthera.2013.04.0070149-2918/$ - see front matter
gies in development for diabetes; only a few with pub-lished data are discussed in this review.
TREATMENT OF DIABETESIt is important to recognize a patient’s perceptionabout new therapies for diabetes and how we can de-crease the burden by decreasing the complexity of themanagement of hyperglycemia as well as their comor-bidities. We need to understand the impact of a pa-
History of US Diabete
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Slide 1.
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Slide 2.
May 2013
tient’s burden, encourage coordination of clinical prac-tice, and prioritize comorbidities and managementstrategies according to a patient’s perspective.6
As new drugs become available, their ability tolower glucose levels compared with placebo will not beenough to ensure a place in the treatment algorithm fordiabetes. Comparative effectiveness research is likelyto become key to such relative evaluation so that ap-propriate choices can be made. Unfortunately, a very
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Clinical Therapeutics
few long-term comparative effectiveness studies havebeen done, particularly with combination therapy,which is so frequently used in management. Becausemonotherapy with metformin is extremely well estab-lished as first-line therapy, future comparative effec-tiveness trials will probably need to study second-linetherapies in combination with metformin. This mayhelp physicians to make decisions of which drug(s) toadd when metformin fails; current guidelines do notoffer sufficient guidance regarding the best choices af-ter monotherapy is no longer effective.6
Insulin SensitizersInsulin sensitizers such as the thiazolidinediones still
have a place in therapy. Over the past few years therehad been considerable concerns about the tolerabilityof drugs in this class. The US Food and Drug Admin-istration issued a safety update on pioglitazone, sug-gesting that there may be an increased risk for bladdercancer; however, this was based on an increased rela-tive risk, whereas the absolute excess remains small.Nonetheless, pioglitazone should not be used in pa-tients with active bladder cancer or a history of bladdercancer, and patients should be monitored for signs andsymptoms such as hematuria, urgency of urination,and abdominal pain on urination. Slide 6 illustratesseveral suggested steps for minimizing the side effectsof pioglitazone, although none of these strategies havebeen evaluated in randomized clinical trials.
A potential strategy for minimizing the side effectsof these drugs is to use lower doses and avoid combi-nation with insulin among high-risk patients as well asin those with a risk for fractures. Decreasing salt and
Despite Important Advances in TherapyGlycemic Control Is Not Optimal
Challenges:• Too many patients! –Burden or prevention opportunity?• Failure to attain and sustain optimal long-term glycemic control• Hypoglycemia risk• Inadequate postprandial glucose control• Unpredictable glucose fluctuations• Weight gain• Excess CVD
Slide 3.
calorie intake, as well avoiding calcium channel block-
716
ers in combination, may also minimize edema andweight gain. Once patients develop excessive weightgain and edema, the drug should be discontinued.
Meanwhile, the search continues for new peroxi-some proliferator activated receptor (PPAR)-� agoniststhat have fewer side effects, and Slide 7 illustrates aossible approach. By developing selective PPAR mod-lators (SPARMs), it may be possible to decrease theisk for side effects. For example, activating the recep-ors only in muscle and fat, but not in the kidney orone, may improve glucose metabolism without con-ributing to fluid retention or bone loss. One such drugndergoing clinical trials is aleglitazar.7 The drug has
been tested for protection from cardiovascular eventsin a large cardiovascular-outcomes trial, as shown inSlide 8. Preliminary data suggest that it may lowerLDL-C, with findings significantly different from theelevations in LDL with pioglitazone.
Inflammation and Antiinflammatory DrugsChronic inflammation is considered to be a funda-
mental abnormality in diabetes as a consequence ofobesity.8,9 Some drugs such as statins, along with life-tyle changes, have been shown to decrease markers ofnflammation, evoking the question: Does reducing in-ammation by a specific anti-inflammatory drug im-rove glycemic control? Therefore, the TINSAL-T2DTargeting Inflammation using Salsalate for Type 2 Di-betes) trial was funded by the US National Institutesf Health as a multisite study to examine the antiin-ammatory effects of salicylates for their effect on gly-emic control. Preliminary data suggest that salicylatesower glucose levels, thereby improving insulin sensi-ivity; lower triglycerides and free fatty acids; and ele-ate adiponectin levels in people with diabetes.9,10 The
TINSAL-T2D stage 1 trial clearly showed a significantreduction in A1c, with few side effects.11 Similarly,Larsen et al12 demonstrated that anakinra, an interleu-in-1 receptor antagonist approved for the treatmentf rheumatoid arthritis, reduced A1c and fasting glu-ose while improving �-cell function.
GLP-1 Receptor AgonistsDrugs affecting the incretin system, including gluca-
gon peptide(GLP)-1 receptor agonists and dipeptidyl-dipeptidase (DDP)-4 inhibitors, have become well-es-tablished in clinical practice. The former are availableby injection only, whereas the latter have the advantage
How Can We Minimize the Side Effectsof PPARγγ Agonists?
• Use lower doses• Avoid using in combination with insulin in high-risk patients• Avoid use in patients with high risk for fractures• Decrease salt and calorie intake• Avoid calcium channel blockers• Discontinue if patients have weight gain and edema• Develop new PPARγ agonists that have less side effects
Slide 6.
May 2013
of being oral medications that are well-tolerated andweight neutral. The GLP-1 receptor agonists have beenshown to be effective for the treatment of diabetes inmany clinical trials and have the advantage of causingsome weight loss and improving postprandial control.Some debate exists as to whether they are more effectivethan insulin. However, irrespective of which is used first,it is likely that many patients will use the 2 together.
Two evolving trends in the area of GLP-1 agonistsinclude the development of long-acting agents such assustained-release exenatide and albiglutide, both of
which are effective for at least 1 week between injections.Another important development is the potential of com-bining a GLP-1 agonist with basal insulin in a single in-jection. Clinical trials have reported that as 2 separateinjections this combination therapy works well.13
Slide 9 suggests that the combination into 1 injec-tion is scientifically logical because basal insulin ana-logues control fasting glucose and are effective inachieving A1c targets with modest weight gain. Incontrast, GLP-1 agonists have a major effect onpostprandial glucose, do not increase the risk forhypoglycemia, and may lower weight and thereforemay balance out the weight-increasing effects of in-sulin.14 Of considerable interest is the choice be-tween a combination of insulin and a GLP-1 agonistcompared with advancing insulin therapy from basalto basal bolus therapy. The benefits of combiningthese 2 drugs suggest that this combination will bethe regimen of choice.
SGLT2 InhibitorsThe sodium glucose transporter (SGLT)-2 is a
high-capacity transporter in the proximal renal tu-
Phase III, double-blind, parallrecent ACS and T2DM. Targe
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Slide 8.
bule that causes reabsorption of glucose and sodium
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from the urine and is involved in ensuring that gly-cosuria does not occur in normal individuals. Inhi-bition of this transporter with drugs such as dapa-gliflozin and canagliflozin will lead to glycosuria andthereby contribute to weight reduction and a reduc-tion in plasma glucose.15 Several drugs in this classare being developed and show a reduction in A1c offrom �0.6% to 0.9%. Benefits include a reduction insodium, the mechanism of which is unclear, as wellas a reduction in body weight possibly due to calo-rie loss. These characteristics are summarized inSlide 10.
There had been concerns about tolerability with thisclass of drugs. Partly related to the increase in glucosein the urine, the rate of genital and urinary tract infec-tions is increased. In addition, the FDA has delayedapproval of dapagliflozin due to questions about animbalance in the rates of bladder cancer between thepatients treated with the active drug and the compara-tor. Approval of canagliflozin is awaited and althoughan advisory committee recommended approval, sev-eral members expressed concern about the potential of
omized trial in patients withle size = 6000-7000 patients.ast 2.5 years.
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Other AgentsThe enzyme 11�-hydroxysteroid dehydrogenase
HSD)-1 is another potential new therapeutic target foriabetes. This enzyme converts the inactive hormoneortisone to the active component cortisol, and muchf this conversion occurs in metabolically active tissues
ncluding adipose tissue, the liver, skeletal muscle, andhe pancreas, as shown in Slide 11. Selective inhibitionf this enzyme in fact may be effective for the treatmentf diabetes and the metabolic syndrome among obese
Combination of BGLP-1 Agonist h
Basal insulin analogues• Simple to initiate• Control nocturnal and FPG• Lower hypoglycemia risk vs NPH• Modest weight increase (1 to 3 kg)• Achieve A1c targets in ~50–60%
Complac
Adef
Slide 9.
Clinical Evidence for SGLT2 Inhibition in Diabetes
• SGLT2 inhibition results in
• Glucosuria and resultant decrease in HbA1c, FPG and PPG• FPG decrease evident within one week• Effective as monotherapy and as add-on to other oral agents and insulin• Associated with weight loss and decrease in BP• Hypoglycemia generally not different from placebo• Increased frequency in genital infections and UTIs
• Mechanism independent of insulin resistance or severity of β-cell dysfunction• Evidence of efficacy throughout the progression of T2D• Do they cause bladder cancer? Do they raise LDL-C?
Slide 10.
May 2013
ndividuals, with improvements in glycemic control re-orted in 1 study.16
G protein–coupled receptor (GPR) 40 is a receptorpresent in the pancreas that binds to fatty acids. Stim-ulation of this receptor leads to insulin secretion. Slide12 illustrates the results from a comparative trial inwhich glimepiride TAK875, a GPR40 agonist, was as-sociated with significantly reduced blood glucose to thesame degree as glimepiride, without contributing asmuch hypoglycemia—an unexpected outcome consid-ering that this agent stimulates insulin secretion.17
Insulin Analogues Under DevelopmentSlide 13 illustrates several late-stage investigational
asal insulins. These include insulin lispro protamineuspension, degludec insulin, and pegylated insulin lis-ro. These preparations have the advantage of a longalf-life, with less day-to-day variability. Furthermore,here have been reports of less hypoglycemia, particu-arly nocturnal hypoglycemia, with glycemic controlith insulin degludec similar to that with glargine.18
A number of rapid-acting insulins are also in de-velopment, including monomeric human insulin aswell as a combination of insulin with hyaluronidase,which cause the breakdown of insulin in subcutane-
Insulin with acientific Logic
GLP-1 agonists• Simple to initiate• Pronounced PPG control• No increase in hypoglycemia• Weight lowering/neutral effects• Achieve A1c targets in ~40–60%
ary
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719
Clinical Therapeutics
insulin, with rapid glycemic control in the postpran-dial phase. Hyaluronidase is a naturally occurringenzyme and it has been approved for use in otherconditions as an adjuvant to desorption and absorp-tion of injected drugs.19
11ββHSD1 as an In• Patients with Cushing’s syndrome – closely resemble patients with T
– Insulin resistant, glucose int
• 11βHSD1 catalyzes the intracellul cortisone to active cortisol in met
– Adipose, liver, skeletal musc
• Adipose 11βHSD1 activity is upre and insulin resistance
– This dysregulation can prod phenotype in rodents
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Novel Treatment StrategiesSlide 14 illustrates several other investigational in-
sulin-delivery technologies. These include inhaled insu-lin, jet injection, a new oral insulin, and “closed-loop”insulin delivery. The closed-loop concept refers to a
tion Point in T2Dlating cortisol excess
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complete system that incorporates both monitoringand an insulin pump. Others are attempting to under-stand the efficacy of suspending insulin-pump therapyduring periods of hypoglycemia.20
Islet-cell transplantation has also been reported toproduce insulin independence in a few patients but
Late-Stage Investig
Insulin Administr
Insulin lispro protaminesuspension (ILPS)1-3
Once or tdaily
Pegylated insulin lispro(LY2605541)4-5
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Degludec (NN1250)6-8 Once dathrice wee
8. Nosek L, e
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*None of these insulins are FDA approved.
Slide 13.
Investigational Insuli
Delivery Method Administration
Inhaled insulin1,2 Thrice daily
Jet injection3 Once daily
Oral insulin (IN-105)4 Thrice daily
Closed-loop insulindelivery5 Continuous
*None of these insulins or administration routes are FD
Slide 14.
May 2013
more importantly contributes to a reduction in hypo-glycemia compared with insulin. A number of attemptsat immunomodulation have also been tried amongpeople with type 1 diabetes, but these efforts havethus far failed to prevent diabetes. A number of stud-ies of monoclonal antibodies against the variety of
al Basal Insulins*
Status PeakEffectiveDuration
Approvedoutside US
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Phase 3 Peakless 24-44 h
Filed forapproval
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1. Fogelfeld L, et al. Diabet Med. 2010;27:181-188.
2. Strojek K, et al. Diabetes Obes Metab. 2010;12:916-922.
3. Ocheltree SM, et al. Eur J Endocrinol. 2010;163:217-223.
7. Birkeland KI, et al. Diabetes Care. 2011;34:661-665.
rican Diabetes Association 71st Annual Scientific Sessions. 2011: 49-LB.
also in development.5
livery Technologies*
Clinical TrialPhase
PeakEffective
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3 20-80 min < 4 h
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2 NA NA
1. Boss AH, et al. Drug Dev Res. 2008;69:138-142;
2. Rosenstock J, et al. Lancet. 2010;375:2244-2253;
3. Engwerda EE, et al. Diabetes Care. 2011;34:1804-1808;
4. Khedkar A, et al. Diabetes Obes Metab. 2010;12:659-664;
5. Dassau E, et al. Int J Clin Pract. 2011;65(suppl 170):20-25.
oved.
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Clinical Therapeutics
immune-modulating substances may offer hope forthe treatment of diabetes in the early stages. How-ever, a number of side effects were reported, partic-ularly infections, so longer-term clinical trials arenecessary. Finally, stem cell therapy offers hope foreither regeneration of new cells in the pancreas ormodulation of the immune process to allow self-re-generation or preservation of �-cell function andthereby better glycemic control.21
ACKNOWLEDGMENTSThe author thanks the organizers of the symposium formaking this article possible.
CONFLICT OF INTERESTDr. Fonseca has received research grant support (toTulane) from NovoNordisk, The sanofi-aventisGroup, Eli Lilly, Abbott Laboratories, Pamlabs, andReata; and honoraria for consulting and lectures fromAstra-Zeneca, Abbott Laboratories, Bristol-MyersSquibb, GlaxoSmithKline, Takeda, NovoNordisk, Thesanofi-aventis Group, Eli Lilly, Daiichi Sankyo, Pam-labs, and Xoma. The author has indicated that she hasno other conflicts of interest with regard to the contentof this article.
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1. Goldfine AB, Fonseca V, Jablonski KA, et al, for theTINSAL-T2D (Targeting Inflammation Using Salsalate inType 2 Diabetes) Study Team. The effects of salsalate onglycemic control in patients with type 2 diabetes: arandomized trial. Ann Intern Med. 2010;152:346–357.
2. Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N EnglJ Med. 2007;356:1517–1526.
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19. Muchmore DB, Vaughn DE. Acceler-ating and improving the consistencyof rapid-acting analog insulin ab-sorption and action for both subcu-taneous injection and continuoussubcutaneous infusion using recom-binant human hyaluronidase. J Dia-betes Sci Technol. 2012;6:764–772.
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Address correspondence to: Vivian Fonseca, MD, Tulane University HealthSciences Center, Department of Medicine and Pharmacology, Tullis TulaneAlumni Chair in Diabetes, 1430 Tulane Avenue - SL 53, New Orleans, LA
