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Cartilage Restoration in the Patellofemoral Joint

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Article

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Thu, 09/19/2019 - 13:21

Author(s)

Betina B. Hinckel, MD, PhD

Andreas H. Gomoll, MD

Jack Farr II

Take-Home Points

Careful evaluation is key in attributing knee pain to patellofemoral cartilage lesions-that is, in making a "diagnosis by exclusion".
Initial treatment is nonoperative management focused on weight loss and extensive "core-to-floor" rehabilitation.
Optimization of anatomy and biomechanics is crucial.
Factors important in surgical decision-making incude defect location and size, subchondral bone status, unipolar vs bipolar lesions, and previous cartilage procedure.
The most commonly used surgical procedures-autologous chondrocyte implantation, osteochondral autograft transfer, and osteochondral allograft-have demonstrated improved intermediate-term outcomes.

Patellofemoral (PF) pain is often a component of more general anterior knee pain. One source of PF pain is chondral lesions. As these lesions are commonly seen on magnetic resonance imaging (MRI) and during arthroscopy, it is necessary to differentiate incidental and symptomatic lesions.¹ In addition, the correlation between symptoms and lesion presence and severity is poor.

PF pain is multifactorial (structural lesions, malalignment, deconditioning, muscle imbalance and overuse) and can coexist with other lesions in the knee (ligament tears, meniscal injuries, and cartilage lesions in other compartments). Therefore, careful evaluation is key in attributing knee pain to PF cartilage lesions—that is, in making a "diagnosis by exclusion."

From the start, it must be appreciated that the vast majority of patients will not require surgery, and many who require surgery for pain will not require cartilage restoration. One key to success with PF patients is a good working relationship with an experienced physical therapist.

Etiology

The primary causes of PF cartilage lesions are patellar instability, chronic maltracking without instability, direct trauma, repetitive microtrauma, and idiopathic.

Patellar Instability

Patients with patellar instability often present with underlying anatomical risk factors (eg, trochlear dysplasia, increased Q-angle/tibial tubercle-trochlear groove [TT-TG] distance, patella alta, and unbalanced medial and lateral soft tissues²). These factors should be addressed before surgery.

Patellar instability can cause cartilage damage during the dislocation event or by chronic subluxation. Cartilage becomes damaged in up to 96% of patellar dislocations.³ Most commonly, the damage consists of fissuring and/or fibrillation, but chondral and osteochondral fractures can occur as well. During dislocation, the medial patella strikes the lateral aspect of the femur, and, as the knee collapses into flexion, the lateral aspect of the proximal lateral femoral condyle (weight-bearing area) can sustain damage. In the patella, typically the injury is distal-medial (occasionally crossing the median ridge). A shear lesion may involve the chondral surface or be osteochondral (Figure 1A).

In an osteochondral lesion, the area of cartilage damage is often larger than the bony fragment indicates (Figure 1A), and even small fractures visible on radiographs can portend extensive cartilage damage. In addition, isolated cartilage flaps can occur; if suspected, they should be assessed with MRI. The extent of cartilage damage is related to the magnitude of energy required to cause the dislocation and/or to the frequency of events. In more normal anatomy, more energy is required to provoke a dislocation, and damage to articular cartilage is greater. In recurrent patellar dislocation, each event can cause additional injury, and the size of the lesion tends to increase with the number of dislocations.⁴ Patellar dislocation can result in chronic patellar subluxation, or dislocations that often lead to recurrent or chronic patellar instability. With recurrent instability, the medial patellar facet becomes damaged as it displaces out of the trochlea during subluxation and dislocation events. With lateral patellar maltracking, the contact area is reduced. With overall similar PF forces, a smaller contact area results in increased point loading, thus increasing stress and promoting cartilage wear.

Chronic Maltracking Without Instability

Chronic maltracking is usually related to anatomical abnormalities, which include the same factors that can cause patellar instability. A common combination is trochlear dysplasia, increased TT-TG or TT-posterior cruciate ligament distance, and lateral soft-tissue contracture. These are often seen in PF joints that progress to lateral PF arthritis. As lateral PF arthritis progresses, lateral soft-tissue contracture worsens, compounding symptoms of laterally based pain. With respect to cartilage repair, these joints can be treated if recognized early; however, once osteoarthritis is fully established in the joint, facetectomy or PF replacement may be necessary.

Direct Trauma

With the knee in flexion during a direct trauma over the patella (eg, fall or dashboard trauma), all zones of cartilage and subchondral bone in both patella and trochlea can be injured, leading to macrostructural damage, chondral/osteochondral fracture, or, with a subcritical force, microstructural damage and chondrocyte death, subsequently causing cartilage degeneration (cartilage may look normal initially; the matrix takes months to years to deteriorate). Direct trauma usually occurs with the knee flexed. Therefore, these lesions typically are located in the distal trochlea and superior pole of the patella.

Repetitive Microtrauma

Minor injuries, which by themselves do not immediately cause apparent chondral or osteochondral fractures, may eventually exceed the capacity of natural cartilage homeostasis and result in repetitive microtrauma. Common causes are repeated jumping (as in basketball and volleyball) and prolonged flexed-knee position (eg, what a baseball catcher experiences), which may also be associated with other lesions caused by extensor apparatus overload (eg, quadriceps tendon or patellar tendon tendinitis, and fat pad impingement syndrome).

Idiopathic

In a subset of patients with osteochondritis dissecans, the patella is the lesion site. In another subset, idiopathic lesions may be related to a genetic predisposition to osteoarthritis and may not be restricted to the PF joint. In some cases, the PF joint is the first compartment to degenerate and is the most symptomatic in a setting of truly tricompartmental disease. In these cases, treating only the PF lesion can result in functional failure, owing to disease progression in other compartments. Even mild disease in other compartments should be carefully evaluated.

History and Physical Examination

Patients often report a history of anterior knee pain that worsens with stair use, prolonged sitting, and flexed-knee activities (eg, squatting). Compared with pain alone, swelling, though not specific to cartilage disease, is more suspicious for a cartilage etiology. Identifying the cartilage defect as the sole source of pain is particularly difficult in patients with recurrent patellar instability. In these patients, pain and swelling, even between instability episodes, suggest that cartilage damage is at least a component of the symptomology.

Important diagnostic components of physical examination are gait analysis, tibiofemoral alignment, and patellar alignment in all 3 planes, both static and functional. Patella-specific measurements include medial-lateral position and quadrants of excursion, lateral tilt, and patella alta, as well as J-sign and subluxation with quadriceps contraction in extension.

It is also important to document effusion; crepitus; active and passive range of motion (spine, hips, knees); site of pain or tenderness to palpation (medial, lateral, distal, retropatellar) and whether it matches the complaints and the location of the cartilage lesion; results of the grind test (placing downward force on the patella during flexion and extension) and whether they match the flexion angle of the tenderness and the flexion angle in which the cartilage lesion has increased PF contact; ligamentous and soft-tissue stability or imbalance (tibiofemoral and patellar; apprehension test, glide test, tilt test); and muscle strength, flexibility, and atrophy of the core (abdomen, dorsal and hip muscles) and lower extremities (quadriceps, hamstrings, gastrocnemius).

Imaging

Imaging should be used to evaluate both PF alignment and the cartilage lesions. For alignment, standard radiographs (weight-bearing knee sequence and axial view; full limb length when needed), computed tomography, and MRI can be used.

Meaningful evaluation requires MRI with cartilage-specific sequences, including standard spin-echo (SE) and gradient-recalled echo (GRE), fast SE, and, for cartilage morphology, T2-weighted fat suppression (FS) and 3-dimensional SE and GRE.⁵ For evaluation of cartilage function and metabolism, the collagen network, and proteoglycan content in the knee cartilage matrix, consideration should be given to compositional assessment techniques, such as T2 mapping, delayed gadolinium-enhanced MRI of cartilage, T1ρ imaging, sodium imaging, and diffusion-weighted sequences.⁵ Use of the latter functional sequences is still debatable, and these sequences are not widely available.

Treatment

In general, the initial approach is nonoperative management focused on weight loss and extensive core-to-floor rehabilitation, unless surgery is specifically indicated (eg, for loose body removal or osteochondral fracture reattachment). Rehabilitation focuses on achieving adequate range of motion of the spine, hips, and knees along with muscle strength and flexibility of the core (abdomen, dorsal and hip muscles) and lower limbs (quadriceps, hamstrings, gastrocnemius). Rehabilitation is not defined by time but rather by development of an optimized soft-tissue envelope that decreases joint reactive forces. The full process can take 6 to 9 months, but there should be some improvement by 3 months.

Corticosteroid, hyaluronic acid,⁶ or platelet-rich plasma⁷ injections can provide temporary relief and facilitate rehabilitation in the setting of pain inhibition. As stand-alone treatment, injections are more suitable for more diffuse degenerative lesions in older and low-demand patients than for focal traumatic lesions in young and high-demand patients.

Surgery is indicated for full-thickness or nearly full-thickness lesions (International Cartilage Repair Society grade 3a or higher) >1 cm² after failed conservative treatment.

Optimization of anatomy and biomechanics is crucial, as persistent abnormalities lead to high rates of failure of cartilage procedures, and correction of those factors results in outcomes similar to those of patients without such abnormal anatomy.⁸The procedures most commonly used to improve patellar tracking or unloading in the PF compartment are lateral retinacular lengthening and TT transfer: medialization and/or distalization for correction of malalignment, and straight anteriorization or anteromedialization for unloading. These procedures can improve symptoms and function in lateral and distal patellar and trochlear lesions even without the addition of a cartilage restoration procedure.

Factors that are important in surgical decision-making include defect location and size, subchondral bone status, unipolar vs bipolar lesions, and previous cartilage procedure.

Location. The shapes of the patella and trochlea vary much more than the shapes of the condyles and plateaus. This variability complicates morphology matching, particularly with involvement of the central TG and median patellar ridge. Therefore, focal contained lesions of the patella and trochlea may be more technically amenable to cell therapy techniques than to osteochondral procedures, which require contour matching between donor and recipient

Size. Although small lesions in the femoral condyles can be considered for microfracture (MFx) or osteochondral autograft transfer (OAT), MFx is less suitable because of poor results in the PF joint, and OAT because of donor-site morbidity in the trochlea.

Subchondral bone status. When subchondral bone is compromised, such as with bone loss, cysts, or significant bone edema, the entire osteochondral unit should be treated. Here, OAT and osteochondral allograft (OCA) are the preferred treatments, depending on lesion size.

Unipolar vs bipolar lesions. Compared with unipolar lesions, bipolar lesions tend to have worse outcomes. Therefore, an associated unloading procedure (TT osteotomy) should be given special consideration. Autologous chondrocyte implantation (ACI) appears to have better outcomes than OCA for bipolar PF lesions.^9,10

Previous surgery. Although a failed cartilage procedure can negatively affect ACI outcomes, particularly in the presence of intralesional osteophytes,¹¹ it does not affect OCA outcomes.¹² Therefore, after previous MFx, OCA instead of ACI may be considered.

Fragment Fixation

Viable fragments from traumatic lesions (direct trauma or patellar dislocation) or osteochondritis dissecans should be repaired if possible, particularly in young patients. In a fragment that contains a substantial amount of bone, compression screws provide stable fixation. More recently, it has been recognized that fixation of predominantly cartilaginous fragments can be successful¹³ (Figure 1B). Débridement of soft tissue in the lesion bed and on the fragment is important in facilitating healing, as is removal of sclerotic bone.

MFx

Although MFx can have good outcomes in small contained femoral condyle lesions, in the PF joint treatment has been more challenging, and clinical outcomes have been poor (increased subchondral edema, increased effusion).¹⁴ In addition, deterioration becomes significant after 36 months. Therefore, MFx should be restricted to small (<2 cm²), well-contained trochlear defects, particularly in low-demand patients.

ACI and Matrix-Induced ACI

As stated, ACI (Figure 2) is suitable for PF joints because it intrinsically respects the complex anatomy.

Multiple case series with midterm and long-term follow-up have found improved outcomes for patella and trochlea.^8,15 With careful assessment and correction of malalignment, outcomes are similar to those of patients with normal anatomy.⁸ Results tend to be better for unipolar lesions than for bipolar lesions.¹⁵ TT osteotomy is a useful adjunct in correcting malalignment and unloading the PF compartment, even more so in the bipolar lesion setting. Previous procedures that violate the subchondral bone increase the risk of failure of subsequent ACI 3- to 7-fold, particularly in the presence of persistent subchondral abnormalities, such as intralesional osteophytes, cysts, and significant edema.¹¹

OAT

As mentioned, donor-site morbidity may compromise final outcomes of harvest and implantation in the PF joint. Nonetheless, in carefully selected patients with small lesions that are limited to 1 facet (not including the patellar ridge or the TG) and that require only 1 plug (Figure 3), OAT can have good clinical results.¹⁶

OCA

Two techniques can be used with OCA in the PF joint. The dowel technique, in which circular plugs are implanted, is predominantly used for defects that do not cross the midline (those located in their entirety on the medial or lateral aspect of the patella or trochlea). Central defects, which can be treated with the dowel technique as well, are technically more challenging to match perfectly, because of the complex geometry of the median ridge and the TG (Figure 4).

The shell technique is an alternative that can be used to treat very large defects. The chondral defect area and subchondral bone are removed with an oscillating saw, using the same plane as for patellar resurfacing (total knee arthroplasty or PF arthroplasty). A matching graft is created with a similar cut, made freehand.

Experimental and Emerging Technologies

Biocartilage

Biocartilage, a dehydrated, micronized allogeneic cartilage scaffold implanted with platelet-rich plasma and fibrin glue added over a contained MFx-treated defect, can be used in the patella and trochlea and has the same indications as MFx (small lesions, contained lesions). There are limited clinical studies of short- or long-term outcomes.

Fresh and Viable OCA

Fresh OCA (ProChondrix; AlloSource) and viable/cryopreserved OCA (Cartiform; Arthrex) are thin osteochondral scaffolds that contain viable chondrocytes and growth factors. They can be implanted alone or used with MFx, and are indicated for lesions measuring 1 cm² to 3 cm². Aside from a case report,¹⁷ there are no clinical studies on outcomes.

Bone Marrow Aspirate Concentrate Implantation

Bone marrow aspirate concentrate from centrifuged iliac crest–harvested aspirate containing mesenchymal stem cells with chondrogenic potential is applied under a synthetic scaffold. Indications are the same as for ACI. Medium-term follow-up studies in the PF joint have shown good results, similar to those obtained with matrix-induced ACI.¹⁸

Particulated Juvenile Allograft Cartilage

Particulated juvenile allograft cartilage (DeNovo NT Graft; Zimmer Biomet) is minced cartilage allograft (from juvenile donors) that has been cut into cubes (~1 mm³). Indications are for patellar and trochlear lesions 1 cm² to 6 cm². For both the trochlea and the patella, short-term outcomes have been good.^19,20

Rehabilitation After Surgery

Isolated PF cartilage restoration generally does not require prolonged weight-bearing restrictions, and ambulation with the knee locked in full extension is permitted as tolerated. Concurrent TT osteotomy, however, requires protection with 4 to 6 weeks of toe-touch weight-bearing to minimize the risk of tibial fracture.

Conclusion

Comprehensive preoperative assessment is essential and should include a thorough core-to-floor physical examination as well as PF-specific imaging. Treatment of symptomatic chondral lesions in the PF joint requires specific technical and postoperative management, which differs significantly from management involving the condyles. Attending to all these details makes the outcomes of PF cartilage treatment reproducible. These outcomes may rival those of condylar treatment.

References

1. Curl WW, Krome J, Gordon ES, Rushing J, Smith BP, Poehling GG. Cartilage injuries: a review of 31,516 knee arthroscopies. Arthroscopy. 1997;13(4):456-460.

2. Steensen RN, Bentley JC, Trinh TQ, Backes JR, Wiltfong RE. The prevalence and combined prevalences of anatomic factors associated with recurrent patellar dislocation: a magnetic resonance imaging study. Am J Sports Med. 2015;43(4):921-927.

3. Nomura E, Inoue M. Cartilage lesions of the patella in recurrent patellar dislocation. Am J Sports Med. 2004;32(2):498-502.

4. Vollnberg B, Koehlitz T, Jung T, et al. Prevalence of cartilage lesions and early osteoarthritis in patients with patellar dislocation. Eur Radiol. 2012;22(11):2347-2356.

5. Crema MD, Roemer FW, Marra MD, et al. Articular cartilage in the knee: current MR imaging techniques and applications in clinical practice and research. Radiographics. 2011;31(1):37-61.

6. Campbell KA, Erickson BJ, Saltzman BM, et al. Is local viscosupplementation injection clinically superior to other therapies in the treatment of osteoarthritis of the knee: a systematic review of overlapping meta-analyses. Arthroscopy. 2015;31(10):2036-2045.e14.

7. Saltzman BM, Jain A, Campbell KA, et al. Does the use of platelet-rich plasma at the time of surgery improve clinical outcomes in arthroscopic rotator cuff repair when compared with control cohorts? A systematic review of meta-analyses. Arthroscopy. 2016;32(5):906-918.

8. Gomoll AH, Gillogly SD, Cole BJ, et al. Autologous chondrocyte implantation in the patella: a multicenter experience. Am J Sports Med. 2014;42(5):1074-1081.

9. Meric G, Gracitelli GC, Gortz S, De Young AJ, Bugbee WD. Fresh osteochondral allograft transplantation for bipolar reciprocal osteochondral lesions of the knee. Am J Sports Med. 2015;43(3):709-714.

10. Peterson L, Vasiliadis HS, Brittberg M, Lindahl A. Autologous chondrocyte implantation: a long-term follow-up. Am J Sports Med. 2010;38(6):1117-1124.

11. Minas T, Gomoll AH, Rosenberger R, Royce RO, Bryant T. Increased failure rate of autologous chondrocyte implantation after previous treatment with marrow stimulation techniques. Am J Sports Med. 2009;37(5):902-908.

12. Gracitelli GC, Meric G, Briggs DT, et al. Fresh osteochondral allografts in the knee: comparison of primary transplantation versus transplantation after failure of previous subchondral marrow stimulation. Am J Sports Med. 2015;43(4):885-891.

13. Anderson CN, Magnussen RA, Block JJ, Anderson AF, Spindler KP. Operative fixation of chondral loose bodies in osteochondritis dissecans in the knee: a report of 5 cases. Orthop J Sports Med. 2013;1(2):2325967113496546.

14. Kreuz PC, Steinwachs MR, Erggelet C, et al. Results after microfracture of full-thickness chondral defects in different compartments in the knee. Osteoarthritis Cartilage. 2006;14(11):1119-1125.

15. Vasiliadis HS, Lindahl A, Georgoulis AD, Peterson L. Malalignment and cartilage lesions in the patellofemoral joint treated with autologous chondrocyte implantation. Knee Surg Sports Traumatol Arthrosc. 2011;19(3):452-457.

16. Astur DC, Arliani GG, Binz M, et al. Autologous osteochondral transplantation for treating patellar chondral injuries: evaluation, treatment, and outcomes of a two-year follow-up study. J Bone Joint Surg Am. 2014;96(10):816-823.

17. Hoffman JK, Geraghty S, Protzman NM. Articular cartilage repair using marrow simulation augmented with a viable chondral allograft: 9-month postoperative histological evaluation. Case Rep Orthop. 2015;2015:617365.

18. Gobbi A, Chaurasia S, Karnatzikos G, Nakamura N. Matrix-induced autologous chondrocyte implantation versus multipotent stem cells for the treatment of large patellofemoral chondral lesions: a nonrandomized prospective trial. Cartilage. 2015;6(2):82-97.

19. Farr J, Tabet SK, Margerrison E, Cole BJ. Clinical, radiographic, and histological outcomes after cartilage repair with particulated juvenile articular cartilage: a 2-year prospective study. Am J Sports Med. 2014;42(6):1417-1425.

20. Tompkins M, Hamann JC, Diduch DR, et al. Preliminary results of a novel single-stage cartilage restoration technique: particulated juvenile articular cartilage allograft for chondral defects of the patella. Arthroscopy. 2013;29(10):1661-1670.

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Author and Disclosure Information

Authors' Disclosure Statement: Dr. Gomoll reports that he is a paid consultant/advisory board member for Vericel, Joint Restoration Foundation, LifeNet, Smith & Nephew, and NuTech Medical. Dr. Farr reports that he is a paid consultant/advisory board member for Arthrex, Osiris Therapeutics, Vericel, and Zimmer Biomet; receives research/institutional support from Arthrex, RTI Biologics, Vericel, and Zimmer Biomet; and holds a design patent for a DePuy Synthes patellofemoral arthroplasty device. Dr. Hinckel reports no actual or potential conflict of interest in relation to this article.

Issue

The American Journal of Orthopedics - 46(5)

Publications

The American Journal of Orthopedics

MDedge Surgery

Topics

Knee

Orthopedics

Page Number

217-222

Read more about Cartilage Restoration in the Patellofemoral Joint

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Clinical Review

Author(s)

Betina B. Hinckel, MD, PhD

Andreas H. Gomoll, MD

Jack Farr II

Author(s)

Betina B. Hinckel, MD, PhD

Andreas H. Gomoll, MD

Jack Farr II

Author and Disclosure Information

Article PDF

ajo046050217.pdf

Article PDF

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Take-Home Points

Careful evaluation is key in attributing knee pain to patellofemoral cartilage lesions-that is, in making a "diagnosis by exclusion".
Initial treatment is nonoperative management focused on weight loss and extensive "core-to-floor" rehabilitation.
Optimization of anatomy and biomechanics is crucial.
Factors important in surgical decision-making incude defect location and size, subchondral bone status, unipolar vs bipolar lesions, and previous cartilage procedure.
The most commonly used surgical procedures-autologous chondrocyte implantation, osteochondral autograft transfer, and osteochondral allograft-have demonstrated improved intermediate-term outcomes.

Etiology

The primary causes of PF cartilage lesions are patellar instability, chronic maltracking without instability, direct trauma, repetitive microtrauma, and idiopathic.

Patellar Instability

Chronic Maltracking Without Instability

Direct Trauma

Repetitive Microtrauma

Idiopathic

History and Physical Examination

Imaging

Treatment

Surgery is indicated for full-thickness or nearly full-thickness lesions (International Cartilage Repair Society grade 3a or higher) >1 cm² after failed conservative treatment.

Factors that are important in surgical decision-making include defect location and size, subchondral bone status, unipolar vs bipolar lesions, and previous cartilage procedure.

Fragment Fixation

MFx

ACI and Matrix-Induced ACI

As stated, ACI (Figure 2) is suitable for PF joints because it intrinsically respects the complex anatomy.

OAT

OCA

Experimental and Emerging Technologies

Biocartilage

Fresh and Viable OCA

Bone Marrow Aspirate Concentrate Implantation

Particulated Juvenile Allograft Cartilage

Rehabilitation After Surgery

Conclusion

Take-Home Points

Careful evaluation is key in attributing knee pain to patellofemoral cartilage lesions-that is, in making a "diagnosis by exclusion".
Initial treatment is nonoperative management focused on weight loss and extensive "core-to-floor" rehabilitation.
Optimization of anatomy and biomechanics is crucial.
Factors important in surgical decision-making incude defect location and size, subchondral bone status, unipolar vs bipolar lesions, and previous cartilage procedure.
The most commonly used surgical procedures-autologous chondrocyte implantation, osteochondral autograft transfer, and osteochondral allograft-have demonstrated improved intermediate-term outcomes.

Etiology

The primary causes of PF cartilage lesions are patellar instability, chronic maltracking without instability, direct trauma, repetitive microtrauma, and idiopathic.

Patellar Instability

Chronic Maltracking Without Instability

Direct Trauma

Repetitive Microtrauma

Idiopathic

History and Physical Examination

Imaging

Treatment

Surgery is indicated for full-thickness or nearly full-thickness lesions (International Cartilage Repair Society grade 3a or higher) >1 cm² after failed conservative treatment.

Factors that are important in surgical decision-making include defect location and size, subchondral bone status, unipolar vs bipolar lesions, and previous cartilage procedure.

Fragment Fixation

MFx

ACI and Matrix-Induced ACI

As stated, ACI (Figure 2) is suitable for PF joints because it intrinsically respects the complex anatomy.

OAT

OCA

Experimental and Emerging Technologies

Biocartilage

Fresh and Viable OCA

Bone Marrow Aspirate Concentrate Implantation

Particulated Juvenile Allograft Cartilage

Rehabilitation After Surgery

Conclusion

References

1. Curl WW, Krome J, Gordon ES, Rushing J, Smith BP, Poehling GG. Cartilage injuries: a review of 31,516 knee arthroscopies. Arthroscopy. 1997;13(4):456-460.

3. Nomura E, Inoue M. Cartilage lesions of the patella in recurrent patellar dislocation. Am J Sports Med. 2004;32(2):498-502.

4. Vollnberg B, Koehlitz T, Jung T, et al. Prevalence of cartilage lesions and early osteoarthritis in patients with patellar dislocation. Eur Radiol. 2012;22(11):2347-2356.

5. Crema MD, Roemer FW, Marra MD, et al. Articular cartilage in the knee: current MR imaging techniques and applications in clinical practice and research. Radiographics. 2011;31(1):37-61.

8. Gomoll AH, Gillogly SD, Cole BJ, et al. Autologous chondrocyte implantation in the patella: a multicenter experience. Am J Sports Med. 2014;42(5):1074-1081.

10. Peterson L, Vasiliadis HS, Brittberg M, Lindahl A. Autologous chondrocyte implantation: a long-term follow-up. Am J Sports Med. 2010;38(6):1117-1124.

References

1. Curl WW, Krome J, Gordon ES, Rushing J, Smith BP, Poehling GG. Cartilage injuries: a review of 31,516 knee arthroscopies. Arthroscopy. 1997;13(4):456-460.

3. Nomura E, Inoue M. Cartilage lesions of the patella in recurrent patellar dislocation. Am J Sports Med. 2004;32(2):498-502.

4. Vollnberg B, Koehlitz T, Jung T, et al. Prevalence of cartilage lesions and early osteoarthritis in patients with patellar dislocation. Eur Radiol. 2012;22(11):2347-2356.

5. Crema MD, Roemer FW, Marra MD, et al. Articular cartilage in the knee: current MR imaging techniques and applications in clinical practice and research. Radiographics. 2011;31(1):37-61.

8. Gomoll AH, Gillogly SD, Cole BJ, et al. Autologous chondrocyte implantation in the patella: a multicenter experience. Am J Sports Med. 2014;42(5):1074-1081.

10. Peterson L, Vasiliadis HS, Brittberg M, Lindahl A. Autologous chondrocyte implantation: a long-term follow-up. Am J Sports Med. 2010;38(6):1117-1124.

Issue

The American Journal of Orthopedics - 46(5)

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The American Journal of Orthopedics - 46(5)

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217-222

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217-222

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Individualizing Treatment of Hyperglycemia in Type 2 Diabetes

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Individualizing Treatment of Hyperglycemia in Type 2 Diabetes

Author(s)

Maryam T. Fazel, PharmD, BCPS, BCACP, CDE

Merri L. Pendergrass, MD, PhD

From the University of Arizona College of Pharmacy and the University of Arizona College of Medicine-Tucson, Tucson, AZ.

Abstract

Objective: To summarize key issues relevant to managing hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and review a strategy for initiating and intensifying therapy.
Methods: Review of the literature.
Results: The 6 most widely used pharmacologic treatment options for hyperglycemia in T2DM are metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and insulin. Recent guidelines stress the importance of an individualized, patient-centered approach to managing hyperglycemia in T2DM, although sufficient guidance for nonspecialists on how to individualize treatment is often lacking. For patients with no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Due to the progressive nature of T2DM, glycemic control on metformin monotherapy is likely to deteriorate over time, and there is no consensus as to what the second-line agent should be. A second agent should be selected based on glycemic goal and potential advantages and disadvantages of each agent for any given patient. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added.
Conclusion: Although research is increasingly focusing on what the ideal number and sequence of drugs should be when managing T2DM, investigating all possible combinations in diverse patient populations is not feasible. Physicians therefore must continue to rely on clinical judgment to determine how to apply trial data to the treatment of individual patients.

Key words: type 2 diabetes; patient-centered care; antihyper-glycemic drugs; insulin; therapeutic decision-making.

Diabetes mellitus affects approximately 29.1 million people, or 9.3% of the U.S. population [1,2]. The high prevalence of diabetes and its associated multiple complications, including cardiovascular disease (CVD), blindness, renal failure, lower extremity amputations, and premature death, lead to a tremendous overall burden of disease. The financial cost is staggering as well, with more than 1 in 5 health care dollars spent on treating diabetes or its complications [3]. The goal of diabetes treatment is to prevent acute complications and reduce the risk of long-term complications. Interventions that have been shown to improve diabetes outcomes include medications for glycemic control and treatment of cardiovascular risk factors, nutrition and physical activity counseling, smoking cessation, immunizations, psychosocial care, and ongoing surveillance and early treatment for eye, kidney, and foot problems [4].

Glycemic management in type 2 diabetes mellitus (T2DM), the focus of this review, is growing increasingly complex and has been the subject of numerous extensive reviews [5,6] and published guidelines [4,7]. In the context of an increasing array of available pharmacologic options, there are mounting uncertainties regarding the benefits of intensive glycemic control as well as increasing concerns about potential adverse treatment effects, hypoglycemia in particular. While previous guidelines encouraged specific approaches for most patients, more recent guidelines stress the importance of a patient-centered approach with shared decision-making [4]. Less prescriptive guidelines are more appropriate, given the current state of science, but they also may be viewed as providing insufficient guidance to some providers. It can be overwhelming for a non-specialist to try to match the nuances of antihyperglycemic medications to the nuances of each patient’s preferences and medical characteristics.

This article examines key issues faced by primary care providers when managing hyperglycemia in patients with T2DM and outlines a stepwise approach to determining the optimal antihyperglycemic agent(s) (Table 1).

Focusing on the most widely used agents today, we discuss current evidence and recommendations around glycemic goal setting and the potential risks and benefits of various pharmacologic treatment options with emphasis on hypoglycemia risk, effects on weight, and cardiovascular outcomes.

Confirm Diagnosis of T2DM

It can be difficult to distinguish between type 1 diabetes mellitus and T2DM in some individuals due to overlapping characteristics. However, correctly classifying a patient’s diabetes at the outset is essential, as the classification helps determine the best treatment regimen and is rarely reconsidered [4,8]. Considerable evidence suggests that misclassification of diabetes occurs frequently [9,10], resulting in patients receiving inappropriate treatment. Clinical characteristics suggestive of T2DM include older age and features of insulin resistance such as obesity, hyper-tension, hypertriglyceridemia, and low high-density lipoprotein cholesterol. When these features are not present, an alternate diagnosis should be entertained.

Establish Glycemic Goal

Research over the past decade has led to a growing appreciation of the enormous complexity of hyperglycemia management. During the 1990s, landmark trials such as the Diabetes Control and Complications Trial (DCCT) [11] and UK Prospective Diabetes Study (UKPDS) [12] demonstrated that improving glucose control could reduce the incidence of microvascular complications [11,12], prompting a lower-is-better philosophy regarding glucose targets. Despite limited evidence to support such thinking, this viewpoint was adopted by the developers of many guidelines. During the following decade more research was devoted to determining whether aggressively lowering a patient’s glucose could also improve macrovascular outcomes. Table 2 summarizes microvascular and macrovascular effects of intensive glycemic control seen in major trials [11–23]. After several major trials [20,22] found only mild cardiovascular benefits and even suggested harm [18], experts and policy makers began to reconsider the value of tightly controlling glucose levels [24]. Since then, other studies have demonstrated that the potential benefits and risks of glucose control are strongly related to individual patient factors, such as age and duration of diabetes, and associated comorbidities, such as CVD and impaired renal function [6].

A one-size-fits-all glycemic goal is no longer recommended. Personalization is necessary, balancing the potential benefits and risks of treatments required to achieve that goal. Whereas an A1C of < 7% is an appropriate target for some individuals with diabetes, glycemic targets may be more or less stringent based on patient features including life expectancy, duration of diabetes, comorbidities, and patient attitude and support system (Table 3) [4].

A particular group in which less stringent goals should be considered is older patients, especially those with complex or poor health status [4,25]. The risk of intensive glycemic control may exceed the benefits in these patients, as they are at higher risk of hypoglycemia and polypharmacy [26]. A goal A1C of 7% to 7.5% is now recommended for healthy older adults, and less stringent A1C goals of 7.5% to 8% and 8% to 8.5% should be considered based on the presence and severity of multiple coexisting chronic illnesses, decreased self-care ability, or cognitive impairment [4,25]. Unfortunately, overtreatment is frequently seen in this group. In a recent study of patients over age 65 years, about 40% of those with complex or poor health status had tight glycemic control with A1C below 6.5% [26]. An analysis of U.S. Veterans Affairs administration data showed that only 27% of 12,917 patients older than 65 with very low A1C (< 6%) and about 21% of those with A1C of 6% to 6.5% underwent treatment deintensification [27].

Initiate Treatment with Metformin

There is strong consensus that metformin is the preferred drug for monotherapy due to its long proven safety record, low cost, weight-reduction benefit, and potential cardiovascular advantages [4,16]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. The recommendation is based on the fact that adherence to diet, weight reduction, and regular exercise is not sustained in most patients, and most patients ultimately will require treatment. Since metformin is usually well-tolerated, does not cause hypoglycemia, has a favorable effect on body weight, and is relatively inexpensive, potential benefits of early initiation of medication appear to outweigh potential risks.

The U.S. Food and Drug Administration (FDA) recently relaxed prescribing polices to extend the use of this important medication to patients who have mild–moderate, but stable, chronic kidney disease (CKD) [28]. Metformin is recommended as first-line therapy and should be used unless it is contraindicated (ie, estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m²)[4,7,29].

Add Additional Agent(s) as Needed to Achieve Goal

Other than metformin, evidence is limited for the optimal use of the burgeoning array of available agents, especially in dual or triple combinations [6,30]. Research is now starting to focus more on what the ideal number and sequence of drugs should be. The Glycemic Reduction Approach in Diabetes (GRADE) study, which will compare long-term benefits and risks of the 4 most widely used antihyperglycemic medications in combination with metformin, is now underway [31,32]. The 4 classes being studied are sulfonylurea, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and a basal,

long-acting insulin. From a practical standpoint, investigating all possible combinations in diverse patient populations is not feasible. Physicians therefore must continue to rely on clinical judgment to determine how to apply trial data to the treatment of individual patients.

Eleven classes of non-insulin medications are currently approved for treating hyperglycemia in T2DM [4]. Within each class, numerous agents are available. Six of these classes (ie, α-glucosidase inhibitors, colesevelam, bromocriptine, pramlintide, meglitinides, and thiazolidinediones) are not used frequently

because of their modest efficacy, inconvenient frequency of administration, and/or limiting side effects. The 4 most commonly used non-insulin antihyperglycemic drug classes that can be added to metformin or used if a patient cannot tolerate metformin include the sulfonylureas, DPP-4 inhibitors, GLP-1 receptor agonists, and sodium-glucose cotransporter-2 (SGLT-2) inhibitors. Because T2DM is a progressive disease, many patients eventually may require insulin to achieve their glycemic goals. The primary characteristics of commonly used non-insulin agents are summarized in Table 4 [4,6,29,30,33–37] and the properties of FDA-approved insulins are summarized in Table 5 [37,38].

Consider Effects on A1C

There is a paucity of high-quality, head-to-head comparison trials evaluating the ability of available agents to achieve recommended glycemic targets. This is important because the glucose-lowering effectiveness of individual medications is strongly influenced by baseline characteristics such as A1C, duration of diabetes, and previous therapy. With these limitations in mind, the relative glucose-lowering effectiveness of commonly used agents is shown in Table 4. When used as monotherapy, A1C reductions of approximately 1% to 1.5% are achieved with metformin, sulfonylureas, and GLP-1 receptor agonists [6,30,34,35,39]. DPP-4 inhibitors and SGLT-2 inhibitors have more modest glucose-lowering efficacy, with A1C reductions of approximately 0.5% to 1% [6,30,34,35,39]. Larger effects may be seen in individuals with higher baseline A1C and those who are drug naïve. Insulin is the most effective glucose-lowering agent—it can reduce virtually any level of A1C down to the normal range, with hypoglycemia being the only limiting factor. When a patient has uncontrolled hyperglycemia on metformin monotherapy, or if there is a contraindication or intolerance to metformin, clinicians should consider the potential glucose-lowering effects of other available options and should choose an agent that conceivably could bring a patient close to meeting their treatment goal.

Eliminate Options with Unacceptable Adverse Effects

When the pharmacologic options with acceptable A1C-lowering potential have been identified, the ones with contraindications and potential serious adverse effects for the individual patient can immediately be eliminated (Table 4). For example, if a patient has an eGFR < 30 mL/min/1.73 m², metformin, sulfonylureas, GLP-1 receptor agonists, most DPP-4 inhibitors, and SGLT-2 inhibitors are either contraindicated or should be used with caution. In patients with severe osteoporosis, SGLT-2 inhibitors may not be the best option. In patients with a history of diabetic ketoacidosis (DKA), caution should be used with metformin and SGLT-2 inhibitors. There have been concerns of possible acute pancreatitis and neoplasia with the incretin-based agents, the DPP-4 inhibitors and GLP-1 receptor agonists [40,41], although other clinical trials and observational data have not found increased risk [42–45]. Nevertheless, these agents potentially should be avoided in patients with a history of pancreatitis or neoplasm. SGLT-2 inhibitors may be associated with genitourinary infections and volume depletion [46–48] and probably should be avoided in patients at high risk for these conditions.

If the adverse effects are not serious, changing the way the medication is administered may allow the patient to tolerate agents with high potential benefits. For example, metformin is commonly associated with gastrointestinal (GI) adverse effects, which can be reduced or avoided with slow titration of the dose [6] or by switching to an extended-release formulation [49]. GLP-1 receptor agonists are associated with GI adverse effects [6] and in most cases slow titration is recommended.

Evaluate Potential Risks/Benefits of Remaining Options

Hypoglycemia. The barrier of hypoglycemia generally precludes maintenance of euglycemia and full realization of the long-term benefits of good glucose control over a lifetime. Once considered a trivial issue, concerns about hypoglycemia in T2DM are increasingly being raised [19,50–55]. Clearly, hypoglycemia occurs more often as glycemic targets are lowered to near-normal values, especially in those with advanced age and multiple comorbidities [55]. Various comorbidities frequently encountered particularly as patients age also are associated with increasing propensity for experiencing hypoglycemia and untoward outcomes from it. These include coronary artery disease, heart failure, renal and liver disease, and dementia. Hypoglycemia, when it occurs, may lead to dysrhythmias, dizziness, accidents and falls, work disability, and decreased quality of life. In addition to relaxing blood glucose targets in high-risk patients, drug selection should favor agents that do not precipitate such events (Table 4).

Fortunately, the commonly used non-insulin agents are not associated with hypoglycemia unless they are used in combination with sulfonylureas or insulin. Sulfonylureas should be used with caution and other options considered in patients with high risk for hypoglycemia. When insulin is required, regimens which minimize risk of hypoglycemia should be used. For example, adding a GLP-1 receptor agonist to basal insulin as an alternative to mealtime insulin has been shown to be equally effective with a lower risk of hypoglycemia [4,6]. Also, premixed insulin preparations should be avoided or used cautiously in individuals who miss meals frequently. Additionally, newer basal insulins that exhibit longer duration of action are now available in the United States. Preliminary studies have shown that the newly FDA-approved longer-acting basal insulins, insulin degludec and glargine U-300, may be associated with a reduced risk for hypoglycemia [56,57]. However, it remains unclear how and when these newer agents will best be incorporated into a treatment regimen.

Body weight. Nearly 90% of people living with T2DM are overweight or obese. Given the close tie between obesity and T2DM, treating obesity is an obvious consideration in diabetes treatment. Major trials have shown the effectiveness of lifestyle modifications and weight reduction in delaying, prevention, and management of T2DM [4,58,59].With this in mind, clinicians should consider preferentially using antihyperglycemic agents with weight-lowering or weight-neutral effects. Among commonly used antihyperglycemic agents, metformin, GLP-1 receptor agonists, and SGLT-2 inhibitors have been shown to have weight-reduction benefits, and DPP-4 inhibitors are weight neutral. On the other hand, sulfonylureas and insulin are associated with weight gain. A systematic review and meta-analysis including 204 studies with study durations ranging from 3 months to 8 years showed comparative effects of diabetes medications with a differential effect on weight of up to 5 kg (Table 4) [60].

Metformin is associated with an average weight loss of 1.9 to 3.1 kg that was sustained with long-term use for at least 10 years in the Diabetes Prevention Program Outcomes Study [61].A systematic review of 7 randomized trials showed that in patients with T2DM, the SGLT-2 inhibitors dapagliflozin and canagliflozin were associated with weight loss (mean weighted difference of –1.81 kg and –2.3 kg, respectively) [62]. A systematic review and meta-analysis of 25 randomized controlled trials showed greater weight loss (mean weighted difference of –2.9 kg) in overweight or obese patients with or without T2DM using GLP-1 receptor agonists when compared to placebo, insulin, or oral antihyperglycemic agents [63]. Of note, the GLP-1 receptor agonist liraglutide is now approved for weight loss in patients with or without diabetes [64]. The maximum doses approved for diabetes and obesity treatment are 1.8 and 3.0 mg/day, respectively.

Since weight loss is associated with improved glycemic control, an area of emerging interest is the use of antiobesity medications for managing diabetes. Although most older weight-loss medications were only approved for short-term use, some newer agents are approved for longer-term use. Lorcaserin and the combination drugs topiramate/phentermine and naltrexone/bupropion are approved for chronic therapy, provided certain conditions are met. Patients on weight reduction agents should be monitored regularly.

If weight loss of more than 5% is not achieved after 3 months of treatment, the therapy should be discontinued. Table 6 summarizes the efficacy and characteristics of FDA-approved weight loss medications [4,37,65–68].

An even more radical departure from conventional therapy for diabetes is the consideration of metabolic, or weight-loss, surgery, which has been found to be associated with rapid and dramatic improvements in blood glucose control. Metabolic surgery has been shown to improve glucose control more effectively than any known pharmaceutical or behavioral approach. For example, in an observational study of obese patients with T2DM, bariatric surgery led to diabetes remission rates of 72.3% 2 years after surgery and 30.4% 15 years after surgery compared to 16.4% and 6.5%, respectively, in control patients [69]. With long-term follow-up, significant decreases in microvascular and macrovascular complications were seen in the surgical group [69]. Compared with medical therapy alone, bariatric surgery plus medical therapy has been associated with more weight loss, better glycemic control, less need for diabetes medications, and improved quality of life [70]. A 2016 joint statement by numerous international diabetes organizations recommends considering metabolic surgery as a treatment for T2DM and obesity [71]. American Diabetes Association guidelines recommend consideration of bariatric surgery in individuals with T2DM who have a body mass index greater than 35 kg/m²,especially if achieving disease control is difficult by means of lifestyle modifications and medications [4].

Cardiovascular outcomes. Cardiovascular risk is about 2 to 4 times higher in patients with diabetes, and about half of patients with this condition develop heart failure [4,72]. CVD is responsible for most of the mortality in T2DM [72]. Therefore, prevention of cardiovascular morbidity and mortality is an important goal for diabetes treatment. Due to concerns about potential cardiovascular risks associated with glucose-lowering medications [73–76], the FDA has issued regulatory requirements for manufacturers to monitor the cardiovascular risk profile for these drugs [77]. Recent trials have led to a better understanding of potential cardiovascular benefits or harms of antihyperglycemic medications.

Metformin, the widely recommended first-line therapy for T2DM, carries a large body of evidence supporting its cardiovascular benefits. For example, the UKPDS found that compared to conventional therapy (mostly diet), metformin reduced cardiovascular events and mortality in obese patients with T2DM [15]. This result was supported in Hyperinsulinemia: the Outcome of its Metabolic Effect (HOME) study where, as an add-on to insulin, metformin decreased macrovascular complications when compared to placebo [78]. Research over the past decade also has assuaged concerns about metformin safety in heart failure [60]. A systematic review of observational studies involving 34,000 patients conducted in 2013 showed that metformin is as safe as other glucose-lowering medications in patients with diabetes and heart failure even in the presence of CKD [4,79]. Furthermore, numerous investigations have found metformin is not associated with increased hospitalizations or risk of lactic acidosis [80]. Metformin can be used safely in patients with diabetes and heart failure [60].

Although sulfonylureas have long been a mainstay of diabetes therapy, concerns about their potential adverse cardiovascular effects have been raised by numerous studies [81]. Tolbutamide, a first-generation sulfonylurea, was removed from the market after the University Group Diabetes Program study found increased CVD deaths with this agent versus placebo. Subsequently, the FDA issued a warning for all sulfonylureas [74]. The increased cardiovascular risk associated with sulfonylureas is thought to be due to their effect on cardiac mitochondrial potassium ATP channels. Sulfonylureas bind to these channels, preventing a protective phenomenon called ischemic preconditioning and resulting in a weakened defense against myocardial injury [76]. A recent study showed an increased risk of coronary heart disease associated with long-term use of sulfonylureas in women with diabetes [81].

GLP-1 receptor agonists have recently received much attention for their potential beneficial effects on cardiovascular outcomes. In a recent trial, lixisenatide was shown to be safe in patients with T2DM and acute coronary syndrome when compared to placebo [82]. More recently, the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial demonstrated significant cardiovascular benefits with liraglutide in patients with T2DM and established or high CVD risk [83]. The composite outcome of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction (MI), or nonfatal stroke, occurred less frequently in the liraglutide group compared to placebo (13% versus 14.9%, respectively), and there were fewer deaths from cardiovascular causes in the liraglutide group compared to placebo (4.7% and 6.0%, respectively) [83]. Other trials investigating the cardiovascular outcomes of this class [84,85] are in progress.

Another class with potential cardiovascular benefits is the SGLT-2 inhibitors. In a recent cardiovascular outcome study, empagliflozin significantly lowered the composite of cardiovascular death, nonfatal MI, or nonfatal stroke in T2DM patients with high cardiovascular risk compared to placebo (10.5% and 12.1%, respectively) [86]. There are several large ongoing studies evaluating the cardiovascular effects of other SGLT-2 inhibitors [87–89].

DPP-4 inhibitors were examined in recent studies and have shown no cardiovascular benefits [42,44,90].The studies showed mixed results regarding an association between DPP-4 inhibitors and heart failure. In one study, saxagliptin was associated with increased hospitalization for heart failure compared to placebo [44], while 2 noninferiority trials did not show a significant increase in heart failure hospitalizations associated with alogliptin and sitagliptin when compared to placebo [42,90].

Administration Considerations

Many patients with T2DM require multiple agents for glycemic control. Additional medications used for comorbid conditions add to this burden. When choosing antihyperglycemic agents, the route and frequency of administration, as well as the patients’ preferences and ability, should be considered. Either once or twice daily dosing is available for most agents, and once weekly dosing is available for some of the GLP-1 receptor agonists. Once daily or once weekly formulations may improve adherence and be more desirable than preparations that are dosed twice daily. Most of the commonly used medications are dosed orally. Although many patients find this route of administration preferable to insulin or GLP-1 receptor agonists, which require injections, some patients may prefer the risk/benefit of injectable agents. All GLP-1 receptor agonists come in a pen delivery system, which eliminates mixing and provides more convenient administration. Extended-release exenatide also is available as a single-dose tray that requires mixing and may be more cumbersome to inject.

Insulin requires special consideration. There has been an enormous increase in the number of insulin products on the market in the past 2 decades. These products include insulin analogs, concentrated insulins (U-200, U-300, and U-500), premixed insulin preparations, and ultra-long-acting insulin [91]. The availability of insulin options with different concentrations, onsets, and durations of actions has made decision making on which insulin to use difficult. Clinicians need to consider patient preference, dosing frequency, and timing with regard to meals, insulin dose, administration, as well as cost. For example, concentrated insulin is preferred for a patient on high doses of insulin requiring injecting a large volume of insulin. Rapid-acting insulin analogs would be more appropriate for patients who have difficulty administering their regular insulin 20 to 30 minutes before eating. Premixed insulin preparations make it impossible to independently adjust short- and long-acting components. However, these may be good choices in patients who have consistent meal schedules and who want to simplify administration. Despite a prevailing misconception that NPH must be given twice a day, it has long been recognized that in T2DM, a single daily injection of NPH yields improvements in control similar to those achieved with 2 daily injections [92].

Cost Considerations

Treating T2DM imposes a great financial burden on individuals living with diabetes and their families due to the high cost of the medications. Table 4 and Table 5 provide information on the cost of non-insulin and insulin diabetes medications for patients who do not have prescription insurance coverage. From a practical standpoint, choice of diabetes agents is largely influenced by insurance formularies.

The older agents, metformin and the sulfonylureas, are available for a cash (no insurance) price of as little as $4 per month. This is in stark contrast to the SGLT-2 inhibitors, GLP-1 receptor agonists, and DPP-4 inhibitors, which range in cost between $400 and $600 per month. Of recent concern, the cost of insulin has been skyrocketing, with a more than 500% increase in the cost of certain insulins from 2001 to 2015 [93]. According to the Medical Expenditure Panel Survey (MEPS) from 2002 to 2013, the mean price of insulin increased by about 200% (from $4.34/mL to $12.92/mL) during this period, which was significantly higher than increases in the price of non-insulin comparators [94]. The introduction of biosimilar insulins to the market is expected to offer treatment options with lower cost. This will be tested when the biosimilar glargine, the first FDA-approved biosimilar insulin, becomes available in the U.S. market. However, a significant reduction in insulin prices is not expected soon [95].

When insulin is required, most patients with T2DM can be treated with older human insulins, which have similar efficacy and lower costs than the more expensive newer insulin analogs. A Cochrane review comparing basal insulin analogs to NPH showed similar efficacy in glycemic control with minimal clinical benefit in the form of less nocturnal hypoglycemia in the insulin analog arm [96]. Furthermore, similar glycemic control and risk of hypoglycemia was seen when regular insulin was compared with the rapid-acting insulin analogs [97]. The cost of human NPH insulin for a patient on a total daily dose of 60 units is approximately $52 per month. This contrasts with the most widely used insulin, insulin glargine, which has a cash price of about $500 per month for the same amount (Table 5). Insulin pens, which are convenient, are more expensive. Interestingly, human insulins do not require prescriptions, allowing underinsured, underfunded patients ongoing access to them.

Incorporating Patient Preferences

Research evidence is necessary but insufficient for making patient care decisions. Along with the potential benefits, harms, costs, and inconveniences of the management options, patient perspectives, beliefs, expectations, and health-related goals must be considered. Patients will undoubtedly have preferences regarding defining goals and ranking options. Clinicians should discuss therapeutic goals and treatment options and work collaboratively with patients in determining management strategies [98].

Summary

Potential treatment approaches for treating hyperglycemia in T2DM are summarized in Figure 1 and Figure 2 [4,7]. As long as there are no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Even if metformin monotherapy is initially effective, glycemic control is likely to deteriorate over time due to progressive loss of β-cell function in T2DM.

There is no consensus as to what the second-line agent should be. Selection of a second agent should be made based on potential advantages and disadvantages of each agent for any given patient. A patient-centered approach is preferred over a fixed algorithm. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added. In patients with modestly elevated A1C (below ~8%), addition of a third non-insulin agent may be equally effective as (but more expensive than) addition of insulin.

Patients with significantly elevated A1C levels on non-insulin agents usually should have insulin added to their regimen. When insulin is added, metformin should be continued. DPP-4 inhibitors and sulfonylureas are typically stopped. If SGLT-2 inhibitors and/or GLP-1 receptor agonists are continued, this may aid with weight maintenance. However, continuing these agents is likely to be expensive and associated with problems associated with polypharmacy.

The most widely recommended strategy for initiating insulin in T2DM is to add a single bedtime injection of basal insulin (ie, NPH, glargine, detemir, or degludec) to the patient’s regimen. This regimen has been found to be effective in numerous studies and controls hyperglycemia in up to 60% of patients [99]. If the patient is treated with a single bedtime injection of insulin and the fasting glucose level is within the target range but the A1C level remains above goal, addition of mealtime insulin injections is likely to be beneficial. Alternatively, addition of a GLP-1 receptor agonist to basal insulin has been shown to be equally beneficial [4,6]. When adding mealtime insulin, a common strategy is to add a single injection of a rapid-acting insulin (eg, lispro, aspart, glulisine) before the patient’s largest meal of the day. Additional premeal injections of rapid-acting insulin may be added as needed, based on self-monitoring blood glucose results. If glycemia remains significantly uncontrolled on more than 200 units of insulin per day, switching to a concentrated form of insulin (eg, U-200, U-300, or U-500) should be considered.

Corresponding author: Maryam Fazel, PharmD, BCPS, BCACP, CDE, 1295 N. Martin Ave. (Room B211B), Tucson, Arizona 85721-0202, [email protected].

Financial disclosures: None.

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Issue

Journal of Clinical Outcomes Management - January 2017, Vol. 24, No 1

Publications

Journal of Clinical Outcomes Management

Type 2 Diabetes ICYMI

Topics

Diabetes

Read more about Individualizing Treatment of Hyperglycemia in Type 2 Diabetes

Sections

Clinical Review

Author(s)

Maryam T. Fazel, PharmD, BCPS, BCACP, CDE

Merri L. Pendergrass, MD, PhD

Author(s)

Maryam T. Fazel, PharmD, BCPS, BCACP, CDE

Merri L. Pendergrass, MD, PhD

From the University of Arizona College of Pharmacy and the University of Arizona College of Medicine-Tucson, Tucson, AZ.

Abstract

Objective: To summarize key issues relevant to managing hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and review a strategy for initiating and intensifying therapy.
Methods: Review of the literature.
Results: The 6 most widely used pharmacologic treatment options for hyperglycemia in T2DM are metformin, sulfonylureas, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and insulin. Recent guidelines stress the importance of an individualized, patient-centered approach to managing hyperglycemia in T2DM, although sufficient guidance for nonspecialists on how to individualize treatment is often lacking. For patients with no contraindications, metformin should be recommended concurrent with lifestyle intervention at the time of diabetes diagnosis. Due to the progressive nature of T2DM, glycemic control on metformin monotherapy is likely to deteriorate over time, and there is no consensus as to what the second-line agent should be. A second agent should be selected based on glycemic goal and potential advantages and disadvantages of each agent for any given patient. If the patient progresses to the point where dual therapy does not provide adequate control, either a third non-insulin agent or insulin can be added.
Conclusion: Although research is increasingly focusing on what the ideal number and sequence of drugs should be when managing T2DM, investigating all possible combinations in diverse patient populations is not feasible. Physicians therefore must continue to rely on clinical judgment to determine how to apply trial data to the treatment of individual patients.

Key words: type 2 diabetes; patient-centered care; antihyper-glycemic drugs; insulin; therapeutic decision-making.

Confirm Diagnosis of T2DM

Establish Glycemic Goal

Initiate Treatment with Metformin