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T h e n e w e ng l a n d j o u r na l o f m e dic i n e Interactive at www.nejm.org
Management of Type 2 Diabetes
This interactive feature addresses the diagnosis or management of a clinical case. A case vignette is fol owed by specific clinical options, none of which can be considered either correct or incorrect. In short essays, experts in the field then argue for each of the options. In the online version of this feature, available at www.nejm.org, readers can participate in forming community opinion by choosing one of the options and, if they like, providing their reasons. c a se vigne t te
A 55-year-old woman with type 2 diabetes, obesity, assessment, including cardiorespiratory, abdomi-
and hypertension has been under your care for nal, and neurologic examinations, is normal.
the past 2 years. She has no history of microal- Her glycated hemoglobin level is 8.1%, and buminuria, retinopathy, or neuropathy. She has her creatinine 0.9 mg per deciliter (80 mmol per never had a cardiovascular event and reports no liter). She has no microalbuminuria, and liver- function studies are normal. She seeks advice In the past, she has successfully lost weight about the management of her diabetes.
(from 5 to 12 kg) on various diets but each time has regained all of the weight she lost. She tries tions, any one of which could be considered to walk 30 minutes each day. She monitors her correct, would you find most appropriate for this fasting glucose levels three times weekly using a patient? Base your choice on the published litera- personal glucometer, and her morning fasting ture, your past experience, recent guidelines, and glucose levels have ranged between 110 and other sources of information, as appropriate.
140 mg per deciliter (6.1 and 7.8 mmol liter). She has been receiving metformin (1000 mg twice a 1. Add pioglitazone.
day) and glipizide (10 mg twice daily).
2. Add neutral protamine Hagedorn (NPH) insu-
She has hypertension that is treated with hydro- lin before bedtime.
chlorothiazide (25 mg daily) and lisinopril (20 mg 3. Add exenatide twice daily.
daily). She takes aspirin (81 mg daily) and sim- vastatin (20 mg daily). She notes that she consis- To aid in your decision making, each of these approaches to treatment is defended by an expert She has a family history of cardiovascular dis- in the management of diabetes in the following ease with early stroke. On physical examination, short essays. Given your knowledge of the condi- her body-mass index (the weight in kilograms di- tion and the points made by the experts, which vided by the square of the height in meters) is 31. treatment approach would you choose? Make your Her blood pressure is 128/78 mm Hg. Her general choice on our Web site (www.nejm.org).
tre atment op tion 1
Add Pioglitazone
min and glipizide, as in this patient. Medications such as pioglitazone can delay the almost inevi- table necessity of initiating the use of insulin in The case vignette illustrates a key therapeutic such patients. Furthermore, patients receiving a decision most physicians face when managing thiazolidinedione who later need insulin may type 2 diabetes: namely, how to advance treat- have a better response to it than those not receiv- ment in patients whose glycated hemoglobin lev- ing a thiazolidinedione. However, there are no els remain above the target value despite dual oral comparative data to determine what the optimal
antihyperglycemic therapy, such as with metfor- treatment should be when a patient does not have n engl j med 358;3 www.nejm.org january 17, 2008 Downloaded from www.nejm.org at REGION SKANE on January 20, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e a response to dual oral therapy. I believe the ad- pecially if administered soon after the glycated dition of pioglitazone is a rational next step.
hemoglobin level begins to rise, longer-term stud- Several short-term trials have examined the ies are needed to evaluate the effectiveness of this effects of thiazolidinedione treatment as an approach.
“add-on” therapy in patients with elevated gly- In support of this strategy, the ratio of proin- cated hemoglobin values who are already taking sulin to insulin, considered a marker of beta-cell maximum doses of metformin and a sulfonylu- function, improved when pioglitazone was add- rea. Collectively, these studies demonstrate that ed to metformin and sulfonylurea as treatment.4 the addition of a thiazolidinedione can lower the Pioglitazone also mobilizes fat from the liver, an glycated hemoglobin level by as much as 2 per- effect that is thought to be accompanied by sen- centage points. Three such studies compared the sitization of the liver to insulin. Fatty liver is addition of a thiazolidinedione or insulin to the common in patients with diabetes and is linked metformin–sulfonylurea treatment regimen of sub- in selected patients to the development of steato- jects with baseline glycated hemoglobin values of hepatitis, which pioglitazone has been shown to more than 9.0%.1-3 These studies showed that a ameliorate. thiazolidinedione had an efficacy similar to that Finally, despite the findings in meta-analyses of insulin in lowering glycated hemoglobin levels. that rosiglitazone may increase the risk of ische- Together, the studies suggest that, as compared mic events, a similar effect has not been demon- with treatment with insulin, treatment with pio- strated for pioglitazone.5 In fact, there is evidence glitazone is associated with a lower incidence of that treatment with pioglitazone increases the HDL hypoglycemia, a similar amount of weight gain, cholesterol level by 10 to 15%, lowers the systolic and an increase in the high-density lipoprotein blood pressure by 4 to 5 mm Hg, and reduces the (HDL) cholesterol level. The expenses associated thickness of the carotid wall, as compared with with the triple oral therapies that include a thia- a sulfonylurea. In addition, a marginally beneficial zolidinedione are greater than those of either effect on ischemic events was found when pio- insulin (70% NPH insulin and 30% regular in- glitazone was added to existing treatment in pa- sulin) or insulin glargine added to metformin– tients with type 2 diabetes in the Prospective Pioglitazone Clinical Trial in Macrovascular Pioglitazone is likely to have few side effects Events (PROactive), a randomized, double-blind, and can be taken once daily. The weight gain that controlled clinical trial of a strategy that was typically accompanies its use (3–4 kg, on average) considered cost-effective. In combination, these can be mitigated by intensifying medical nutri- results support the possibility that pioglitazone tion therapy at the time of initiation. Since recent may have cardioprotective effects; it would be evidence suggests that the use of thiazolidine- my choice for this patient.
diones may reduce bone density, a bone-density Dr. Goldberg reports receiving speaker’s honoraria from both scan may be appropriate, particularly for women Takeda and GlaxoSmithKline and consulting fees and grant sup- port from Takeda. No other potential conflict of interest relevant It is possible that the need for initiating insu- lin therapy is delayed by the addition of piogli- From the Division of Endocrinology, Diabetes, and Metabolism, tazone in patients whose diabetes is inadequately Diabetes Research Institute, University of Miami Miller School controlled with the use of metformin and sulfo- nylurea. One study, A Diabetes Outcome Progres- sion Trial (ADOPT), showed that rosiglitazone, Treatment Option 2
when used as initial monotherapy in patients with a recent diagnosis of type 2 diabetes, maintained Add NPH Insulin
glycemic targets for longer than did treatment before Bedtime
with sulfonylurea or metformin and suggested that this might be due to a beneficial effect on beta- Rury Holman, F.R.C.P.
cell function. Though the addition of pioglitazone to a regimen of metformin and a sulfonylurea The case vignette of a patient with type 2 diabe- could be expected to have a durable effect on the tes who has suboptimal glycemic control despite maintenance of improved glycemic control, es- receiving maximum-dose oral therapy with met- n engl j med 358;3 www.nejm.org january 17, 2008 Downloaded from www.nejm.org at REGION SKANE on January 20, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. formin and a sulfonylurea is all too familiar. It Insulin therapy can reduce absolute glycated reflects the progressive nature of the condition, hemoglobin values sufficiently — by 1.5 to 3.5% in which declining beta-cell function results in — to allow glycemic targets to be met.7 Adding elevations in glycemia year after year6 unless an- an intermediate-acting insulin before bedtime is tidiabetes medications are added or the doses of a relatively straightforward approach to increas- these medications are increased. In this obese ing therapy for glycemia. It can be undertaken patient who has no clinical evidence of compli- readily in a community-care–based setting and cations from diabetes and whose cardiovascular obviates the need to amend existing therapy. risk factors are currently well managed, the im- Some patients may be concerned about self-injec- mediate concern is the need to reduce the glycated tion but can be reassured that with modern nee-
hemoglobin level to below that recommended in dles it is a virtually painless process and cer- the International Diabetes Federation 2005 guide- tainly much less onerous than their finger-stick lines (6.5%) to minimize the risk of future com- capillary-glucose measurements. Maintaining plications. Ideally, glycemic control should be existing sulfonylurea therapy when supplement- handled in a proactive manner, according to the ing basal insulin requirements means that the joint consensus algorithm for the management required insulin dose is lower8 and the problem of hyperglycemia from the American Diabetes of offsetting sudden glycemic deterioration when Association (ADA) and the European Association a sulfonylurea is withdrawn can be avoided.9 The for the Study of Diabetes (EASD),7 which sug- initiation of NPH insulin at bedtime involves a gests that a glycated hemoglobin value of 7% or single injection at a time when patients will be more should serve as “a call to action to initiate undressed and does not require them to carry
or change therapy, with the goal of achieving a insulin-injection equipment during the day. Gly- glycated hemoglobin level as close to the non- cemic control can still be monitored, and the need for insulin-dose adjustments can be determined Adding a third oral agent is not recommend- by continuing to measure mainly fasting glucose ed, given that the patient already has a glycated levels.
hemoglobin value of 8.1% and that this approach The Treat-to-Target trial showed that system- is relatively more expensive and potentially not atic titration of bedtime NPH insulin, used in as effective in reducing glycemia as adding insu- addition to oral therapy, can safely achieve a 7% lin would be.7 Adding a basal insulin to existing glycated hemoglobin value in a majority of over- oral therapy has been shown to be more effec- weight patients with type 2 diabetes who have tive in reducing glycated hemoglobin levels than glycated hemoglobin levels between 7.5% and adding a thiazolidinedione — especially at higher 10.0% when receiving oral agents alone. The initial glycated hemoglobin values — with less mean (±SE) weight gain was modest (2.8±0.2 kg) weight gain, no edema, salutary lipid changes, with a confirmed rate of hypoglycemic events of and a lower cost.3 Indeed, the increased risk of 5.1 per patient per year. The Treating to Target edema, congestive heart failure, and fractures in in Type 2 diabetes (4-T) trial showed that adding women now recognized to be associated with a basal insulin, instead of a biphasic insulin thiazolidinediones and the uncertainty about their twice a day or a short-acting insulin three times effects on the risk of cardiovascular disease have a day, to metformin and sulfonylurea reduced led to an updated recommendation by the ADA– the likelihood of hypoglycemia by half to three EASD that greater caution should be exercised in quarters, with a decrease in weight gain by half their use. Adding exenatide in this patient would to two thirds. Insulin doses vary considerably be unlikely to achieve the target glycated hemo- among patients, but safe starting doses can be globin levels (<6.5% or <7.0%), given an expected easily calculated, as shown in the 4-T trial. Pa- absolute decrease in the level of only 0.5 to 1.0%, tients can then adjust their doses, using a simple despite the potential weight loss, and would in- algorithm, as demonstrated in the Treat-to-Tar- cur a risk of gastrointestinal side effects.7 Also, get trial. In the long term, this incremental ap- exenatide requires twice-daily injections, and de- proach to adding insulin therapy as a once-daily spite its increasing use, there have been no large- bedtime injection can ease the transition to a more scale trials to assess its efficacy or safety in the complex insulin regimen in the face of continued n engl j med 358;3 www.nejm.org january 17, 2008 Downloaded from www.nejm.org at REGION SKANE on January 20, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. T h e n e w e ng l a n d j o u r na l o f m e dic i n e Dr. Holman reports receiving consulting or advisory fees A recent meta-analysis of clinical trials in- from Amylin, Eli Lilly, Merck, Novartis, and Sanofi-Aventis; lecture fees from Astella, Ajinomoto, Bayer, GlaxoSmithKline, volving incretin therapies concluded that the ef- Eli Lilly, King Pharmaceuticals, Merck, Merck Serono, and ficacy of these agents was generally similar to Sanofi-Aventis; grant support from Bristol-Myers Squibb, Novar- that of other antidiabetes therapies. Of direct tis, Pfizer, Merck Serono, and Novo Nordisk; and royalties from Owen Mumford for a finger-stick device. No other potential relevance to the treatment of this patient, exena- conflict of interest relevant to this article was reported.
tide produces more potent control of postpran- dial glycemia than NPH insulin or pioglitazone, From the University of Oxford, Diabetes Trials Unit, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill probably because exenatide suppresses gastric Hospital, Oxford, United Kingdom.
emptying. This finding may be important, in view of data linking the control of postprandial glycemia to cardiovascular risk in patients with Tre atment Op tion 3
diabetes. The opportunity to improve postpran- Add Exenatide Twice Daily
dial glucose control, while achieving weight loss, Although considerable preclinical data sug- gest that GLP-1–receptor agonists improve beta- The management options for the treatment of cell function and are cardioprotective, such dis- type 2 diabetes have become more complex since cussions may not be directly relevant for the care the introduction of several new classes of drugs of this patient. The actions of GLP-1–receptor and emerging data about the safety and efficacy agonists on the stimulation of insulin and inhi- of older drugs. It remains difficult to predict the bition of glucagon secretion are glucose-depen- response to specific therapies targeting different dent; hence, there is a very low risk of hypogly- antidiabetes mechanisms, and all three options cemia in the absence of concomitant sulfonylurea posed in the case vignette are reasonable and therapy. The remarkable ability of GLP-1–recep- efficacious. There are no available head-to-head tor agonists to improve the glucose sensitivity of trials that have directly compared the efficacies beta cells and potentiate insulin secretion rap- of pioglitazone, NPH insulin, and exenatide in idly suggests that discontinuation of the glipi- patients in whom glycemic control has not been zide (or alternatively, the initial reduction of the achieved with the use of metformin and a sulfo- dose by 50%), coincident with initiation of ex- nylurea; thus, it seems reasonable to make clini- enatide therapy, would be prudent.
cal decisions on the basis of available data. The The addition of exenatide to ongoing metfor- addition of pioglitazone will improve insulin min and sulfonylurea therapy was associated sensitivity and glucose control but probably will with an absolute reduction of 0.8 to 1.0% in the be associated with fluid retention and weight glycated hemoglobin level, with 0.9 to 1.6 kg of gain and an increased risk of osteoporosis.10 In- weight loss, after 30 weeks of therapy in subjects sulin therapy, while effective, may also be asso- with type 2 diabetes.12 There have been several ciated with weight gain and a need for more fre- head-to-head comparisons of regimens of insulin quent glucose monitoring to minimize the risk administration, as compared with twice-daily exenatide, in patients who did not have adequate Two new classes of antidiabetes agents based glycemic control when they were taking metfor- on the potentiation of incretin action have been min and a sulfonylurea.13,14 The use of exenatide approved for the treatment of type 2 diabetes: and the use of insulin resulted in similar degrees the glucagon-like peptide 1 (GLP-1) receptor of reduction in glycated hemoglobin and similar agonists, exemplified by exenatide, and the di- numbers of hypoglycemic events, but the resul- peptidyl peptidase IV inhibitors that include sita- tant body weight was significantly higher at the gliptin and vildagliptin11; other drugs are currently end of the study in patients receiving insulin, in clinical trials. Exenatide (as well as GLP-1) often as much as 4 kg higher than in subjects lowers blood glucose levels by stimulating insu- taking exenatide.
lin secretion and inhibiting glucagon secretion. What are the potential limitations associated These drugs also appear to inhibit gastric empty- with exenatide therapy? Gastrointestinal side ef- ing and enhance satiety, leading to weight loss in fects, principally nausea, generally abate several weeks after the initiation of exenatide therapy. n engl j med 358;3 www.nejm.org january 17, 2008 Downloaded from www.nejm.org at REGION SKANE on January 20, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved. Nausea and gastrointestinal upset may limit toler- 3. Rosenstock J, Sugimoto D, Strange P, Stewart JA, Soltes-Rak
ability in 10 to 20% of patients, and pancreatitis E, Dailey G. Triple therapy in type 2 diabetes: insulin glargine or rosiglitazone added to combination therapy of sulfonylurea plus has recently been described in subjects treated metformin in insulin-naive patients. Diabetes Care 2006;29: with exenatide, although the actual prevalence is 554-9.
low and the pathophysiological characteristics 4. Dorkhan M, Magnusson M, Frid A, Grubb A, Groop L, Jo-
vinge S. Glycaemic and nonglycaemic effects of pioglitazone in remain uncertain. Exenatide therapy is expen- triple oral therapy of patients with type 2 diabetes. J Intern Med sive, and its long-term durability and safety have 2006;260:125-33.
not been defined. Since incretin drugs are new, 5. Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone
and risk of cardiovascular events in patients with type 2 diabetes they are comparatively more expensive than older mellitus: a meta-analysis of randomized trials. JAMA 2007;298: agents, and we do not yet have outcome studies 1180-8.
to determine the long-term effects of exenatide on 6. U.K. Prospective Diabetes Study Group. U.K. prospective
diabetes study 16: overview of six years’ therapy of type 2 diabe- beta-cell function or cardiovascular events. On the tes: a progressive disease. Diabetes 1995;44:1249-58. [Erratum, other hand, the use of exenatide reduces glyce- Diabetes 1996;45:1655.] mia through multiple mechanisms of action, is 7. Nathan DM, Buse JB, Davidson MB, et al. Management of
hyperglycemia in type 2 diabetes: a consensus algorithm for the simple to use, and provides superior control of initiation and adjustment of therapy. Diabetes Care 2006;29:1963- postprandial glucose. Critically, unlike with ex- 72. [Erratum, Diabetes Care 2006;49:2816-8.] isting diabetes therapies, many subjects will ex- 8. Holman RR, Steemson J, Turner RC. Sulphonylurea failure
in type 2 diabetes: treatment with a basal insulin supplement. perience satiety and weight loss. These features Diabet Med 1987;4:457-62.
make exenatide an appealing option for the treat- 9. Nybäck-Nakell Å, Adamson U, Lins PE, Landstedt-Hallin L.
ment of patients in whom existing antidiabetic Glycaemic responsiveness to long-term insulin plus sulphonyl- urea therapy as assessed by sulphonylurea withdrawal. Diabet agents fail to achieve glycemic control.
Dr. Drucker reports receiving advisory or consulting fees 10. Schwartz AV, Sellmeyer DE, Vittinghoff E, et al. Thiazolidin-
from Amylin Pharmaceuticals, Arisaph Pharmaceuticals, edione use and bone loss in older diabetic adults. J Clin Endocri- Chugai, Conjuchem, Eli Lilly, Emisphere Technologies, Glaxo- nol Metab 2006;91:3349-54.
SmithKline, Glenmark Pharmaceuticals, Isis Pharmaceuticals, 11. Drucker DJ, Nauck MA. The incretin system: glucagon-like
Merck Research Laboratories, Novartis Pharmaceuticals, Novo peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibi- Nordisk, NPS Pharmaceuticals, Phenomix, Takeda, and Transi- tors in type 2 diabetes. Lancet 2006;368:1696-705.
tion Pharmaceuticals; and grant support from Eli Lilly, Merck, 12. Kendall DM, Riddle MC, Rosenstock J, et al. Effects of ex-
and Novo Nordisk. No other potential conflict of interest rele- enatide (exendin-4) on glycemic control over 30 weeks in pa- tients with type 2 diabetes treated with metformin and a sulfo- nylurea. Diabetes Care 2005;28:1083-91.
From Banting and Best Diabetes Centre, University of Toronto, 13. Heine RJ, Van Gaal LF, Johns D, Mihm MJ, Widel MH,
Mount Sinai Hospital, Toronto.
Brodows RG. Exenatide versus insulin glargine in patients with suboptimally controlled type 2 diabetes: a randomized trial. 1. Aljabri K, Kozak SE, Thompson DM. Addition of piogli-
tazone or bedtime insulin to maximal doses of sulfonylurea and 14. Nauck MA, Duran S, Kim D, et al. A comparison of twice-
metformin in type 2 diabetes patients with poor glucose control: daily exenatide and biphasic insulin aspart in patients with type a prospective, randomized trial. Am J Med 2004;116:230-5.
2 diabetes who were suboptimally controlled with sulfonylurea 2. Schwartz S, Sievers R, Strange P, Lyness WH, Hollander P, and metformin: a non-inferiority study. Diabetologia 2007;50:
INS-2061 Study Team. Insulin 70/30 mix plus metformin versus 259-67.
triple oral therapy in the treatment of type 2 diabetes after fail- Copyright 2008 Massachusetts Medical Society. ure of two oral drugs: efficacy, safety, and cost analysis. Diabe- n engl j med 358;3 www.nejm.org january 17, 2008 Downloaded from www.nejm.org at REGION SKANE on January 20, 2008 . Copyright 2008 Massachusetts Medical Society. All rights reserved.

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