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Diabetes?
What's new in diabetes
What's new in ... Diabetes? Sean F Dinneen
The scale of the diabetes pandemic is frightening. As well as seeing increasing numbers of patients, many countries are reporting earlier onset of type 2 diabetes and its associated complications. The United Nations has recently adopted a resolution on diabetes and designated November 14th World Diabetes Day. Lifestyle modification remains the cornerstone of preventive and management strategies, however, it is usually not associated with sustained benefit. Clinicians need more and better drugs in their therapeutic armamentarium. The release of drugs in the incretin class of gut peptide-related compounds is welcome; the withdrawal of inhaled insulin from the market within a few months of its launch is frustrating. Enthusiasm for the use of new pharmacological agents earlier in the course of type 2 diabetes needs to be tempered by concerns about long-term safety of these agents. While the ability of a drug to impact on a surrogate outcome like preservation of beta-cell function is encouraging, it needs to be followed up by studies assessing long-term (mainly cardiovascular) outcomes. Keywords diabetes mellitus; diabetes prevention; DPP-4 inhibitors; GLP-1 analogues; insulin; thiazolidinediones
The global burden of diabetes The worldwide prevalence of diabetes continues to increase. Publication of the 3rd edition of the International Diabetes Federation's e-atlas1 and the regularly updated ‘Diabetes Maps’ from the Centers for Disease Control and Prevention2 provide graphic illustrations of the scale of the problem. The number of adults (aged 20 to 79) with diabetes throughout the world was estimated to be 194 million in 2003. The e-atlas predicts that this figure will increase to 333 million by 2025. Although the majority of individuals with diabetes currently live in North America and Europe, this is expected to change, and by 2025 South East Asia will have more individuals with diabetes than any other part of the world. The increase is due to a rise in the prevalence of type 2 diabetes which in turn is caused by the adoption of an unhealthy Western lifestyle. The e-atlas data highlight aspects of the diabetes pandemic which might not
be apparent to a casual observer. For instance, type 2 diabetes has historically been considered a disease of older adult life. However, the occurrence of adolescent- or even childhood-onset type 2 diabetes is becoming increasingly recognized.3 Paediatricians, who have traditionally reached for the insulin syringe or pen when diabetes occurs in childhood, now have to add drugs like metformin and glimepiride to their therapeutic armamentarium. A related aspect of the pandemic is the major economic implications of diabetes to individual countries and to the global economy. The e-atlas provides estimates of the direct costs of diabetes care by region while acknowledging that the indirect costs of diabetes are likely to be as great. Consider the situation in India where not only is diabetes on the increase but also the complications of diabetes (in particular cardiovascular events) are occurring at an age when people are economically productive. The data in the e-atlas call for a major response, not just
Sean F Dinneen MD FRCPI FACP is a Consultant Endocrinologist at Galway University Hospitals and Senior Lecturer in Medicine at the National University of Ireland, Galway, Ireland. Competing interests: none declared.
MEDICINE 36:1
58
from healthcare professionals, but also from policy makers, town planners, roads authorities, etc. At a minimum we need to make it easier for people to be physically active and have less easy access to energy rich foods. The recent adoption of a UN resolution on diabetes may represent the beginning of this campaign.4
Recent guidelines and new clinical trial evidence Management of type 2 diabetes involves controlling weight and optimizing levels of blood glucose, blood pressure, lipids and thereby reducing cardiovascular risk.5 While diet and exercise remain the cornerstone of management only a minority of patients achieve optimal control through lifestyle efforts alone. Pharmacotherapy is almost always required. A recent joint consensus statement from the American Diabetes Association and European Association for the Study of Diabetes emphasized metformin as the preferred option for initial monotherapy.6 Due to the progressive beta-cell failure that occurs as part of the natural history of type 2 diabetes most patients eventually fail monotherapy. The joint consensus statement did not recommend a single
© 2007 Elsevier Ltd. All rights reserved.
What's new in diabetes
option for second line therapy. Instead it recommended that the choice of second drug be guided by factors additional to the need to improve glycemic control. For example, if cost is a major consideration then sulphonylurea therapy would be the choice. If longevity of action is the main requirement then a basal insulin (such as glargine or detemir) should be chosen. If avoidance of hypoglycemia is the main concern then a thiazolidinedione should be considered. Guidance on which drug to use as second or third line therapy in type 2 diabetes is necessarily based on opinion rather than evidence. Very few studies have been done comparing different treatment regimens. ADOPT The ADOPT study had as its main outcome monotherapy failure.7 The study randomly assigned over 4300 drug naive patients with type 2 diabetes to treatment with a sulphonylurea (glyburide), metformin or a thiazolidinedione (rosiglitazone). Monotherapy failure was defined as a fasting plasma glucose above 10 mmol/l after 6 weeks of therapy with the maximum tolerated dose of the agent being used. Completion rates were poor with only approximately 60% of patients in each arm completing the 5 years of follow-up. The results showed that rosiglitazone, a thiazolidinedione, was superior to metformin which in turn was superior to glyburide in durability of glycaemic control. The length of time taken for the glyburide group to reach an average HbA1c above 7% was 33 months compared to 45 months for the metformin group and 60 months for the rosiglitazone group. Using the homeostatic model (HOMA) the investigators were able to demonstrate that rosiglitazone use was associated with preservation of beta-cell function as well as the expected improvement in insulin action. Rosiglitazone use was associated with an almost 7 kg weight gain (compared to metformin) over the duration of the study. DREAM The results of the DREAM study were published in late 2006.8,9 The study assessed the ability of an ACE inhibitor (ramipril) and a thiazolidinedione (rosiglitazone) to prevent diabetes in individuals at high risk of progression from impaired fasting glucose, impaired glucose tolerance or both. Despite an earlier suggestion
MEDICINE 36:1
that self-reported diabetes was reduced in ramipril-treated patients10 the ramipril arm of the DREAM study was negative.8 The rosiglitazone arm of the study was, however, strikingly positive.9 Over a median follow-up of 3 years, 25% of individuals taking placebo progressed to diabetes compared with 10.6% of those taking rosiglitazone at a dose of 8 mg daily (hazard ratio 0.38; 95% CI 0.33–0.44). Rosiglitazone now joins acarbose,11 metformin12 and the first thiazolidinedione, troglitazone (no longer on the market),13 as drugs that have been shown to prevent diabetes. Whether pharmacotherapy should be used to prevent diabetes when lifestyle interventions12,14 are known to be more effective and carry additional health benefits is debatable.15 If ‘pre-diabetes’ is to become a medical condition amenable to drug therapy then the global market is truly enormous. Although delivering a medication on a large scale is relatively easy to do (and pays huge dividends for the pharmaceutical industry) the case for prevention through lifestyle intervention should not be abandoned. The experience in Finland demonstrates that Diabetes Prevention Programmes can be rolled out at a national level.16 The other reason for caution with preventive pharmacotherapy relates to the potential for harm. Rosiglitazone safety The original prescribing information for rosiglitazone carried a liver function test monitoring advisory. Experience with rosiglitazone and pioglitazone suggests that in many cases these agents lead to improvement rather than worsening of liver function tests. The mechanism is probably through improved insulin action with an associated improvement in non-alcoholic fatty liver disease, common in patients with type 2 diabetes.17 An unanticipated side-effect of rosiglitazone that has recently been identified is an increased risk of fractures.7 The risk appears to be confined to women and the fractures occur in areas not associated with major disability. Whether rosiglitazone causes heart failure, or simply mimics it through fluid retention, was uncertain when the drug was first released. Post-marketing data and recent clinical trial results have confirmed that heart failure is a real side effect of the drug.18 The FDA has upgraded its level of caution regarding this side effect. Of even 59
greater concern is the recent report of an increased risk of myocardial infarction and death from cardiovascular causes among patients assigned to take rosiglitazone in clinical trials. The observation was first made in a meta-analysis published in the New England Journal of Medicine.19 A subsequent rapid publication of an interim analysis of the RECORD study, a large cardiovascular outcomes study evaluating rosiglitazone use, was unable to refute the claim.20 Much has been written about the validity of the metaanalysis,21,22 the regulatory processes that apply to drugs after they get to market23 and even the motives behind the NEJM's ‘attack’ on what is a hugely successful drug.24 A similar meta-analysis of pioglitazone cardiovascular safety (funded by the manufacturer) reported higher rates of heart failure but lower rates of cardiovascular endpoints for pioglitazone compared to comparators.25 At the time of writing the dust has still not settled on this controversy and the diabetes community is anxiously awaiting the deliberations of a specially convened panel of the FDA. The recommendations of this panel are likely to inform future use of rosiglitazone in patients with known type 2 diabetes. In the meantime it seems prudent to use the drug cautiously in patients with known type 2 diabetes and to put its potential use in diabetes prevention on hold.
New drugs and devices Incretin enhancers and mimetics The incretin effect describes the observation that in healthy humans the insulin response to a glucose load delivered orally is far greater than an isoglycemic load delivered by the intravenous route (Figure 1). The incretin effect is believed to be mediated by peptide hormones secreted by endocrine cells in the gut mucosa.26 The two main incretins are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Only the latter is able to improve the impaired incretin effect that is a feature of Type 2 diabetes. In addition to its ability to enhance insulin secretion, GLP-1 has several other properties that make it appealing as a treatment for Type 2 diabetes. These include suppression of glucagon secretion, slowing of gastric emptying, suppression of appetite and concomitant weight loss.27 The problem
© 2007 Elsevier Ltd. All rights reserved.
What's new in diabetes
The incretin effect Oral glucose Intravenous glucose
Plasma glucose (mg/dL)
C-Peptide response (ng/ml)
Incretin effect
Time (min)
Time (min)
a The plasma glucose is the same whether given orally or intravenously. b The incretin effect describes the increase in insulin secretion seen when glucose levels rise in response to oral glucose ingestion as opposed to an isoglycaemic intravenous glucose load. It is believed to be mediated by gut peptides including GIP and GLP-1.
Figure 1
with using GLP-1 as a therapeutic agent is that it has an extremely short half-life in the circulation due to rapid degradation by an enzyme called dipeptidyl peptidase- 4 (DPP-4). Recently incretin enhancers and incretin mimetics have been developed.27 The former work by inhibiting DPP-4 and thereby extending the half-life of endogenous GLP-1. The latter amount to analogues of GLP- 1 that avoid enzymatic degradation and thereby have a prolonged agonistic effect at the GLP- 1 receptor. In general, the incretin mimetics (exenatide and liraglutide) have a greater HbA1c lowering effect than the incretin enhancers (sitagliptin and vildagliptin). But this is at the expense of inconvenience in delivery (subcutaneous versus oral administration) and greater (mainly gastrointestinal) side-effects with the incretin mimetics. The nausea that occurs with exenatide is dose and time related, i.e. it increases with increasing doses of the drug and improves with ongoing use. Both exenatide and liraglutide are associated with weight loss and this appears to be independent of nausea. A recent systematic review of short-term (less than 30 weeks duration) studies using these agents identified an increased risk of infections and headaches with use of the DPP-4 inhibitors.28 The long-term safety of these agents has yet to be established.
MEDICINE 36:1
Inhaled insulin Ever since the discovery of insulin in 1922 patients have struggled with the inconvenience and discomfort associated with its subcutaneous route of delivery. Recently the first inhaled insulin came on the market in the US and Europe. The advances that led to its release were not pharmacological (the insulin molecule is the same) but technological. The devices and the way they can deliver insulin to the lower reaches of the lungs are what constitute the breakthrough. Exubera, the first inhaled insulin to make it to market, uses a dry powder delivered by a hand-held nebuliser type device.29 Future devices will use aqueous aerosols to penetrate to the alveolar surface. The pharmacokinetics of inhaled insulin is similar to that of subcutaneously delivered rapid-acting analogue insulins. Likewise efficacy (HbA1c lowering) and safety (hypoglycemia frequency) are similar in head-to-head comparisons with subcutaneous insulin. Patient satisfaction has been high despite what would appear to be a rather cumbersome device. Pulmonary function tests have been done for up to 2 years after commencement and show no deterioration. Longer term studies are underway. Bioavailability is only 10% compared to subcutaneous delivery and therefore much more insulin has to be produced to supply the inhaled insulin 60
method of delivery. To the dismay of the diabetes community, Pfizer recently took a corporate decision to withdraw Exubera from the market. This decision was driven by economics (i.e. poor uptake by patients) and not by safety concerns. It remains to be seen if other companies will enter the inhaled insulin marketplace.30 ◆
References 1 International Diabetes Federation. Diabetes atlas, 3rd edn. Available from: www.idf. org/e-atlas 2 http://www.cdc.gov/diabetes/statistics/maps/ 3 Fagot-Campagna A, Narayan KMV, Imperatore G. Type 2 diabetes in children. BMJ 2001; 322: 378–9. 4 http://www.unitefordiabetes.org/campaign/ 5 The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology and of the European Assoication for the Study of Diabetes. Guidelines on diabetes, pre-diabetes and cardiovascular diseases. Eur Heart J 2007; doi: 10.1093/eurheartj/ehl261. 6 Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006; 29: 1963–1972.
© 2007 Elsevier Ltd. All rights reserved.
What's new in diabetes
7 Kahn SE, Haffner SM, Heise MA, et al., for the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin or glyburide monotherapy. N Engl J Med 2006; 355: 2427–33. 8 DREAM Trial Investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med 2006; 355: 1551–62. 9 The DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone medication) Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006; 368: 1096–1105. 10 HOPE Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular outcomes in high-risk patients. N Engl J Med 2000; 342: 145–53. 11 Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Lakkso M. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP NIDDM trial. JAMA 2003; 290: 486–494. 12 Diabetes Prevention Program Research Group. Reduction in incidence of Type 2 diabetes with lifestlye intervention or metformin. N Engl J Med 2002; 346: 393–403. 13 Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic β-cell function
MEDICINE 36:1
and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes 2002; 51: 2796–2803. 14 Tuomilehto J, Lindstrom J, Eriksson JG, et al. Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343–50. 15 Montori V, Isley W, Guyatt G. Waking up to the DREAM of preventing diabetes with drugs. BMJ 2007; 334: 882–4. 16 http://www.diabetes.fi/english/index.htm 17 McCullough AJ. Thiazolidinediones for nonalcoholic steatohepatitis: promising but not ready for prime time. N Engl J Med 2006; 355: 2361–3. 18 Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American diabetes Association. Diabetes Care 2004; 27: 256–63. 19 Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007; 356: 2457–2471. 20 Home PD, Pocock SJ, Beck-Nielsen H, et al. Rosiglitazone evaluated for cardiovascular outcomes-an interim analysis. N Engl J Med 2007; 357: 28–38.
61
21 Nathan DM. Rosiglitazone and cardiotoxicity-weighing the evidence. N Engl J Med 2007; 357: 64–66. 22 Bilous RW. Rosiglitazone and myocardial infarction: cause for concern or misleading meta-analysis? Diabet Med 2007; 24: 931–933. 23 Psaty BM, Furberg CD. Rosiglitazone and cardiovascular risk. N Engl J Med 2007; 356: 3522–3524. 24 Fuster V, Farkouh ME. Faster publication isn't always better. Nat Clin Pract Cardiovasc Med 2007; 4: 345. 25 Lincoff MA, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2007; 298: 1180–88. 26 Holst JJ, Orskov C. The incretin approach for diabetes treatment: modulation of islet hormone release by GLP-1 agonism. Diabetes 2004; 53(suppl 3): S197–S204. 27 Drucker DJ, Nauck MA. The incretin system: glucagons-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006; 368: 1696–1705. 28 Amori RE, Lau J, Pittas AG. Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and metaanalysis. JAMA 2007; 298: 194–206. 29 McMahon GT, Arky RA. Inhaled insulin for diabetes mellitus. N Engl J Med 2007; 365: 497–502. 30 http://www.lifeforachild.org/
© 2007 Elsevier Ltd. All rights reserved.
What's new in ... Diabetes? Sean F Dinneen
The scale of the diabetes pandemic is frightening. As well as seeing increasing numbers of patients, many countries are reporting earlier onset of type 2 diabetes and its associated complications. The United Nations has recently adopted a resolution on diabetes and designated November 14th World Diabetes Day. Lifestyle modification remains the cornerstone of preventive and management strategies, however, it is usually not associated with sustained benefit. Clinicians need more and better drugs in their therapeutic armamentarium. The release of drugs in the incretin class of gut peptide-related compounds is welcome; the withdrawal of inhaled insulin from the market within a few months of its launch is frustrating. Enthusiasm for the use of new pharmacological agents earlier in the course of type 2 diabetes needs to be tempered by concerns about long-term safety of these agents. While the ability of a drug to impact on a surrogate outcome like preservation of beta-cell function is encouraging, it needs to be followed up by studies assessing long-term (mainly cardiovascular) outcomes. Keywords diabetes mellitus; diabetes prevention; DPP-4 inhibitors; GLP-1 analogues; insulin; thiazolidinediones
The global burden of diabetes The worldwide prevalence of diabetes continues to increase. Publication of the 3rd edition of the International Diabetes Federation's e-atlas1 and the regularly updated ‘Diabetes Maps’ from the Centers for Disease Control and Prevention2 provide graphic illustrations of the scale of the problem. The number of adults (aged 20 to 79) with diabetes throughout the world was estimated to be 194 million in 2003. The e-atlas predicts that this figure will increase to 333 million by 2025. Although the majority of individuals with diabetes currently live in North America and Europe, this is expected to change, and by 2025 South East Asia will have more individuals with diabetes than any other part of the world. The increase is due to a rise in the prevalence of type 2 diabetes which in turn is caused by the adoption of an unhealthy Western lifestyle. The e-atlas data highlight aspects of the diabetes pandemic which might not
be apparent to a casual observer. For instance, type 2 diabetes has historically been considered a disease of older adult life. However, the occurrence of adolescent- or even childhood-onset type 2 diabetes is becoming increasingly recognized.3 Paediatricians, who have traditionally reached for the insulin syringe or pen when diabetes occurs in childhood, now have to add drugs like metformin and glimepiride to their therapeutic armamentarium. A related aspect of the pandemic is the major economic implications of diabetes to individual countries and to the global economy. The e-atlas provides estimates of the direct costs of diabetes care by region while acknowledging that the indirect costs of diabetes are likely to be as great. Consider the situation in India where not only is diabetes on the increase but also the complications of diabetes (in particular cardiovascular events) are occurring at an age when people are economically productive. The data in the e-atlas call for a major response, not just
Sean F Dinneen MD FRCPI FACP is a Consultant Endocrinologist at Galway University Hospitals and Senior Lecturer in Medicine at the National University of Ireland, Galway, Ireland. Competing interests: none declared.
MEDICINE 36:1
58
from healthcare professionals, but also from policy makers, town planners, roads authorities, etc. At a minimum we need to make it easier for people to be physically active and have less easy access to energy rich foods. The recent adoption of a UN resolution on diabetes may represent the beginning of this campaign.4
Recent guidelines and new clinical trial evidence Management of type 2 diabetes involves controlling weight and optimizing levels of blood glucose, blood pressure, lipids and thereby reducing cardiovascular risk.5 While diet and exercise remain the cornerstone of management only a minority of patients achieve optimal control through lifestyle efforts alone. Pharmacotherapy is almost always required. A recent joint consensus statement from the American Diabetes Association and European Association for the Study of Diabetes emphasized metformin as the preferred option for initial monotherapy.6 Due to the progressive beta-cell failure that occurs as part of the natural history of type 2 diabetes most patients eventually fail monotherapy. The joint consensus statement did not recommend a single
© 2007 Elsevier Ltd. All rights reserved.
What's new in diabetes
option for second line therapy. Instead it recommended that the choice of second drug be guided by factors additional to the need to improve glycemic control. For example, if cost is a major consideration then sulphonylurea therapy would be the choice. If longevity of action is the main requirement then a basal insulin (such as glargine or detemir) should be chosen. If avoidance of hypoglycemia is the main concern then a thiazolidinedione should be considered. Guidance on which drug to use as second or third line therapy in type 2 diabetes is necessarily based on opinion rather than evidence. Very few studies have been done comparing different treatment regimens. ADOPT The ADOPT study had as its main outcome monotherapy failure.7 The study randomly assigned over 4300 drug naive patients with type 2 diabetes to treatment with a sulphonylurea (glyburide), metformin or a thiazolidinedione (rosiglitazone). Monotherapy failure was defined as a fasting plasma glucose above 10 mmol/l after 6 weeks of therapy with the maximum tolerated dose of the agent being used. Completion rates were poor with only approximately 60% of patients in each arm completing the 5 years of follow-up. The results showed that rosiglitazone, a thiazolidinedione, was superior to metformin which in turn was superior to glyburide in durability of glycaemic control. The length of time taken for the glyburide group to reach an average HbA1c above 7% was 33 months compared to 45 months for the metformin group and 60 months for the rosiglitazone group. Using the homeostatic model (HOMA) the investigators were able to demonstrate that rosiglitazone use was associated with preservation of beta-cell function as well as the expected improvement in insulin action. Rosiglitazone use was associated with an almost 7 kg weight gain (compared to metformin) over the duration of the study. DREAM The results of the DREAM study were published in late 2006.8,9 The study assessed the ability of an ACE inhibitor (ramipril) and a thiazolidinedione (rosiglitazone) to prevent diabetes in individuals at high risk of progression from impaired fasting glucose, impaired glucose tolerance or both. Despite an earlier suggestion
MEDICINE 36:1
that self-reported diabetes was reduced in ramipril-treated patients10 the ramipril arm of the DREAM study was negative.8 The rosiglitazone arm of the study was, however, strikingly positive.9 Over a median follow-up of 3 years, 25% of individuals taking placebo progressed to diabetes compared with 10.6% of those taking rosiglitazone at a dose of 8 mg daily (hazard ratio 0.38; 95% CI 0.33–0.44). Rosiglitazone now joins acarbose,11 metformin12 and the first thiazolidinedione, troglitazone (no longer on the market),13 as drugs that have been shown to prevent diabetes. Whether pharmacotherapy should be used to prevent diabetes when lifestyle interventions12,14 are known to be more effective and carry additional health benefits is debatable.15 If ‘pre-diabetes’ is to become a medical condition amenable to drug therapy then the global market is truly enormous. Although delivering a medication on a large scale is relatively easy to do (and pays huge dividends for the pharmaceutical industry) the case for prevention through lifestyle intervention should not be abandoned. The experience in Finland demonstrates that Diabetes Prevention Programmes can be rolled out at a national level.16 The other reason for caution with preventive pharmacotherapy relates to the potential for harm. Rosiglitazone safety The original prescribing information for rosiglitazone carried a liver function test monitoring advisory. Experience with rosiglitazone and pioglitazone suggests that in many cases these agents lead to improvement rather than worsening of liver function tests. The mechanism is probably through improved insulin action with an associated improvement in non-alcoholic fatty liver disease, common in patients with type 2 diabetes.17 An unanticipated side-effect of rosiglitazone that has recently been identified is an increased risk of fractures.7 The risk appears to be confined to women and the fractures occur in areas not associated with major disability. Whether rosiglitazone causes heart failure, or simply mimics it through fluid retention, was uncertain when the drug was first released. Post-marketing data and recent clinical trial results have confirmed that heart failure is a real side effect of the drug.18 The FDA has upgraded its level of caution regarding this side effect. Of even 59
greater concern is the recent report of an increased risk of myocardial infarction and death from cardiovascular causes among patients assigned to take rosiglitazone in clinical trials. The observation was first made in a meta-analysis published in the New England Journal of Medicine.19 A subsequent rapid publication of an interim analysis of the RECORD study, a large cardiovascular outcomes study evaluating rosiglitazone use, was unable to refute the claim.20 Much has been written about the validity of the metaanalysis,21,22 the regulatory processes that apply to drugs after they get to market23 and even the motives behind the NEJM's ‘attack’ on what is a hugely successful drug.24 A similar meta-analysis of pioglitazone cardiovascular safety (funded by the manufacturer) reported higher rates of heart failure but lower rates of cardiovascular endpoints for pioglitazone compared to comparators.25 At the time of writing the dust has still not settled on this controversy and the diabetes community is anxiously awaiting the deliberations of a specially convened panel of the FDA. The recommendations of this panel are likely to inform future use of rosiglitazone in patients with known type 2 diabetes. In the meantime it seems prudent to use the drug cautiously in patients with known type 2 diabetes and to put its potential use in diabetes prevention on hold.
New drugs and devices Incretin enhancers and mimetics The incretin effect describes the observation that in healthy humans the insulin response to a glucose load delivered orally is far greater than an isoglycemic load delivered by the intravenous route (Figure 1). The incretin effect is believed to be mediated by peptide hormones secreted by endocrine cells in the gut mucosa.26 The two main incretins are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). Only the latter is able to improve the impaired incretin effect that is a feature of Type 2 diabetes. In addition to its ability to enhance insulin secretion, GLP-1 has several other properties that make it appealing as a treatment for Type 2 diabetes. These include suppression of glucagon secretion, slowing of gastric emptying, suppression of appetite and concomitant weight loss.27 The problem
© 2007 Elsevier Ltd. All rights reserved.
What's new in diabetes
The incretin effect Oral glucose Intravenous glucose
Plasma glucose (mg/dL)
C-Peptide response (ng/ml)
Incretin effect
Time (min)
Time (min)
a The plasma glucose is the same whether given orally or intravenously. b The incretin effect describes the increase in insulin secretion seen when glucose levels rise in response to oral glucose ingestion as opposed to an isoglycaemic intravenous glucose load. It is believed to be mediated by gut peptides including GIP and GLP-1.
Figure 1
with using GLP-1 as a therapeutic agent is that it has an extremely short half-life in the circulation due to rapid degradation by an enzyme called dipeptidyl peptidase- 4 (DPP-4). Recently incretin enhancers and incretin mimetics have been developed.27 The former work by inhibiting DPP-4 and thereby extending the half-life of endogenous GLP-1. The latter amount to analogues of GLP- 1 that avoid enzymatic degradation and thereby have a prolonged agonistic effect at the GLP- 1 receptor. In general, the incretin mimetics (exenatide and liraglutide) have a greater HbA1c lowering effect than the incretin enhancers (sitagliptin and vildagliptin). But this is at the expense of inconvenience in delivery (subcutaneous versus oral administration) and greater (mainly gastrointestinal) side-effects with the incretin mimetics. The nausea that occurs with exenatide is dose and time related, i.e. it increases with increasing doses of the drug and improves with ongoing use. Both exenatide and liraglutide are associated with weight loss and this appears to be independent of nausea. A recent systematic review of short-term (less than 30 weeks duration) studies using these agents identified an increased risk of infections and headaches with use of the DPP-4 inhibitors.28 The long-term safety of these agents has yet to be established.
MEDICINE 36:1
Inhaled insulin Ever since the discovery of insulin in 1922 patients have struggled with the inconvenience and discomfort associated with its subcutaneous route of delivery. Recently the first inhaled insulin came on the market in the US and Europe. The advances that led to its release were not pharmacological (the insulin molecule is the same) but technological. The devices and the way they can deliver insulin to the lower reaches of the lungs are what constitute the breakthrough. Exubera, the first inhaled insulin to make it to market, uses a dry powder delivered by a hand-held nebuliser type device.29 Future devices will use aqueous aerosols to penetrate to the alveolar surface. The pharmacokinetics of inhaled insulin is similar to that of subcutaneously delivered rapid-acting analogue insulins. Likewise efficacy (HbA1c lowering) and safety (hypoglycemia frequency) are similar in head-to-head comparisons with subcutaneous insulin. Patient satisfaction has been high despite what would appear to be a rather cumbersome device. Pulmonary function tests have been done for up to 2 years after commencement and show no deterioration. Longer term studies are underway. Bioavailability is only 10% compared to subcutaneous delivery and therefore much more insulin has to be produced to supply the inhaled insulin 60
method of delivery. To the dismay of the diabetes community, Pfizer recently took a corporate decision to withdraw Exubera from the market. This decision was driven by economics (i.e. poor uptake by patients) and not by safety concerns. It remains to be seen if other companies will enter the inhaled insulin marketplace.30 ◆
References 1 International Diabetes Federation. Diabetes atlas, 3rd edn. Available from: www.idf. org/e-atlas 2 http://www.cdc.gov/diabetes/statistics/maps/ 3 Fagot-Campagna A, Narayan KMV, Imperatore G. Type 2 diabetes in children. BMJ 2001; 322: 378–9. 4 http://www.unitefordiabetes.org/campaign/ 5 The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology and of the European Assoication for the Study of Diabetes. Guidelines on diabetes, pre-diabetes and cardiovascular diseases. Eur Heart J 2007; doi: 10.1093/eurheartj/ehl261. 6 Nathan DM, Buse JB, Davidson MB, et al. Management of hyperglycemia in Type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. Diabetes Care 2006; 29: 1963–1972.
© 2007 Elsevier Ltd. All rights reserved.
What's new in diabetes
7 Kahn SE, Haffner SM, Heise MA, et al., for the ADOPT Study Group. Glycemic durability of rosiglitazone, metformin or glyburide monotherapy. N Engl J Med 2006; 355: 2427–33. 8 DREAM Trial Investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med 2006; 355: 1551–62. 9 The DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone medication) Trial Investigators. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial. Lancet 2006; 368: 1096–1105. 10 HOPE Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular outcomes in high-risk patients. N Engl J Med 2000; 342: 145–53. 11 Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Lakkso M. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP NIDDM trial. JAMA 2003; 290: 486–494. 12 Diabetes Prevention Program Research Group. Reduction in incidence of Type 2 diabetes with lifestlye intervention or metformin. N Engl J Med 2002; 346: 393–403. 13 Buchanan TA, Xiang AH, Peters RK, et al. Preservation of pancreatic β-cell function
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