Have we confirmed that controlling hyperglycaemia is not the magic bullet for preventing macrovascular disease in patients with type 2 diabetes?

Blair Hesp explores the benefits of controlling hyperglycaemia to prevent macrovascular disease in type 2 diabetes patients in our cardiovascular themed month.

In early September 2013 full results from the first major prospective study specifically investigating macrovascular outcomes in patients administered an antihyperglycaemic agent from the dipeptidyl peptidase-4 (DPP-4) inhibitor class will be released. However, we already know from an early press release that no improvement in the risk of major adverse cardiovascular events (a composite endpoint of death from cardiovascular causes, myocardial infarction or stroke) was observed.1 So should we be surprised by this?

Is this proof that inadequate glycaemic control is not the root of all macrovascular disease in patients with type 2 diabetes?

We know that up to 80% of patients with type 2 diabetes will die from cardiovascular disease.2 However, while improved glycaemic control translates into improved microvascular outcomes, thereby reducing the risk of nephropathy, neuropathy and retinopathy, the same has not been proven for macrovascular disease.2 Furthermore, and perhaps more importantly, there is increasing evidence linking antidiabetic treatment-related adverse events and macrovascular disease.3–5

Initial evidence from a number of retrospective meta-analyses from trials of DPP-4 inhibitors suggested that these drugs may reduce the risk of major adverse cardiovascular events.6 Accordingly, the hypothesis appeared to be that improved glycaemic control may decrease the risk of macrovascular events when it is achieved without:

• Increasing the risk of hypoglycaemia

• Weight gain

• Adversely affecting a patients lipid profile

Basically, manufacturers of DPP-4 inhibitors appear to have subscribed en masse to the belief that the negative effects of treatment-related hypoglycaemia and weight gain masked the macrovascular benefits of improved glycaemic control in past studies, and instituted large prospective studies to confirm this hypothesis. However, the neutral results from the first prospective study to report any findings points to patients treated with DPP-4 inhibitors avoiding further harm as opposed to achieving any benefit.1

"...while improved glycaemic control translates into improved microvascular outcomes, thereby reducing the risk of nephropathy, neuropathy and retinopathy, the same has not been proven for macrovascular disease."

Could the first reported result be an anomaly?

The failure of one member of the DPP-4 inhibitor class to reduce the risk of macrovascular events1 has now increased the stakes for the on-going cardiovascular studies in this class that have not yet reported. However, given the generally consistent efficacy and safety profile of the various members of the DPP-4 inhibitor class of antidiabetic agents,6,7 the merits of any positive future results will no doubt be debated on the basis of the characteristics of individual drugs and the nuances of clinical trial design.

Have all the type 2 diabetes cardiovascular disease eggs been put in the hyperglycaemia basket?

The joint guidelines issued by the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) in 2012 promote an individualised treatment approach for patients with type 2 diabetes, and comment on the need to avoid treatment-related adverse events, such as hypoglycaemia and weight gain, that could contribute to cardiovascular disease.8 Importantly, these comments are only made in the context of controlling hyperglycaemia. In contrast, joint guidelines issued by the European Society for Cardiology (ESC) highlight the need to actively address, and pharmacologically treat, if necessary, highly prevalent comorbidities such as hypertension and dyslipidaemia, as well as hyperglycaemia. to ensure the best cardiovascular outcomes in these patients.9

Given that the majority of patients with type 2 diabetes will develop macrovascular disease,2 it makes sense that a multifactorial treatment approach, as advocated by the ESC, is required to effectively control the risk of cardiovascular disease in this population. In contrast, the ADA and EASD focus almost exclusively on antihyperglycaemic treatment and its role in cardiovascular disease, and it must be presumed that cardiovascular risk factors in patients with type 2 diabetes will be managed independently without impacting day-to-day antihyperglycaemic treatment8

"Not only will there be interest in whether a lack of macrovascular efficacy is observed across the DPP-4 inhibitor class, but whether the lack of efficacy is consistently observed across secondary endpoints and subgroup analyses as well."

Is there a cardiovascular elephant in the room with patients with type 2 diabetes?

The vast majority of antidiabetic treatments, including DPP-4 inhibitors, control hyperglycaemia by modulating or supplementing the body's own mechanisms of maintaining glucose homeostasis.10.11 Notably, most antidiabetic treatments have a mechanism of action that either directly or indirectly uses insulin to improve glycaemic control, but these treatments inevitably lose efficacy with time as insulin resistance increases with disease duration.8,10–12 So here lies the potential elephant in the room – insulin resistance is a major risk factor for cardiovascular disease that is not actively addressed by DPP-4 inhibitors, so perhaps it is insulin resistance, not hyperglycaemia or treatment-related adverse events, that is the major driver of macrovascular disease in patients with type 2 diabetes.13

Completing the picture

So now the scene is set for further reporting with the devil potentially being in the detail. Not only will there be interest in whether a lack of macrovascular efficacy is observed across the DPP-4 inhibitor class, but whether the lack of efficacy is consistently observed across secondary endpoints and subgroup analyses as well. Likewise, the search for a cardiovascular benefit from antidiabetic treatment may now shift its focus to the new class of insulin-independent antidiabetic treatments, sodium-glucose co-transporter-2 inhibitors.

The above article is not intended to substitute for informed medical advice. Patients should consult an appropriate healthcare provider for medical advice.

References

1. Bristol-Myers Squibb/AstraZeneca. AstraZeneca and Bristol-Myers Squibb Announce Top Line Results for SAVOR-TIMI-53 Cardiovascular Outcomes Trial of Onglyza® (saxagliptin). 19 June 2013. Available at: http://news.bms.com/press-release/astrazeneca-and-bristol-myers-squibb-announce-top-line-results-savor-timi-53-cardiovas.

2. Buse JB, et al. Primary prevention of cardiovascular disease in people with diabetes mellitus: A scientific statement from the American Heart Association and the American Diabetes Association. Circulation 2007;115:114–126.

3. Zoungas S, et al. Severe hypoglycaemia and risks of vascular events and death. N Engl J Med 2010;363:1410–1418.

4. Johnston SS, et al. Evidence linking hypoglycemic events to an increased risk of acute cardiovascular events in patients with type 2 diabetes. Diabetes Care 2011;34:1164–1170.

5. Giorgino F, et al. Cardiovascular disease and glycemic control in type 2 diabetes: now that the dust is settling from large clinical trials. Ann N Y Acad Sci 2013;1281:36–50.

6. Scheen AJ. Cardiovascular effects of didpeptidyl peptidase-4 inhibitos: From risk factors to clinical outcomes.

7. Baetta R, Corsini A. Pharmacology of dipeptidyl peptidase-4 inhibitors: similarities and differences. Drugs 2011;71:1441–1467.

8. Inzucchi SE, et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012;35:1364–1379.

9. Perk J, et al. European Guidelines on cardiovascular disease prevention in clinical practice (version 2012). Eur Heart J 2012;33:1635–1701.

10. Krentz AJ, Bailey CJ. Oral antidiabetic agents: Current role in type 2 diabetes mellitus. Drugs 2005;65:385–411.

11. Stonehouse AH, et al. Incretin-based therapies. J Diabetes 2012;4:55–67.

12. Retnakaran R, et al. Changes over time in glycemic control, insulin sensitivity, and β-cell function in response to low-dose metformin and thiazolidinedione combination therapy in patients with impaired glucose tolerance. Diabetes Care 2011;34:1601–1604.

13. Bornfeldt KE, Tabas I. Insulin resistance, hyperglycemia and atherosclerosis. Cell Metab 2011;14:575–585.

About the author:

Blair Hesp is a Director of Kainic Medical Communications Ltd., a New Zealand-based medical communications agency that specialises in providing on-demand, overnight medical communications resource to overseas agencies and pharmaceutical companies. Blair has a PhD in Pharmacology from the University of Otago and a New Zealand Diploma in Business. In addition to several years' experience working in the Global and European medical communications industry in the United Kingdom, he has also spent several years working in the international intellectual property industry. Disclosure: Kainic Medical Communications has provided medical communications support on a freelance basis to agencies developing diabetes-related materials for Bristol-Myers Squibb/AstraZeneca.

Will a lack of macrovascular efficacy be observed across the DPP-4 inhibitor class in diabetic patients?