The MD Daily Contract review

August 6, 2018 • By Guest

Second line DM treatments

The sequelae of Type 2 Diabetes (Type 2 DM) is seen throughout all medical specialties, as nearly 26 million Americans suffer from the disease.1 With the high rate of obesity in Americans and the ensuing metabolic derangements, there is an urgent need to determine the best evidence-based strategies to reduce the burden of this disease. Diabetes is a “cardiovascular risk equivalent” and patients have the same risk of myocardial infarction as patients with a personal history of MI.2 Over the past several years, there has been an influx of new research aimed at improving the management of type 2 diabetes in an effort to improve the quality of life and mortality associated with the disease.

The cornerstone of type 2 DM management remains lifestyle modification, specifically dietary changes and an increase in physical activity. These actions can decrease HgbA1c as by 0.6%, as much as some oral medications. Despite their efficacy, many individuals go on to require medication to manage their diabetes. Metformin is still considered the initial medication for diabetes management due to its low cost and known safety and efficacy.3 However, recent research has sparked new debate as to the best second line medications for diabetes management, when single medical therapy does not adequately control the disease.

An important clinical question in diabetes management is whether strict control of blood glucose levels, with a HgbA1c goal of less than 7% (or 6.5% for newly diagnosed patients), decreases cardiovascular events and mortality in patients.4 While tight glucose clearly improves microvascular complications such as renal and eye disease5, the results related to cardiovascular events have been mixed. Some long-term studies like the United Kingdom Prospective Diabetes Study (UKPDS) and the Action to Control Cardiovascular Risk in Diabetes (ACCORD) showed a reduction in cardiovascular events, whereas others such as the Action in Diabetes and Vascular disease (ADVANCE) showed no benefit.1,6   In the Veterans Affairs Diabetes Trial (VADT), there was a 17% reduction in cardiovascular events such as stroke and myocardial infarction after 10 years with strict glucose control, however more recent evidence indicates that this benefit disappears at 15 years. Furthermore, there was no difference in either cardiovascular or overall mortality.

Of course, the patient populations in these studies differed, suggesting that patient variables affect the outcomes of management. Both the ACCORD and VADT trials recruited older patients with a long history of diabetes whereas the UKPDS was comprised of younger, newly diagnosed patients.6 Another important finding across these studies was the difficulty in maintaining strict glycemic control. Many patients, after attaining tight HgbA1c control, eventually rebound to HgbA1c levels as high as 8%. Furthermore, strict control is associated with a two to three times increased risk of hypoglycemic events. For elderly or frail diabetics, the risk-benefit ratio may become unfavorable, especially as they face a limited life expectancy.3 

Physicians must shift the focus from a target number to the individual patient. A holistic approach that looks at the patient’s medical history, comorbidities, compliance and financial constraints is vital to obtaining the best results.3,4 While many diabetic medications are effective at managing hyperglycemia, this has not necessarily translated into a reduced cardiovascular risk for patients.2 Many diabetes medications increase weight gain, hypoglycemia and even produce a modestly increased risk of myocardial infarction. It is timely then, that recent studies are specifically evaluating the cardiovascular risks and benefits of new medications on diabetic populations.

Recently, experts of the American Diabetes Association/European Association for the Study of Diabetes (ADA/EASD) convened a consensus report on based on this new research. The general agreement is that the key determinant in managing patients with diabetes is an initial assessment of their cardiovascular status as diabetic patients with cardiovascular comorbidities face an increased risk of mortality compared to diabetic patients without a cardiovascular history.3 The recent trials evaluating empagliflozin (EMPA-REG OUTCOME), semaglutide (SUSTAIN-6) and liraglutide (LEADER) have all shed light on the best avenues for preventing cardiovascular complications. Overall, these studies have shown that two classes, the injectable glucagon-like peptide-1 (GLP-1) agonist and oral sodium glucose cotransporter 2 (SGLT2) inhibitors should be the second line treatment of choice for diabetic patients with a cardiovascular history.

GLP-1 agonists are effective management for patients with atherosclerotic cardiovascular disease (ASCVD). They act by increasing incretin receptor signaling which is naturally secreted in the postprandial state. This class of medications significantly decreases overall cardiovascular endpoints in both the LEADER and SUSTAIN-6 trials, with liraglutide coming to the forefront in terms of benefit.2 In addition, this class is associated with weight loss, decreased blood pressure, less postprandial hypoglycemia and renoprotection. They are divided into long- and short-acting agents, with the short acting medications associated with more gastrointestinal side effects. They also increase the risk of tachycardia and are contraindicated in patients with renal failure. There are rare reports of pancreatitis and pancreatic cancer and the class should be avoided in patients with a personal or familial history of medullary cancer of the thyroid.

For patients with a history of congestive heart failure (CHF), SGLT2 inhibitors are the consensus second line therapy for diabetes management, especially the agent empagliflozin.7 These medications work by inhibiting glucose reabsorption in the proximal nephron and increasing urinary glucose excretion, independent of insulin secretion.3 This class of agents reduces cardiovascular death, while decreasing body weight, blood pressure and the risk of hypoglycemia.7 In addition, SGLT2 inhibitors decrease the risk of CHF related hospitalizations by 35%.2 The major side effects are an increase in LDL, mycotic genital and urinary tract infections and volume depletion.

For those patients without a history of cardiovascular events, the wide range of diabetic medications are still considered second line therapies.2 The goal of treatment for these patients is increased life years and quality of life years, and the prevention of future diabetic complications.1 As such, sulfonylureas, thiazolidinediones and dipeptidyl peptidase-4 inhibitor (DPP-4) remain options as their high efficacy may mitigate the side effects of increased weight gain (sulfonylureas and thiazolidinediones) and the mild increase in heart failure risk (DPP-4 inhibitors). A study looking at several second line therapies indicated that head-to-head, sulfonylurea, DPP-4 and GLP-1 inhibitors performed equally as second line therapies in achieving target HgbA1c levels and delaying the time to insulin dependence. However, sulfonylureas are the most cost-effective, which may be a significant factor for many patients.

The new guidelines indicate that rather than focusing on a single goal number for HgbA1c, a holistic approach to diabetes management is needed that takes an individualized approach to second line therapies. All else being equal, GLP1 inhibitors are best suited for patients with ACSVD while SGLT2 inhibitors are the best second line therapy for patients with CHF. There is still no clear second line agent for patients with average risk and to lack cardiovascular risk factors. Sulfonylureas are attracted because of their efficacy and low-cost, but risk of hypoglycemia limits their use. Above all else, the consensus statements emphasize and reinforce the importance of shared decision-making so that patients and healthcare providers can reach the best treatment decisions together.


1. Zhang Y, McCoy RG, Mason JE, Smith SA, Shah ND, Denton BT. Second-Line Agents for Glycemic Control for Type 2 Diabetes: Are Newer Agents Better? Diabetes Care. 2014;37(5):1338-1345. doi:10.2337/dc13-1901

2. Paneni F, Luscher TF. Cardiovascular Protection in the Treatment of Type 2 Diabetes: A Review of Clinical Trial Results across Drug Classes. Am J Cardiol. 2017;120(1s):S17-s27. doi:10.1016/j.amjcard.2017.05.015

3. Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of Hyperglycemia in Type 2 Diabetes, 2015: A Patient-Centered Approach: Update to a Position Statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2015;38(1):140-149. doi:10.2337/dc14-2441

4. Silver B, Ramaiya K, Andrew SB, et al. Eadsg Guidelines: Insulin Therapy in Diabetes. Diabetes Ther. 2018;9(2):449-492. doi:10.1007/s13300-018-0384-6

5. Hemmingsen B, Lund SS, Gluud C, et al. Targeting Intensive Glycaemic Control Versus Targeting Conventional Glycaemic Control for Type 2 Diabetes Mellitus. Cochrane Database Syst Rev. 2013(11):Cd008143. doi:10.1002/14651858.CD008143.pub3

6. Hayward RA, Reaven PD, Wiitala WL, et al. Follow-up of Glycemic Control and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med. 2015;372(23):2197-2206. doi:10.1056/NEJMoa1414266

7. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. New England Journal of Medicine. 2017;377(7):644-657. doi:10.1056/NEJMoa1611925

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  1. Jeff Carstens  • 

    We definitely need to move the needle and get away from a sole focus on HgbA1c. Therapy should be tailored when possible for other comorbidities, particularly for patients with cardiovascular disease where we have some of the exciting new drug noted in the article.