CASE B1. Newly Diagnosed T2DM in Patient with Prior MI

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1 Newly Diagnosed T2DM in Patient with Prior MI 1

2 Our case involves a gentleman with acute myocardial infarction who is newly discovered to have type 2 diabetes. 2

3 One question is whether anti-hyperglycemic therapy is warranted upon discharge in this individual. His medical history includes well-controlled hypertension, dyslipidemia, gout, obesity, and obstructive sleep apnea. He does not smoke, and he has no symptoms to suggest hyperglycemia. So clearly his diabetes is asymptomatic. His father has type 2 diabetes and is currently on dialysis. 3

4 One point to make on the next slide is that type 2 diabetes is often diagnosed during or soon after acute cardiovascular events. It's been noted that in an AMI population, one-third of patients already have diabetes; another third have newly diagnosed diabetes or pre-diabetes; and the remaining third, while euglycemic, may have insulin resistance or metabolic syndrome. The treatment of type 2 diabetes needs to be carefully considered in the context of patients with recent cardiovascular events, specifically myocardial infarction. Hypoglycemia is to be avoided because it activates the adrenergic nervous system. Sulfonylureas themselves not only can induce hypoglycemia, but there's also this concern about ischemic preconditioning, which we'll talk about in a couple of slides. 4

5 On the next slide is a review of some 30 to 35 years of diabetes trials and their impact on vascular complications. Starting with the UKPDS in type 2 diabetes, the DCCT and its follow-up study known as EDIC in type 1 diabetes, and then ACCORD, ADVANCE, and VADT in more complicated older patients with type 2 diabetes. The message here is clear that in each of these studies, more intensive vs conventional therapy led to an improvement in microvascular outcomes, such as retinopathy and albuminuria. But the impact of more intensive glucose control on cardiovascular complications and especially mortality is essentially neutral.

6 On the next slide we've reviewed the cardiovascular impact of various type 2 diabetes therapies excluding insulin. 6

7 The next slide shows one example of a study that hinted that sulfonylurea monotherapy may increase mortality, as well as overall major adverse cardiovascular events, compared to metformin. This is not necessarily borne out in clinical trials but appears to be a consistent theme that we see in studies of an observational nature. 7

8 On the next slide we see a cartoon of sulfonylureas and ischemic preconditioning. We mentioned the potential effect of these drugs to impair the heart's natural ability to reduce its myocardial oxygen demand in the setting of repeated ischemia. And this might explain why in some studies sulfonylureas appear to exacerbate cardiovascular mortality. 8

9 Here is a description of the potential role of hypoglycemia in cardiovascular risk. We know from both observational as well as randomized clinical trials that the history of severe hypoglycemia confers with it a two to threefold increase in cardiovascular events, including cardiovascular mortality. And here are just some hypotheses as to how this might be the case, if indeed there is a direct correlation. 9

10 Improving the Prognosis of Patients with Type 2 Diabetes Slide 29. UKPDS: Myocardial Infarction in Metformin Study. On the next slide are famous data from the UKPDS. remember that there was a small substudy within the UKPDS and overweight patients that tested metformin as monotherapy. There was a 39 percent reduction in MIs and a 50 percent reduction in coronary deaths compared to the control group, which in the UKPDS was treated with diet.

11 On the next slide we see the follow-up study from the metformin substudy in the UKPDS. Similarly, the 10-year follow-up data would suggest that there's a persistent benefit on myocardial infarction. 11

12 And here now is the ProACTIVE study. This is the secondary endpoint of major adverse cardiovascular events. In ProACTIVE, the primary endpoint, which contains some peripheral vascular disease endpoints, was negative. But pioglitazone appears to reduce MACE events by about 16 percent. So either of the two insulin-sensitizing drugs, metformin, as well as pioglitazone, could be associated with beneficial effects on cardiovascular outcomes. 12

13 Here are some large cardiovascular outcomes trials underway in diabetes the DPP-4 inhibitors, the GLP-1 receptor agonists, and the SGLT-2 inhibitors. 13

14 On the next slide we have from the ACE the diabetes algorithm, a chart that describes the profiles of antidiabetic agents as related to a variety of adverse effects. And we focused here on heart failure and cardiovascular disease. 14

15 And finally, this is the algorithm from the American Diabetes Association, the European Association for the Study of Diabetes. 15

16 Here are the key teaching points that I'd like to make. This individual will certainly benefit from a trial of therapeutic lifestyle change. Certainly if a drug were necessary, the evidence would suggest that metformin monotherapy would be an ideal drug in this individual, as long as no renal insufficiency was documented. If a second agent is needed, it's not entirely clear which is the best drug to use. I personally would probably avoid sulfonylureas because of the concerns that we've described. Insulin would probably not be a popular maneuver for this patient who just was diagnosed with diabetes. Also there'd be the risk of hypoglycemia. Reasonable options included the DPP-4 inhibitors, the GLP-1 receptor agonists, a TZD, or SGLT-2 inhibitor. And again, I would caution that issues regarding heart failure and TZDs and this new concern about heart failure with the DPP-4 inhibitor. 16

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