Case Studies

Type 2 Diabetes Management in Patients with Cardiovascular Disease Risk

Middle-aged woman getting blood pressure checked

EARN CME CREDIT FOR THIS CASE

Respond to questions about key points in the patient's care and get expert opinion from Dr. Doron Schneider, internist and Dr. Bernard Zinman, endocrinologist.

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Disclosures:

The Endocrine Society has reviewed all disclosures and resolved or managed all identified conflicts of interest, as applicable.

This activity is supported by an educational grant from Novo Nordisk, Inc.

The following faculty reported relevant financial relationships: Doron Schneider, MD: Consultant, Janssen Pharmaceuticals, Inc., Lilly USA, LLC, Novo Nordisk Inc. Bernard Zinman, MD: Consultant, Merck, Novo Nordisk Inc., Sanofi-Aventis, Eli Lilly, AstraZeneca, Janssen Pharmaceuticals, Inc., and Boehringer Ingelheim, and grant support to his institution from Merck, Novo Nordisk, and Boehringer Ingelheim

The following SPC Committee members reported relevant financial relationships: Neda Rasouli, MD: Research Support, Novo Nordisk, Calibra, INTARCIA Therapeutics, GlaxoSmithKline, Bristol Meyer Squibb, AstraZeneca /Amylin, Ionis Pharmaceuticals, Boehringer Ingelheim

Endocrine Society and Knighten Health staff associated with the development of content for this activity reported no relevant financial relationships.


 

Roberta, is a 62-year-old African American school secretary who comes to see you for a three-month follow-up visit. You diagnosed her with type 2 diabetes (T2DM) 12 years ago, and eight years later at age 58 she had a myocardial infarction, although she has had no recent cardiovascular symptoms. She has a history of hypertension and hyperlipidemia and has been taking lisinopril (20 mg), simvastatin (20 mg), and metformin (1,000 mg BID).

 

Today she is without complaint but comments that she needs to lose weight when you have her step on the scale. She has expressed frustration in the past about controlling her weight, attributing the problem to the sedentary nature of her job and the frequent sweets that pass through the school office. She has been smoking since she was 14 and reports gaining weight every time she has tried to stop. She still smokes half a pack of cigarettes a day and, at present, is not making any active attempt to quit. She reports drinks socially on weekends, usually a couple of beers or a glass of wine at most.

 

Other than a BMI is 33 kg/m2 and a blood pressure of 138/70 mmHg, Roberta's physical examination is unremarkable. Her labs reveal an A1C of 8.2% (up  from 7.5% three months ago), an LDL of 110 mg/DL, an HDL of 38 mg/DL, triglycerides of 208 mg/DL, and a serum creatinine level of 1.1 mg/DL with an eGFR of  62 mL/min per 1.73 m2.

 

Questions:

What non-hypoglycemic options would you advise to reduce Roberta's risk of a myocardial infarction?

What strategy for glycemic control would you choose that might also reduce Roberta's risk of developing a cardiovascular event?


 

What non-hypoglycemic options would you advise to reduce Roberta's risk of a myocardial infarction?

Expert Opinion:

Roberta represents a common patient in the primary care practice. She is clearly at high risk for having another cardiovascular (CV) event. To demonstrate that risk to a patient like Roberta, it may be helpful to use the ASCVD calculator app on a smart phone and directly "plug in" her numbers in front of her. This approach allows patients to see the impact that their individual risk factors have on their chance of having a cardiovascular event in the next 10 years. These results can be used to facilitate shared decision-making and goal-setting with Roberta using motivational interviewing techniques. Using this calculator, Roberta's risk comes to 44% in the next 10 years – and is actually higher given that she already had a previous event.

 

Roberta has been smoking for decades, but her clinician should not give up on encouraging her to stop. If she were to stop smoking, her risk would be cut almost in half – to 25%.  If Roberta is interested (the key element), the clinician could consider a multimodal approach of pharmacologic therapy (such as buproprion, varenicline, etc.), nicotine replacement, and counseling. To blunt the expected weight gain from smoking cessation, an exercise program should be prescribed as well. The approach here would be to focus on increased activity in a patient-centered manner by encouraging Roberta to do more of what she likes to do and already does. This approach is more likely to be effective than saying something like "join a gym" — something that Roberta is unlikely to do at this point in her life.

 

At the same time, Roberta should be encouraged to adopt a food diary approach and focus on portion control, thus sensitizing her to food intake. This approach is the easiest way to encourage patients to change their dietary habits – without actually changing their diet – with an overall goal to decrease caloric intake immediately after smoking cessation. Radical diet change is often unrealistic when patients are concurrently struggling with the issues of trying to quit tobacco.

 

The next challenge involves Roberta's statin medication. Recent AHA/ACC guidelines recommend a high-intensity statin for patients who have had a cardiovascular event. They similarly recommend that all patients with diabetes between ages 40 to 75 be on a statin and that those that have a 10-year risk of a CV event greater than 7.5% be on a high-intensity statin. Roberta fits this profile, and thus her simvastatin needs to be changed to rosuvastatin or atorvastatin.  Roberta's LDL levels should be checked going forward as well to look for reductions toward 70mg/DL, and to ensure adherence. Given the limited evidence about efficacy, it does not make sense to add additional agents such as niacin to increase her HDL level.

 

Roberta’s blood pressure management is a bit of a trickier question. Several recent trials inform us about blood pressure control in a patient with her history.  The highly touted SPRINT trial randomized patients with cardiovascular disease (CVD) or at high risk of CVD to a systolic blood pressure target of 140 mmHg or 120 mmHg and found a reduction in cardiovascular events for patients in the 120 mmHg group.  Given that people with diabetes were excluded from this trial, it does not inform decision-making for Roberta. The ACCORD BP trial does, however.  This trial (though smaller and less powered than SPRINT) did not find improved outcomes for reduction of blood pressure to 120 mmHG as compared to 140 mmHg.  The ADA 2016 guidelines recommend treatment of people with diabetes to a blood pressure target of < 140/90 mmHg.  An additional recommendation is to have lower systolic targets – such as 130 mmHg for younger patients, those with albuminuria, and patients with additional cardiovascular disease risk factors if the patient can tolerate additional treatment. To that end, adding hydrochlorothiazide in combination with the lisinopril to try to get Roberta's blood pressure closer to 130 mmHg makes sense.

 

The role of aspirin is evolving in the prevention of cardiovascular events. For patients such as Roberta, adding a daily aspirin at 81 mg is advisable given that the benefits in CVD risk reduction far outweigh the bleeding risk in her situation.

 

What strategy for glycemic control would you choose that might also reduce Roberta's risk of developing a cardiovascular event?

Expert Opinion:

Roberta’s glycemic control clearly has worsened in the past three months, with her A1C climbing from 7.5% to 8.2%.  To diagnose the "why," the clinician should first and foremost assess Roberta's adherence to metformin. Given the high rate of non-adherence to medications for chronic disease, it would be pointless to further intensify treatment if she has simply stopped taking it! It would also be valuable to ask Roberta how important it is for her to get better control of her blood sugar. If her answers suggest that she is not convinced of the importance of good glycemic control, she should be reeducated with data showing improved outcomes for microvascular complications of diabetes associated with good glycemic control.

 

Once it is established that better glucose control is essential and that Roberta is adherent to her metformin regimen, new options can be reviewed as well. For the first time, medications are available that can help Roberta control her glucose but that also have the potential to reduce her risk of having another heart attack.  Despite past concerns that intensive antihyperglycemic therapies might jeopardize cardiovascular safety, Roberta can be assured that glycemic control and improved cardiovascular outcomes can now go hand-in-hand. In fact, recent evidence has associated certain newer antihyperglycemic medications with reductions in macrovascular, not just microvascular, complications of type 2 diabetes., By anchoring on real negative events that she can clearly recall and understand (such as her heart attack) as opposed to theoretical downstream risks (such as blindness or amputation), moreover, the clinician may make it more likely that Roberta will accept yet another medication for a condition that she feels is not causing symptoms – her diabetes.

 

Just what should the add-on medication be? Almost certainly not a sulfonylurea drug, given the associated weight gain seen with the class (already a concern of Roberta's) and the propensity to cause hypoglycemia. There are also questions about how effective a sulfonylurea drug would be over the long term relative to other agents. Adding basal insulin (at this point) would lead to additional weight gain. Changing the metformin and replacing it with basal insulin (at this point) would similarly lead to additional weight gain. On the other hand, to squeeze perhaps more glycemic control and potential weight loss out of a drug that she is already tolerating, her clinician might consider an increase in metformin to 2,000 mg per day and assess tolerability. Should nausea or other GI side effects develop at 2,000 mg, dosage should be backed down to the 1 gram per day. There are no demonstrable benefits in increasing metformin beyond 2,000 mg per day, only an increased risk of GI side effects. 

 

Even better options might be adding an SGLT2 inhibitor or a GLP-1 analog to the metformin. In fact, while Roberta is already in advanced cardiovascular disease, this more aggressive approach can make sense even for patients earlier in their disease course. The combination of all three agents (SGLT2 inhibitor, GLP-1 analog, and metformin) is an evolving paradigm of care given the synergies of effectiveness, low rates of hypoglycemia, and weight loss.

 

Yet another option might be to add a DPP-4 inhibitor, particularly if Roberta refuses an injectable and has an SGLT2 contraindication such as recurrent urinary tract infections (UTIs) or mycotic vaginal infections— especially as there are now several metformin combination options. Unlike the sulfonylureas, this highly used class of oral agents has the benefit of being weight-neutral – with the potential for some weight loss. Its low associated risk of hypoglycemia, especially when used with metformin, is another benefit. However, there is little evidence that a DPP-4 inhibitor will reduce Roberta's risk of a subsequent CVD event, and the likelihood of it getting Roberta to her A1C goal of 7% from her current 8.2% are low.

 

A better choice, especially since Roberta's eGFR is acceptable and she wants to lose weight, could be an SGLT2 agent. Associated with weight loss, SGLT2s can be given as either monotherapy or add-on therapies and, like the DPP-4 agents, can be provided in a fixed-dose combination. SGLT2 inhibitors reduce hyperglycemia in patients with T2DM by decreasing renal glucose reabsorption, thereby increasing urinary glucose and sodium excretion. Their most common side effects are genital tract infections. There may also be a small increase in urinary tract infections.

 

The recent EMPA-REG study demonstrated a 14% reduction in major adverse cardiac events (MACE) with the use of the SGLT2 drug empagliflozin in subjects with type 2 diabetes and at high risk for CVD events. This reduction was driven primarily by a 38% reduction in cardiovascular mortality – a finding that began to emerge within three months of drug initiation. Also seen was a reduction in hospitalization for heart failure as well as all-cause mortality. Given this cardiovascular benefit, as well as the SGLT2 class proven rates of good efficacy, low rates of hypoglycemia, and associated weight loss in the SGLT2 class, empagliflozin could well be a good option for Roberta, especially if she refuses an injectable agent.  It is important to note, however, that at this point the cardiovascular benefit shown in the EMPA-REG trial is specific to empagliflozin; without more definitive clinical trial data, we do not yet know if it is a class benefit. In addition, if Roberta does start taking this agent, her GFR will have to be watched, since it cannot be used if the GFR falls below 45.

 

Although empaglifozin may be a reasonable option for Roberta, a GLP-1 analog could be another viable alternate approach if she is willing to accept an injectable agent and has no history of pancreatitis. Injectable via a pen device, liraglutide and other GLP-1 analogs promote weight loss, have been shown to have good clinical effectiveness in lowering blood sugar, and have low associated rates of hypoglycemia. Weight loss may be particularly pronounced when these agents are used with SGLT2 agents, as the effect on weight loss are likely to be complementary. Unlike the SGLT2 agents, however, liraglutide can be continued even if Roberta develops renal impairment. In fact, this drug has been shown to be safe in patients with an eGFR between 30 and 59.

 

As with the SGLT2 agents, recent research suggests that a GLP-1 agent may also help reduce Roberta's risk of a subsequent CVD event. In the recent LEADER trial, the GLP-1 analog liraglutide in particular showed clear CVD benefits, including reductions of 22% in major cardiovascular events — in addition to improvements in cardiovascular risk factors such as weight loss and blood pressure.

 

Zinman B, Wanner C, Lachin JM, et al. Empaglifozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-2128. DOI: 10:1056/NEJMMoa1504720.

Marso SP, Daniels GH, Brown-Frandsen K, et al. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2016;375:311-322. DOI: 10.1056/NEJMoa1603827.

Kahn SE, Haffner SM, Heise MA, et a. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med 2006;355:2427-2443.

ClinicalTrials.gov. Efficacy and safety of liraglutide versus placebo as add-on to existing diabetes medication in subjects with type 2 diabetes and moderate renal impairment. Available at: https://clinicaltrials.gov/ct2/show/NCT01620489?term=LIRA-RENAL&rank=2

Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014 Jun 24;129(25 Suppl 2): S1-45. Doi: 10.1161/01.cir.0000437738.63853.7a.
 
The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:21-3-2103.  10.1056/NEJMoa1001286.
 
The ACCORD study Group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575-1585. DOI:  10.1056/NEJMoa1001286.