Abstract
The following illustrative case presentation was introduced by Jeffrey S. Freeman, DO, at the symposium titled “Incretin-Based Therapies: Bridging the Gap Between Clinical Experiences and Emerging Applications in Type 2 Diabetes.” The program was conducted Thursday, November 5, 2009, at the American Osteopathic Association's 114th Annual Osteopathic Medical Conference and Exposition in New Orleans, Louisiana. Discussion excerpts from the symposium participants regarding treatment options for the patient are included.
Dave, a 58-year-old retired teacher, was diagnosed as having type 2 diabetes mellitus (T2DM) 2 months before his visit to your office. At diagnosis, his glycated hemoglobin (HbA1c) level was 7.8% and his mean glucose was 177 mg/dL. He has hypertension and hyperlipidemia.
Table 1 shows Dave's patient history. Two years ago, he underwent placement of several cardiac stents after having a myocardial infarction. At that time, he gave up smoking cigarettes, which at one time was about 20 packs per year, and he started exercising at a gym 4 times each week.
Table 1
A 58-Year-Old Man With T2DM: Patient History
History
|
At Diagnosis (2 months ago)
|
Present
|
|---|
| General | □ Retired teacher | □ Lost 2 pounds |
| | □ T2DM diagnosed 2 months ago | □ Feels well |
| □ High blood pressure | □ Unable to check finger sticks daily |
| | □ High lipids | |
| □ Cardiac stents placed after MI | |
| Social | Former cigarette smoker | |
| Family | □ High blood pressure | |
| □ Premature heart disease | |
| Medications | □ Lisinopril, 20 mg daily | |
| □ Fish oil capsules, 4 mg daily | |
| | □ Simvastatin, 40 mg daily | |
| □ Metoprolol, 50 mg daily | |
| | □ Lecithin | |
| □ B-complex vitamins | |
Table 1
A 58-Year-Old Man With T2DM: Patient History
History
|
At Diagnosis (2 months ago)
|
Present
|
|---|
| General | □ Retired teacher | □ Lost 2 pounds |
| | □ T2DM diagnosed 2 months ago | □ Feels well |
| □ High blood pressure | □ Unable to check finger sticks daily |
| | □ High lipids | |
| □ Cardiac stents placed after MI | |
| Social | Former cigarette smoker | |
| Family | □ High blood pressure | |
| □ Premature heart disease | |
| Medications | □ Lisinopril, 20 mg daily | |
| □ Fish oil capsules, 4 mg daily | |
| | □ Simvastatin, 40 mg daily | |
| □ Metoprolol, 50 mg daily | |
| | □ Lecithin | |
| □ B-complex vitamins | |
×
Medications included lisinopril, 20 mg daily; fish oil capsules, 4 g daily; aspirin, 81 mg daily; simvastatin, 40 mg daily; metoprolol succinate, 50 mg daily; lecithin; and B-complex vitamins.
Since he began his aerobic and anaerobic exercise program 2 months ago, he has lost 2 pounds. He does not perform daily finger sticks because of cost.
Physical Examination
Physical examination indicated that the patient's height is 5 feet 9 inches; weight, 178 lb; calculated body mass index, 26.3; waist circumference, 38 inches; blood pressure, 132/76 mm Hg; and heart rate, 76 beats per minute. Other physical examination findings are normal, excluding some funduscopic changes consistent with hypertension.
Considerations
When comparing baseline laboratory test results with current results (
Table 2), his HbA
1c decreased from 7.8% to 7.4%. Dave's fasting glucose and mean glucose levels also decreased (187 mg/dL to 132 mg/dL and 177 mg/dL to 166 mg/dL, respectively).
Table 2
A 58-Year-Old Man With T2DM: Laboratory Results
Measure*
|
At Diagnosis (2 months ago)
|
Present
|
|---|
| ▪ Glycated Hemoglobin, % | 7.8 | 7.4 |
| ▪ Fasting Glucose | 187 | 132 |
| ▪ Mean Glucose | 177 | 166 |
| ▪ Liver Function Studies | Normal | Normal |
| ▪ Electrolytes | Normal | Normal |
| ▪ BUN/Creatine | 16/0.8 | 16/0.8 |
| ▪ Urine: Microalbumin/Creatinine, μg/mg | 14 | 14 |
| ▪ Lipid Profile | | |
| □ Total cholesterol | 154 | NA |
| □ LDL-C | 68 | NA |
| □ HDL-C | 58 | NA |
| □ Triglycerides | 89 | NA |
| □ Non-HDL-C | 96 | NA |
Table 2
A 58-Year-Old Man With T2DM: Laboratory Results
Measure*
|
At Diagnosis (2 months ago)
|
Present
|
|---|
| ▪ Glycated Hemoglobin, % | 7.8 | 7.4 |
| ▪ Fasting Glucose | 187 | 132 |
| ▪ Mean Glucose | 177 | 166 |
| ▪ Liver Function Studies | Normal | Normal |
| ▪ Electrolytes | Normal | Normal |
| ▪ BUN/Creatine | 16/0.8 | 16/0.8 |
| ▪ Urine: Microalbumin/Creatinine, μg/mg | 14 | 14 |
| ▪ Lipid Profile | | |
| □ Total cholesterol | 154 | NA |
| □ LDL-C | 68 | NA |
| □ HDL-C | 58 | NA |
| □ Triglycerides | 89 | NA |
| □ Non-HDL-C | 96 | NA |
×
Liver function studies, electrolytes, serum urea nitrogen/creatinine ratio, and urine for microalbumin were all normal at baseline and at presentation. Lipid profile, taken at diagnosis, revealed a total cholesterol of 154 mg/dL; low-density lipoprotein cholesterol, 68 mg/dL; high-density lipoprotein cholesterol, 58 mg/dL; and triglycerides, 89 mg/dL. His calculated non–high-density lipoprotein cholesterol was 96 mg/dL.
Given Dave's profile at baseline and then 2 months later at presentation, you must consider how to move forward in terms of treating this patient.
Discussion
Is this patient at HbA1c goal at the 2-month mark? If not, what should the HbA1c goal be for this patient?
Jay Shubrook, DO: This patient is not at goal at 2 months. This is a young patient who is relatively new to diabetes, so the target HbA1c should be 6.5%. This person can be protected for a number of years, so if he can get his HbA1c below 6.5% without hypoglycemia, that would be acceptable.
Frank Lavernia, MD: I agree that he is not at goal. If he can avoid hypoglycemia and weight gain and keep his HbA1c levels between 6.5% and 7.0%, that would be a satisfactory target.
Jeffrey S. Freeman, DO: I agree also. This patient was diagnosed as having diabetes only 2 months ago, but he has probably had diabetes for 5 to 7 years. His treatment has only just begun, so there is ample time to try different strategies and make therapeutic change. The patient's history of coronary artery disease may preclude the ability to drive his HbA1c levels to 6.5% or lower.
What is the next approach to treatment, given that the patient is not being treated for diabetes?
Frank Svec, MD, PhD: Both metformin and exenatide are good options. I think exenatide is going to be an exciting possibility because of its effect on weight and its other actions. However, exenatide is still a fairly new agent and more data are needed before using it for first-line therapy. On the other hand, metformin is a good initial therapy because of its effect in overweight patients, as shown in the UKPDS [United Kingdom Prospective Diabetes Study].
1 Metformin also reduces the risk of cardiovascular outcomes. Currently, my first choice would be metformin because we have outcome data to support its use as a first-line therapy.
Dr Lavernia: I agree with Dr Svec that metformin should be the first choice. The patient's HbA1c levels do not dictate that he should begin with dual therapy. Metformin as monotherapy could be effective in reducing his HbA1c levels.
Dr Shubrook: You could pick any agent and he would improve. His improvement would be even better if the patient included lifestyle changes also. I choose one agent for each percentage point that the patient is beyond the goal. So, at 7.4%, one agent would be adequate, at 8.4%, two agents are needed, and at 9.4%, I would add insulin or insulin replacement therapy. Metformin is definitely my first choice of therapy.
If monotherapy or lifestyle modification are not effective in sufficiently reducing the HbA1c levels, what is the next step in treatment?
Dr Shubrook: This is where the physician needs to individualize treatment decisions. I would ask the patient to check his fasting and postprandial blood glucose levels. I would want to determine whether there is a difference between them. I would also want to discuss his goals with him, find out what his insurance will cover, and encourage him to decide what he wants to do. If he has dyslipidemia or fatty liver disease, I would choose a TZD [thiazolidinedione]; if he has postprandial hyperglycemia, I would choose a secretagogue; and if weight is an issue, I would choose a DPP-4 [dipeptidyl peptidase-4] inhibitor or exenatide.
Dr Lavernia: My concern is whether this patient will agree to inject himself. I would want to see whether he can tolerate the medications, so I would start him on free samples of the agents. If he loses weight, he will most likely be satisfied with the medication and be willing to continue using it. If he develops nausea and can't tolerate the medication, I will move on to something else. Cost must also be considered, as well as weight gain and hypoglycemia, which are possible with a sulfonylurea. Basal insulin also has a cost attached, particularly if taken twice a day. Analog insulin, which is the glargine, is more expensive and effective.
Dr Svec: I am strongly opposed to using a sulfonylurea. The UKPDS trial
1 showed that the combination of metformin and a sulfonylurea leads to increased complications. No one initially believed that result, but a meta-analysis found that the sulfonylurea/metformin combination increased cardiovascular complications. Sulfonylureas are inexpensive and have been available for 50 years, but there is no study showing that they reduce complications. Other medications, such as TZDs, DPP-4 inhibitors, and exenatide are expensive. Exenatide is a very good choice because of its effect on weight and because it has a favorable effect on lipids.
Dr Freeman: This patient is overweight but not obese. He lost 2 pounds in 2 months with some lifestyle modifications. He also has a history of cardiac disease. I would not rule out a TZD/metformin combination in this particular patient because they have not been shown to cause myocardial infarction. There are data showing that TZDs may improve the proinflammatory environment.
Dr Svec: TZDs do not cause heart attacks, but they also do not reduce those events. The outcome data must be considered, but findings are limited.
Dr Freeman: The PROactive trial
2 compared a TZD to placebo, and there are data from the RECORD trial
3,4 that showed some measures of improvement in CVD risk or neutrality, but these studies were conducted in high-risk patients.
What if this patient was aged 86 years rather than 58 years? What should the HbA1c goal be for this older patient with active coronary artery disease or unstable angina?
Dr Shubrook: The American Diabetes Association has recommended a higher HbA1c target for someone with a limited life expectancy, other complicating factors, or if the patient is a child. If this patient were aged 86 years, I would focus more on this patient's blood pressure than his glucose. I would not give metformin to an 86-year-old patient. Many hospitals do not use metformin in patients older than 75 years because of the higher incidence of renal disease associated with it, which is harder to monitor in older patients.
Dr Lavernia: For this older patient, it is important to monitor the estimated GFR [glomerular filtration rate]. If the GFR is far below 50 mL per minute, I would be cautious about administering metformin. If you are considering using metformin for the first time with an older patient, assess the estimated GFR.
Dr Svec: For an 86-year-old patient, I would be satisfied with an HbA1c of 8%. I would consider prescribing acarbose because it is a mild agent and does not cause hypoglycemia. The medication can be taken as needed and it helps relieve constipation in elderly patients.
Dr Freeman: Acarbose actually led to a 25% reduction in myocardial infarction in one of the leading diabetes prevention trials.
5
What if this 86-year-old patient was concerned about preserving cognitive function? We know the association between sustained hyperglycemia and cognitive function. Should we allow this man to sustain an HbA1c at a certain point to drive cognitive function?
Dr Svec: This could cause more problems. Metformin is associated with renal problems. Thiazolidinediones are associated with edema. I would not use any agent that poses a risk of hypoglycemia in this patient. I wouldn't want him to have HbA1c levels of 11% to 13%, but if he can achieve an HbA1c of 8%, I would be satisfied. I do not think there is going to be an advantage of achieving an HbA1c of 7% as opposed to 8% for this patient.
Dr Shubrook: I believe DPP-4 inhibitors would be an ideal agent for patients with a limited lifespan and for those in a nursing home. Diabetes is difficult to manage in the elderly, and an agent that is glucose-dependent that could be implemented with minimal monitoring would be ideal. Patients in nursing homes should not be administered glyburide because of the risk of hypoglycemia and the difficulty of monitoring these patients by nursing staff.
Dr Freeman: In a study comparing sitagliptin to placebo specifically in elderly patients (aged ≥65 years), it was observed that there were no safety issues with sitagliptin compared to placebo.
6
This supplement is supported by an independent educational grant from Amylin Pharmaceuticals, Inc, and Lilly USA, LLC.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) [published correction appears in Lancet. 1998;352(9139):1558]. Lancet. 1998;352(9131):854-865.
Charbonnel B, Dormandy J, Erdmann E, Massi-Benedetti M, Skene A; PROactive Study Group. The prospective pioglitazone clinical trial in macrovascular events (PROactive): can pioglitazone reduce cardiovascular events in diabetes? Study design and baseline characteristics of 5238 patients. Diabetes Care. 2004;27(7):1647-1653.
Home PD, Pocock SJ, Beck-Nielsen H, Gomis R, Hanefeld M, Dargie H, et al. Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD): study design and protocol [published online ahead of print July 16, 2005]. Diabetologia. 2005;48(9):1726-1735.
Home PD, Pocock SJ, Beck-Nielsen H, Curtis PS, Gomis R, Hanefeld M, et al; RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial [published online ahead of print June 6, 2009]. Lancet. 2009;373(9681):2125-2135.
Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M; STOP-NIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomized trial. Lancet. 2002;359(9323):2072-2077.
Barzilai N, Mahoney EM, Guo H, et al. Sitagliptin is well tolerated and leads to rapid improvement in blood glucose the first days of monotherapy in patients aged 65 years and older with TDM. Diabetes. 2009;suppl 1:A158 .