1. DIABETES MELLITUS IN THE AMBULATORY SETTING
Evaluation and Treatment Strategies in the General Internal Medicine Clinic
Jan Cooper, M.D.

2. How big is the problem in the U. S
How big is the problem in the U.S.? *Diabetes Mellitus (DM) was declared an epidemic in the U.S. by the CDC in 2001.
11% of people ≥ age 20, including 27% of those ≥ age 65, have DM!
Another 35% of people ≥ age 20, including 50% of those ≥ age 65, have pre-diabetes!
This is no surprise, as 67% of people ≥ age 20, including 70% of those ≥ age 65, are overweight or obese!
What’s even worse is that 27% of those with DM don’t even know that they have it!
CDC.National Diabetes Fact Sheet,2011; CDC/NCHS Obesity and Overweight FastStats,2010; CRC Obesity Among Older Americans,2009.

3. Why is DM so important?
Diabetics have a 2 to 4 times increased risk of, and death from, cardiovascular disease (CVD).
Diabetic retinopathy is the # 1 cause of new blindness in adults in our country.
Diabetic nephropathy is the # 1 cause of end stage renal disease in our country.
Diabetic neuropathy and PVD are the major causes of non-traumatic amputations in our country.
Treatment of DM and its complications accounts for about 10% of our country’s healthcare costs, while treatment of diabetics overall accounts for about 20%.
CDC. National Diabetes Fact Sheet, 2011; ADA.Diabetes Care, Economic Costs of Diabetes in the U.S. in 2012, online March 2013. 3

4. Type 1 DM vs Type 2 DM
Type 1 DM is a disease of beta cell destruction and insulin deficiency. It accounts for % of cases.
Type 2 DM is a disease of insulin resistance and progressive beta cell failure, resulting in relative or absolute insulin deficiency. It accounts for % of cases.
90% of patients with DM are managed by primary care physicians, but many/most patients with Type 1 DM are managed by endocrinologists and pediatricians.
Today’s discussion is limited to Type 2 DM.
Recommendations are from the guidelines of the American Diabetes Association (ADA) - newest guidelines issued January 2014 (hyperglycemia management updated 6/12).

5. First Case
A 61 year old African American woman comes to see you for a checkup after being told her BP was elevated at a church screening. She is asymptomatic. She has no PMH, has not seen a doctor in many years, and is on no prescription or OTC medications. She does not exercise or eat a healthy diet, and she does not smoke or drink. She has no health insurance. Her mother and 2 sisters have DM and HTN.
On PE her BP is 155/95, she weighs 220 pounds, is 5’2” tall, and has a BMI of 40. Otherwise, her PE is normal.
What labs would you order at this point?

6. Who should be screened for DM?
Everyone age 45 and over.
Everyone under 45 with a BMI ≥ 25 kg/m² and one other risk factor for DM:
▪ Family history in a 1st degree relative.
▪ Race/ethnicity of Native American, African American,
Latino, Asian American, or Pacific Islander.
▪ History of gestational DM or delivery of a baby ≥ 9 lbs.
▪ Polycystic ovary syndrome, HTN, lipid disorder,
acanthosis nigricans, CVD or sedentary lifestyle.
• If screening is normal, it should be repeated every 3 years.
ADA.Diabetes Care,2014;37(Suppl 1):S5-S80.

7. First Case (cont) Lab Results
•Fasting glucose: 150 mg/dl •Chol: 240 mg/dl
•CMP otherwise: normal •TG: 250 mg/dl
•CBC: normal •HDL: 36 mg/dl
•TSH: normal •LDL: 154 mg/dl
•U/A: normal •HBA1C: 8.8%
What diagnoses would you give her at this time?

8. How do you diagnose DM? Fasting plasma glucose ≥ 126 mg/dl, or
2 hour plasma glucose ≥ 200 mg/dl during an oral glucose tolerance test, or
Symptoms of hyperglycemia and a random plasma glucose ≥ 200 mg/dl, or
HBA1C ≥ 6.5%.
All should be repeated before making the diagnosis, unless 2 different tests are both consistent with DM.
ADA.Diabetes Care.2014;37(Suppl 1):S5-S80.

9. How do you diagnose pre-diabetes?
Impaired Fasting Glucose (IFG): fasting plasma glucose ≥ 100 mg/dl and ≤ 125 mg/dl, or
Impaired Glucose Tolerance (IGT): 2 hour plasma glucose ≥ 140 mg/dl and ≤ 200 mg/dl during an oral glucose tolerance test, or
HBA1C %.
All should be repeated before making the diagnosis.
ADA.Diabetes Care.2014;37(Suppl 1):S5-S80.

10. Why and how should we treat pre-diabetes?
It confers an increased risk of CVD, and without intervention, most will develop DM within 10 years.
Aim for a weight loss of % and at least 150 minutes of moderate activity per week.
Consider metformin for those with a BMI > 35, those who are younger than 60, and women with prior gestational diabetes.
• Monitor at least yearly.
ADA.Diabetes Care.2014;37(Suppl 1):S5-S80.

11. First Case (cont)
What treatment would you institute for this patient with newly diagnosed DM and a HBA1C of 8.8%?

12. How do you manage DM?
Referral to a Diabetes Education Program to assist in education on Medical Nutrition Therapy (MNT), exercise, and all aspects of the disease, including treatment, self monitoring, complications, and the concept that it is a progressive disease leading to insulin therapy in most patients.
Medication for glycemic control.
Monitoring for complications.
Treatment of HTN, lipids and hypercoagulability.
Smoking cessation.
Consider referral for bariatric surgery if BMI ≥ 35.
ADA.Diabetes Care.2014;37(Suppl 1):S5-S80.

13. What are the glycemic goals?
HBA1C < 7%.
Fasting/Preprandial/Bedtime (AC and HS) capillary blood glucose (CBG) mg/dl.
Postprandial CBG hours after starting a meal < 180 mg/dl.
Goal is to achieve glycemic target without causing hypoglycemia.
Reaching goal glycemia has been clearly shown to prevent microvascular complications; its effect on the prevention of macrovascular complications is less clear, but seems to be most important when attained early in the course of DM. Control of BP & lipids, use of ASA, and smoking cessation are essential in preventing CVD.
ADA.Diabetes Care, 2014;37 (Suppl 1):S5-S80.

14. Does tight glycemic control prevent macrovascular disease?
• Based upon the findings of the UKPDS, ACCORD, ADVANCE and VADT trials, the ADA, AHA, and ACC issued a joint statement supporting the individualization of treatment goals, and stressing the importance of aggressive treatment and control early in the course of the disease.
Patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular and macrovascular complications, extensive comorbidities, or longstanding difficult to control DM, may reasonably have a HBA1C goal that is > 7%.
Patients with a shorter duration of DM, a long life expectancy, and no significant complications, may reasonably have a HBA1C goal that is lower, < 6.5% or even < 6.0%.
Skyler etal.Diabetes Care.2009;32:

15. How do you choose medication for glycemic control?
Choose based upon potency, safety, side effects, ease of use, effect on other risk factors, and cost.
• There is no good data yet showing that one class of medication prevents complications better than another, other than through the level of glycemic control and effects on other risk factors.
• New guidelines June 2012 are less prescriptive and algorithmic, and are more patient-centered. 15

16. Medications for DM:
▪ Biguanides - Metformin (Glucophage) - decrease hepatic glucose output - weight neutral or mild loss, no hypoglycemia, cheap - GI side effects, contraindicated in CRI and unstable CHF because of risk of lactic acidosis, B12 deficiency.
▪ Sulfonylureas - Glipizide (Glucotrol), glimeperide (Amaryl) - enhance insulin secretion - cheap - weight gain, hypoglycemia.
*Glyburide and chlorpropamide are not recommended because of long half lives and risk of severe hypoglycemia.
▪ Insulins - Lispro (Humalog), aspart (Novolog), glulisine (Apidra); Regular; NPH; glargine (Lantus), detemir (Levemir); and fixed combinations - no dose limit, NPH and Regular are cheap, improve lipids - injections, weight gain, hypoglycemia, analogs are expensive.
*Inhaled insulin (Exubera) was taken off of the market because of poor sales. 16

17. Medications for DM: (cont)
▪ Thiazolidinediones (TZD’s or Glitazones) - Pioglitazone (Actos) - increase sensitivity to insulin - improve lipids, potential decrease in MI, no hypoglycemia - fluid retention, weight gain, CHF, fractures, expensive, ?bladder cancer (taken off of market in France and Germany).
* Rosiglitazone (Avandia) is not recommended because of
possible cardiovascular risks, taken off the market in Europe, and its use restricted by the FDA in 9/10 (*restriction lifted in 11/13).
▪ DPP-4 Inhibitors - Sitagliptin (Januvia), saxagliptan (Onglyza), linagliptin (Tradjenta), alogliptin (Nesina) - increase glucose-mediated insulin secretion, suppress glucagon secretion - weight neutral, no hypoglycemia - expensive, ?effects on immune system/pancreatitis/pancreatic cancer, long term effects not known.
▪ GLP-1 Agonists (Incretin Mimetics) - Exenatide (Byetta, Bydureon), liraglutide (Victoza) - potentiate glucose-stimulated insulin secretion, suppress glucagon secretion, slow gastric motility - weight loss, ?delay/prevention of beta cell failure, no hypoglycemia - injections, expensive, GI side effects, ?pancreatitis/pancreatic cancer, ?medullary CA of the thyroid, long term effects not known. 17

18. Other Medications for DM :
▪ α-Glucosidase Inhibitors - Acarbose (Precose), miglitol (Glyset) - reduce the rate of digestion of polysaccharides - weight neutral, no hypoglycemia - severe GI side effects, expensive, three times daily.
▪ Glinides - Nateglinide (Starlix), repaglinide (Prandin) - stimulate insulin secretion - weight gain, three times daily, expensive, hypoglycemia.
▪ Amylin Agonists - Pramlintide (Symlin) - slow gastric emptying, decrease glucagon secretion - weight loss, no hypoglycemia - injections, expensive, GI side effects, long term effects not known.
▪ Bile Acid Resins - Colesevelam (WelChol) - mechanism of action unknown.
▪ Dopamine Receptor Agonists - Bromocriptine (Cycloset) - mechanism of action unknown, but probably normalizes aberrant hypothalamic neurotransmitter activities.
▪ Sodium-glucose Transporter-2 Inhibitors (SGLT2s) - Canagliflozin (Invokana) - block reabsorption of glucose in the kidneys. 18

19. How potent are these medications
How potent are these medications? *If initial HBA1C is ≥ 9%, use 2 medications. If initial glucose is ≥ mg/dl, or HBA1C is ≥ 10-12%, use insulin.
Medication
Biguanides
Sulfonylureas
Insulin
TZD’s
DPP - 4 Inhibitors
GLP - 1 Agonists
α - Glucosidase Inhibitors
Glinides
Amylin Agonists
Colesevelam
Bromocriptine
Canagliflozin
Expected decrease in HBA1C
No limit

20. T2DM Antihyperglycemic Therapy: General Recommendations
Moving from the top to the bottom of the figure, potential sequences of anti-hyperglycaemic therapy. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis (unless there are explicit contraindications).
T2DM Antihyperglycemic Therapy: General Recommendations
Diabetes Care, Diabetologia. 19 April 2012
[Epub ahead of print]

21. T2DM Antihyperglycemic Therapy: General Recommendations
If the A1c target is not achieved after ~3 months, consider one of the 5 treatment options combined with metformin (dual combination): a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 receptor agonist or basal insulin. Note that the order in the chart is determined by historical introduction andr oute of administration and is not meant to denote any specific preference. Choice is based on patient and drug characteristics, with the over-riding goal of improving glycemic control while minimizing side effects. Shared decision-making with the patient may help in the selection of therapeutic options.
Rapid-acting secretagogues (meglitinides) may be used in place of sulfonylureas. Consider in patients with irregular meal schedules or who develop late postprandialhypoglycemia on sulfonylureas. Other drugs not shown (α-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used where available in selected patients but have modest efficacy and/or limiting side effects.
In patients intolerant of, or with contraindications for, metformin, select initial drug from other classes depicted, and proceed accordingly.
Consider starting with 2-drug combinations in patients with very high HbA1c (e.g. ≥9%).
T2DM Antihyperglycemic Therapy: General Recommendations
Diabetes Care, Diabetologia. 19 April 2012
[Epub ahead of print]

22. T2DM Antihyperglycemic Therapy: General Recommendations
Further progression to 3-drug combinations are reasonable if 2-drug combinations do not achieve target. If metformin contraindicated or not tolerated, while published trials are generally lacking, it is reasonable to consider 3-drug combinations other than metformin.
Insulin is likely to be more effective than most other agents as a third-line therapy, especially when HbA1c is very high (e.g. ≥9.0%). The therapeutic regimen should include some basal insulin before moving to more complex insulin strategies (see Fig. 3)
T2DM Antihyperglycemic Therapy: General Recommendations
Diabetes Care, Diabetologia. 19 April 2012
[Epub ahead of print]

23. Diabetes Care, Diabetologia. 19 April 2012 [Epub ahead of print]
Ultimately, more intensive insulin regimens may be required (see Figure 3.)
Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a 2-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycaemia (e.g. HbA1c ≥ %).
Consider beginning with insulin if patient presents with severe hyperglycemia (≥ mg/dl [≥ mmol/l]; HbA1c ≥ %) with or without catabolic features (weight loss, ketosis, etc).
Diabetes Care, Diabetologia.
19 April 2012 [Epub ahead of print]

24. T2DM Anti-hyperglycemic Therapy: General Recommendations
Overview of anti-hyperglycemic therapy in T2DM (Figure 2.) What follows are variations of this figure to help guide the clinician in choosing agents which may be most appropriate under certain situations: to avoid weight gain, to avoid hypoglycemia, and to minimize costs.
T2DM Anti-hyperglycemic Therapy: General Recommendations
Diabetes Care, Diabetologia. 19 April 2012
[Epub ahead of print]

25. Adapted Recommendations: When Goal is to Minimize Costs
Fig. 2C should be considered when the goal is to minimize costs. This reflects prevailing costs in the North America and Europe in early 2012; costs of certain drugs may vary considerably from country to country and as generic formulations become available.  
Adapted Recommendations: When Goal is to Minimize Costs
Diabetes Care, Diabetologia. 19 April 2012
[Epub ahead of print]

26. Adapted Recommendations: When Goal is to Avoid Hypoglycemia
Fig. 2B should be considered when the goal is to avoid weight gain. Note that "hidden" agents may obviously still be used when required, but additional care is needed to avoid adverse events. Here, the chances of weight gain when using the hidden agents will be mitigated by more rigorous adherence to dietary recommendations and optimal dosing.
Adapted Recommendations: When Goal is to Avoid Hypoglycemia
Diabetes Care, Diabetologia. 19 April 2012
[Epub ahead of print]

27. First Case (cont)
She was referred to the Diabetes Center for MNT and general teaching.
She was started on metformin 500 mg twice daily, and was told to increase to 1000 mg twice daily after 2 weeks.
She was referred to Ophthalmology.
She was scheduled to return to clinic in 3 months for follow-up, with a HBA1C and a urine microalbumin/creatinine one week before her appointment.
Should any other medications be prescribed at this time?

28. What other disorders need treatment in patients with DM?
In addition to treating the glucose, we must also treat the HTN, lipid abnormalities and hypercoagulability.
▪ ACE Inhibitor (or ARB) for HTN, with a goal BP of ≤ 130/80 140/80 (per ACCORD tight control of HTN arm), although lower may be appropriate for some patients. Take at least one medication at bedtime. (*JNC 8 and ASH/ISH guidelines differ.)
▪ Statin if above goal. Statin if overt CVD, or over age 40 with one or more other risk factors, regardless of baseline LDL. Goal LDL less than 100 mg/dl, and less than 70 mg/dl for overt CVD (or % below baseline). May need additional treatment for TG and HDL if abnormal. Treat TG if >1000 mg/dl. (*ACC/AHA guidelines use intensity of therapy rather than goals.)
▪ Low dose ASA if overt CVD. Low dose ASA for men over 50 and women over 60 who have one or more other risk factors. Clopidogrel (Plavix) should be used in the case of ASA allergy.
ADA.Diabetes Care,2014;37(Suppl 1):S5-S80.

29. First Case (cont) Lisinopril 20 mg daily was added, and a
BMP was ordered for 2 weeks.
Atorvastatin 40 mg daily was added, and lipids and LFT’s were ordered for one week before her 3 month appointment.
ASA 81 mg daily was added.

30. How do you monitor therapy?
HBA1C level every 3 months if uncontrolled or if therapy is changed, otherwise every 6 months.
Self monitoring of blood glucose is definitely indicated for patients on multiple daily doses of insulin, and may be indicated for patients on one dose of insulin daily, or on non insulin therapy particularly if there is a risk of hypoglycemia.
Novel methods of monitoring are being evaluated e.g. continuous monitoring, contact lenses, service dogs and tattoos.

31. First Case (cont)
She returns to clinic in 3 months. She has lost 5 lbs.
HBA1C is 6.1%, BP is 145/85, electrolytes were normal, Chol is 180 mg/dl, LDL is 68 mg/dl, HDL is 40 mg/dl, TG is 210 mg/dl, and she has no albuminuria.
HCTZ 25 mg daily is added.
Fenofibrate 145 mg daily is added.
You are satisfied with her DM control.
She is scheduled to return to clinic in 3 months with a BMP.

32. First Case (cont)
She unfortunately does not return to see you for one year, but she has continued to take her medications as prescribed. She has gained 15 pounds.
Now her BP is 120/75, the BMP is normal and a POC HBA1C is 7.8%.
What medication adjustments, if any, do you make at this time?

33. First Case (cont) You add glipizide ER 10 mg daily.
You send her back to diabetes education to reinforce diet and exercise.
She returns to clinic in 3 months with a HBA1C of 7.4%, an LDL at goal, and no albuminuria. She has lost 10 lbs.
What medication adjustments, if any, do you make at this time?

34. First Case (cont)
You add NPH 10 units twice daily. (She knows how to use insulin from giving it to her mother.)
She returns to clinic in 3 months with a HBA1C of 6.0%. She has lost another 5 lbs.
You are happy with her control, and schedule her to return to clinic in 6 months with a HBA1C before.

35. Are we doing a good job with treatment?
Only 52.5% of diabetics have a HBA1C < 7%.
Only 51.1% of diabetics have a BP < 130/80.
Only 56.2% of diabetics have an LDL cholesterol
< 100 mg/dl.
Only 18.8% of diabetics are meeting all 3 goals!
Casagrande S.S. etal.Diabetes Care.2013;36:

36. Why do we do such a poor job?
Patient reasons: Cost, side effects, fear of side effects, fear of injections, and denial of disease.
Physician reasons: “Clinical inertia” - not enough time, not enough resources, concern about cost and pill burden, care directed at acute problems, and lack of knowledge of goals.

39. Complications: Macrovascular
DM increases the risk of coronary artery disease, stroke, and peripheral vascular disease 2 to 4 times.
Although controlling the glucose may be important early in the disease, controlling the BP and lipids, avoiding smoking, and taking ASA when indicated are much more important for prevention.

41. Complications: Neuropathy
Present in % of diabetics. Symmetric distal polyneuropathy is the most common type,
and leads to Charcot joints, dislocations, fractures, ulcers, infections, and amputations.
Prevention/Treatment: Control glucose, teach good foot care, do a foot exam yearly, refer to Podiatry if neuropathy or its complications are present, and control pain: tricyclics, topicals and anticonvulsants.

46. Complications: Microvascular Nephropathy
Present in % of diabetics.
Prevention/Treatment: Maintain BP ≤ 140/80, keep glucose at goal, and check urine albumin/creatinine ratio yearly. Use ACE inhibitor or ARB to treat BP.

48. Complications: Microvascular Retinopathy
Present in % of diabetics.
Prevention/Treatment: Control BP and glucose to previously mentioned goals, and refer to Ophthalmology for yearly screening exam/treatment.

49. Health Maintenance Pneumovax once, then repeat after age 65.
Hepatitis B vaccine now recommended by the ACIP/CDC.
All other vaccinations as are appropriate for age.
Routine dental exams.
Contraception counseling for women of child bearing age.
Age appropriate cancer screening only (the meaning of the increased risk of liver, pancreas, uterus, colon, breast and bladder cancers, and the decreased risk of prostate cancer, is unclear).

50. Second Case
This is a 69 year old Hispanic woman who has been followed elsewhere for DM for 15 years, HTN for 8 years, osteoporosis for 3 years, and hyperlipidemia for 5 years. She has had several episodes of hypoglycemia recently, usually after being late for a meal, and once in the middle of the night requiring an ER visit after a fall. She does not smoke or drink, lives alone, and has no family in town.
Meds: Glyburide 5 mg daily, metformin 1000 mg twice daily, ramipril 10 mg daily, chorthalidone 12.5 mg daily, simvastatin 40 mg daily, ASA 81mg daily, alendronate 70 mg weekly, and OTC calcium with vitamin D.

51. Second Case (cont)
BP 128/78, BMI 35, fundi are normal, she has decreased sensation to filament exam on both feet, and the remainder of the PE is normal.
She checks her CBG’s AC breakfast and dinner, and they are AC breakfast and low 200’s AC dinner.
HBA1C is 7.9%, but the remainder of her labs are normal.
What medication adjustments, if any, do you make?

52. Second Case (cont) Glyburide was D/C’d.
Exenatide 5 ug SQ twice daily was added, and titrated up to 10 ug twice daily at her next visit.
She was referred to the Diabetes Educator to learn injection and reinforce prior teaching.
Follow-up HBA1C is 6.8%, her CBG’s are at goal, and she has had no further episodes of hypoglycemia.
She has also lost 10 pounds.

53. Third Case
A 42 year old man with HTN, hyperlipidemia and an ischemic cardiomyopathy with an EF of 25% and severe SOB on minimal exertion, is referred to you by his cardiologist for management of fairly newly diagnosed DM.
Meds: Metformin 500 mg twice daily, pioglitazone 15 mg daily, carvedilol 25 mg twice daily, furosemide 40 mg daily, lisinopril 40 mg daily, rosuvastatin 20 mg daily, and ASA 325 mg daily.

54. Third Case (cont)
BP 110/60, Wt 240 lbs, BMI 35, fundi difficult to visualize, elevated neck veins, S3 gallop, holosystolic murmur, 1+ edema, but foot exam was otherwise normal.
He brings in a copy of recent labs:
HBA1C 10.2%, FBS 252 mg/dl, Crt 1.8 mg/dl, and Ur Alb/Crt 50 mg/g (nl < 30).
What medication adjustments, if any, would you make?

55. Third Case (cont) Metformin and pioglitazone were both D/C’d.
Insulin glargine 30 units daily was started, and he was sent to the Diabetes Educator to learn injection, self monitoring techniques, and self titration of insulin to reach a target FBS.
He was also referred to Ophthalmology.
He returned to clinic in 3 months on 45 units of insulin glargine daily with a glucose log showing fasting CBG’s at goal, but a HBA1C of 7.9%.

56. Third Case (cont)
He then began checking AC and HS CBG’s. The AC breakfast and dinner CBG’s were at goal, but the AC lunch and HS CBG’s were high, prompting the addition of 3 units of insulin lispro before breakfast and dinner. He was instructed on self titration of the insulin lispro, which was raised to 6 units at both times, resulting in AC and HS CBG’s that were all at goal.
A follow up HBA1C in 3 months was 6.8%.

57. What should you remember?
• Screen for DM – it’s an EPIDEMIC!
Treat glucose, BP and lipids early, aggressively, and to goal; use ASA when appropriate; insist on smoking cessation; and watch for complications.
Empower patients to be involved in their DM management.
Remember that DM is a progressive disease, so expect to change therapy over time – let patients know this at diagnosis.
Stay informed about the current management of DM – it’s changing constantly!

58. Suggested Reading
American Diabetes Association: Standards of Medical Care in Diabetes Diabetes Care 37 (Supplement I): S5-S80, 2014.
Inzucchi SE, Bergenstal RM, Buse JB, etal.: Management of Hyperglycemia in Type 2 Diabetes: A Patient-Centered Approach. Diabetes Care 35: 1364 – 1379, 2012.
Skyler JS, Bergenstal R, Bonow RO, etal.: Intensive Glycemic Control and the Prevention of Cardiovascular Events: Implications of the ACCORD, ADVANCE, and VA Diabetes Trials. Diabetes Care 32: , 2009.