1. Endocrinology: Type 2 Diabetes Mellitus
Southwest Ohio Regional Updates in Internal Medicine 2018
Endocrinology: Type 2 Diabetes Mellitus
Michael Canos, MD, MPH, MSc, FACE, FACP
Associate Professor of Clinical Medicine
Division of Endocrinology

2. Background DM2 is the MC, costly endocrine dz.
Polygenic disease of impaired insulin secretion (beta-cell dysfx) and insulin resistance
Predisposes for micro- and macro-vascular dz and early death
Broad range of tx options but dz is progressive

3. Prevalence of Diabetes Mellitus
>30 Million Americans Have DM2
2017 CDC National Diabetes Statistics Report
As of 2015, 9.4% of the US population (30.3 million people) have diabetes, while million have prediabetes.
25% of adults older than 65 have diabetes
4% of adults ages 18 to 44 have diabetes
Type 1
5%-10%
Type 2
90%-95%
(80% Obese)
N2017ation

4. Dx’c Criteria for Diabetes
Test
Normal (mg/dL)
IFG (mg/dL)
IGT (mg/dL)
Diabetes
FPG
<100
≥ 126 mg/dL
2-hr PPG
<140
mg/dL
≥ 200 mg/dL
Random plasma glucose
≥ 200 mg/dL plus symptoms of diabetes
HbA1c less than 5.7% is normal.
HbA1c between 5.7% and 6.4% represents prediabetes
HbA1c of 6.5% or greater is consistent with diabetes
American Diabetes Association . Pharmacologic Approaches to glycemic treatment.
Section 8 in Standards of Medical Care in Diabetes Diabetes Care 2017; 40(Suppl. 1) :S64—S74
FPG = fasting plasma glucose

5. Natural History of DM2mand β-cell Fx
Bergenstal R, et al. Endocrinology. Philadelphia, PA: WB Saunders Co;2001:

6. Ominous Octet
DeFronzo RA. Diabetes. 2009;58:

7. 2017 ADA Standards of Medical Care in Diabetes

9. Biguanides Disadvantages: GI side effects
Compounds: Metformin
MOA: Activates AMP-kinase
Primary physiological action(s):↓ Hepatic glucose production
Advantages:
Extensive experience
No weight gain
No hypoglycemia
↓ CV events (UKPDS subgroup analysis)
Disadvantages:
GI side effects
(diarrhea, abdominal cramping)
Lactic acidosis (rare)
Vitamin B12 deficiency
Multiple contraindications:
CKD, acidosis, hypoxia, dehydration, etc.
Cost: Low
Diabetes Care 2012; 35:
Diabetalogia 2012; 55:

10. Sulfonylureas Compounds: Disadvantages:
Glyburide, Glipizide, Glimepiride
MOA:
Closes K+ATP channels on beta cell plasma membranes
Primary physiological action(s):
↑ Insulin secretion
Advantages:
Extensive experience
↓ Microvascular risk (UKPDS)
Disadvantages:
Hypoglycemia
Weight gain
? Glyburide blunts myocardial ischemic preconditioning
Low durability
Cost: Low
Diabetes Care 2012; 35:
Diabetalogia 2012; 55:

11. DPP-4 inhibitors Compounds: MOA: Primary physiological action(s):
Sitagliptin, Saxagliptin, Linagliptin, Alogliptin
MOA:
Inhibits DPP-4 activity,
Inc’s postprandial active incretin (GLP-1,GIP) concentrations
Primary physiological action(s):
↑ Insulin secretion(glucose- dependent)
↓ Glucagon secretion(glucose- dependent)
Advantages:
No hypoglycemia
Well tolerated
Disadvantages:
Generally modest HbA1c efficacy
Urticaria/angioedema
? Pancreatitis
? ↑ risk of heart failure with saxagliptin
Cost: Moderate
Diabetes Care 2012; 35:
Diabetalogia 2012; 55:

12. Thiazolidinediones Compounds: Pioglitazone Disadvantages: MOA:
Activates the nuclear transcription factor PPAR-gamma
Primary physiological action(s):
↑ Insulin sensitivity
Advantages:
No hypoglycemia
Durability of Response
↑ HDL-C, ↓ Triglycerides
Improves Fatty Liver
Disadvantages:
Weight gain
Edema/heart failure
Bone fractures
↑ LDL-C (rosiglitazone)
? ↑ MI (meta analyses,rosiglitazone)
? ↑ Bladder cancer (pioglitazone)
Cost: Low to Moderate
Diabetes Care 2012; 35:
Diabetalogia 2012; 55:

13. SGLT-2 Inhibitors Compounds: Disadvantages: MOA:
Canagliflozin, Dapagliflozin, Empagliflozin
MOA:
Inhibits renal SGLT-2
Primary physiological action(s):
Inc’s glucosuria
Advantages:
Cardiovascular protection (empagliflozin)
No hypoglycemia
Use across spectrum of DM stages
Weight loss
Dec’s BP (Dec’s plasma volume via natriuresis)
Disadvantages:
Genital mycotic infections
UTIs
Inc’d LDL-C
? Dehydration
? Renal effects
Cost: Moderate to High

14. GLP-1 Receptor Agonists
Compounds:
Exenatide, Exenatide ER, Liraglutide, Dulaglutide, Abliglutide
MOA: Activates GLP-1 receptors
Primary physiological action(s):
↑ Insulin secretion (glucose-dependent)
↓ Glucagon secretion (glucose-dependent)
Slows gastric emptying and ↑ Satiety
Diabetes Care 2012; 35:
Diabetalogia 2012; 55:

15. GLP-1 Receptor Agonists
Advantages:
No hypoglycemia
Weight reduction
Potential for improved beta cell fx
Potential Cardiovascular protection (Liraglutide)
Disadvantages:
GI side effects (nausea/vomiting)
Risk of acute pancreatitis
C-cell hyperplasia/medullary thyroid tumors in female rats
Injectable
Training requirements
Cost: Moderate to High
Diabetes Care 2012; 35:
Diabetalogia 2012; 55:

16. Diabetes Meds and Cardiovascular Outcomes
Fitchett et all European Journal of Heart Failure (2017) 19,43–53

18. Initiating Basal Insulin
2017 ADA Standards of Medical Care for the initiation and adjustment of Basal Insulin:
Start with a basal insulin initiated at 10 units/day or 0.2 units/kg/day
Check fasting glucose daily and inc dose by 2 Units every 3 days until fasting glucose values are consistently in the target range ( mg/dL)

19. Basal Insulin Therapy Key Concepts
Basal insulin regulates hepatic glucose production
High doses of basal insulin do not provide adequate coverage of prandial insulin requirements.
Avoid excessive basal insulin dosing by initiating prandial insulin or a GLP-1 Receptor agonist when the blood glucose log shows inadequate post prandial glucose control

20. Basal Insulin Type Onset Peak Duration NPH 2-4 hrs 4-6 hrs 12-16 hrs
Glargine hrs hrs ~24 hrs
Detemir hrs hrs hrs(dose dependent)
U-300 Glargine (Tuojeo) hrs hrs /-3hrs(dose dependent)
U-200 Degludec (Tresiba) hr 9 hrs 42 hrs (after 8 doses)
CADRE Handbook of Diabetes Management.

21. Prandial Insulin Insulin Type Onset Peak Duration
Regular min hrs hrs
Lispro min hr 4-5 hrs
Aspart min hr 4-5 hrs
Glulisine min hr 4-5 hrs
Lispro U min hr 4-5 hrs
CADRE Handbook of Diabetes Management.

22. Insulin Duration of Action
CADRE Handbook of Diabetes Management.

23. Initiating Prandial Insulin
ADA/EASD Consensus Statement Recommendation for Prandial Insulin Dosing
(4-3-2 approach)
Start with 4 units of prandial insulin
Then every 3 days
Inc by 2 units until the 1-2 hour postprandial glucose is less than 180 mg/dL.
Some patients may benefit from a slightly lower or higher starting point or require a dose titration of 1 unit every three days.
Some patients may need to have the basal insulin dose reduced to prevent nocturnal hypoglycemia.
Nathan DM et al. Diabetes Care. 2009; 32 (1):
ADA. Diabetes Care. 2011; 34(Suppl 1): S11-S61.

24. Questions

25. Continue diet and exercise for additional 3 months Start Liraglutide
An overweight 50-year-old woman comes to the office for hyperglycemia. For the past 3 months, she has tried to lower her high blood sugars by a strict low carbohydrate diet and exercise. She reports no polyuria, polydipsia, or weight loss. Her father died of DM. Vital signs and physical examination are normal except for a BMI of 28. Fasting glucose 140 mg/dL (on 4 occasions), HbA1c 8.6 %, serum creatinine is 0.8 m/dL, and the urine is negative for microalbuminuria. Current meds are Lisinopril, Hydrochlorothiazide and Atorvastatin Which of the following is the most appropriate next step to improve hyperglycemia?
Continue diet and exercise for additional 3 months
Start Liraglutide
Start Metformin
Start Pioglitazone
Start Glipizide
C - Metformin

26. EDUCATIONAL OBJECTIVE: Oral antihyperglycemic monotherapy for type 2 DM
Answer A is incorrect: This patient has Type 2 DM. Diet and exercise for additional 3 months is unlikely to improve glycemic control.
Answer B is incorrect: Liraglutide is a GLP-1 agonist, an injectable agent, only approved by the FDA for use in combination with other hypoglycemic agents.
Answer C is correct: Many medications exist for initial therapy of T2DM and have similar efficacy as hypoglycemic agents. Metformin is recommended as first-line therapy because is effective, safe and inexpensive, and may reduce risk of cardiovascular events. Metformin should be started at diagnosis of T2DM, unless there are contraindications (kidney dis.)) or is not tolerated ( GI symptoms). Metformin can be used safely in patients with an estimated glomerular filtration rate (eGFR) as low as 30 ml/min/1.73m2 (Previously, metformin was contraindicated with creatinine levels >1.4 mg/dL (women) and >1.5 mg/dL (men).
Answer D is incorrect: Pioglitazone, an insulin sensitizer and PPARgamma agonist, could be used as monotherapy for T2DM, but is associated with side effects (weight gain, peripheral edema, increased risk of bone fractures in women) and is comparatively more expensive.
Answer E is incorrect: Glimepiride is a sulfonylurea, insulin secretagogue, and could be used as initial monotherapy for T2DM but it is a/w weight gain and can cause hypoglycemia
Question 1

28. Impaired Fasting Glucose Impaired Glucose tolerance Metabolic Syndrome
A 45 yo man comes to your office for a routine physical examination. He has no personal medical history. Many relatives including his parents have diabetes mellitus. He takes no medications. Physical exam is normal and BMI is Laboratory tests show a random plasma glucose level of 158 mg/dL (8.8 mmol/L) Which of the following diagnoses is the best considering his glycemic status?
Impaired Fasting Glucose
Impaired Glucose tolerance
Metabolic Syndrome
T2DM
Cannot establish a diagnosis based on the glycemic status

29. EDUCATIONAL OBJECTIVE: Diagnosis of pre-Diabetes or diabetes mellitus
Answer A is incorrect: Impaired fasting glucose is defined as a FPG of equal or above 126 mg/dL
Answer B is incorrect: Impaired Glucose tolerance is defined by a 2HR PG equal or above 200 mg/dL
Answer C is incorrect: we have no information about whether this patient has the Metabolic Syndrome, which is characterized by 2 out 5 criteria: waste circumference above 40 inches in men and 35 inches in women, insulin resistance, hypertension, hypertriglyceridemia, impaired fasting glucose
Answer D is incorrect: A diagnosis of DM is possible if a random plasma glucose is above 200 and not 158 mg/dL.
Answer E is correct: Cannot establish a diagnosis based on the glycemic status. The only information we have about this patient’s glycemic status is a random glucose level of 158 mg/dL. DM can be diagnosed when only a random glucose levels is available that is above 200 mg/dL in the presence of symptoms of hyperglycemia.
Question 2

30. From
American Diabetes Association . Pharmacologic Approaches to glycemic treatment.
Section 8 in Standards of Medical Care in Diabetes Diabetes Care 2017; 40(Suppl. 1) :S64—S74

31. Start pre-mixed insulin 70/30 once daily Start Sitagliptin
A 63-year old man is admitted to the hospital because of nausea, poor appetite, hypoglycemia, and worsening renal function. His serum creatinine levels have inc’d to 3.5 mg/dL from previous values of 1.4 mg/dL of three months ago. He has T2DM for 15 years and is currently taking glyburide and metformin. His fasting BG levels have ranged from mg/dL, but pt recalls many episodes of symptomatic hypoglycemia in the past month. He is on losartan and furosemide. On admission, random plasma glucose is 95 mg/dL and A1c is 7.0 %. DM medications are discontinued. His anorexia improves, his fasting BG values increase over next 3 days to mg/dL, and creatinine at discharge is 1.8 mg/dL. Which of the following hypoglycemic medications should be prescribed for this pt?
Start pre-mixed insulin 70/30 once daily
Start Sitagliptin
Restart Glyburide only
Restart Metformin only
Restart both Glyburide and Metformin

32. Answer A is incorrect: premixed insulin 70/30 can cause hypoglycemia
EDUCATIONAL OBJECTIVE: Management of T2DM in chronic renal disease
Answer A is incorrect: premixed insulin 70/30 can cause hypoglycemia
Answer B is correct: Linagliptin, a DPP-IV inhibitor is often used in T2DM with CKD. The inhibition of DPP-IV increases glucagon-like peptide 1 (GLP-1) levels, which lead to inc’d insulin secretion and action, and decreased glucagon secretion.
Linagliptin is metabolized in the liver and excreted unchanged in the urine. It can be used in patients with any stage of CKD. As monotherapy, linagliptin can cause a reduction of HbA1c in the range of %.
Answer C is incorrect: Glyburide is a sulfonylurea with the longest duration of action. This patient’s recent hypoglycemia may be due to his use of Glyburide. Therefore, Glyburide is not recommended in patients with CKD. Other secretagogues such as glimepiride or non-sulfonylurea secretagogue (repaglinide) could also be tried.
Answer D is incorrect: Metformin is contraindicated in men with serum creatinine levels greater than 1.5 mg/dL or women with serum creatinine levels greater than 1.4 mg/dL. A decreased glomerular filtration rate can cause accumulation of circulating metformin, which can increase the risk of lactic acidosis.
Answer E is incorrect: Obviously this answer is incorrect: Metformin ( because of CKD) and Glyburide because of the risk of hypoglycemia
Question 3

33. Recommend diet and exercise
A 48 yo woman returns to your office for a follow-up after routine laboratory tests show a fasting plasma glucose of 115 mg/dL. Her father and maternal grandmother have type 2 DM. Physical exam is normal except for blood pressure is 140/86mmHg and BMI is 29. Laboratory tests: During an oral glucose tolerance test her 2-hour glucose level increases to 137 mg/dL. Hemoglobin A1c 5.8% LDL-cholesterol 105 mg/dL HDL-cholesterol 45 mg/dL Triglycerides mg/dL Which of the following is the most appropriate treatment for control of glycemia?
Start Metformin
Start Pioglitazone
Start Lisinopril
Start Acarbose
Recommend diet and exercise

34. EDUCATIONAL OBJECTIVE: Diagnosis and management of preDM
Answer A is incorrect: Metformin therapy is associated with a relative reduction risk (RRR) of 31%, which is inferior to the 58 % RRR achieved with lifestyle changes. It is recommended that metformin therapy be initiated in patients with both IFG and IGT, who might be at higher risk for developing DM. This patient does not have IGT ( plasma glucose levels of mg/dL at the 2-hr mark of an OGTT) and so should not take metformin.
Answer B is incorrect: Both Rosiglitazone & Pioglitazone have been associated with 62 and 81 % RRRs in the incidence of DM. However, their use in preDM is not recommended because of side effects (edema, weight gain, increased fracture risk in women).
Answer C is incorrect: Lisinopril might improve BP but will not prevent DM as demonstrated by the DM Reduction Assessment with Ramipril and Rosiglitazone (DREAM).
Answer D is incorrect: In clinical studies, Acarbose ( an oral hypoglycemic agent that inhibits alpha-glucosidase and therefore slows down the absorption of glucose from the gut) was associated with only 25 % of RRR, much inferior to the RRR of diet and exercise ( 58%)
Answer E is correct: Diet and exercise are the recommended intervention for patients with either IFG or impaired glucose tolerance (IGT), both states of preDM. The Diabetes Prevention Program Trial has shown that the RRR in the incidence of DM in patients with IGT or IFT who where assigned to intensive lifestyle change was 58%.

36. EDUCATIONAL OBJECTIVE: Diagnosis and therapy of pre-DM. DM vs pre-DM
To test for pre-DM, fasting plasma glucose, 2-hr plasma glucose after 75-g OGTT, and A1c are equally appropriate
In pts with pre-DM, identify and, if appropriate, treat other cardiovascular dz risk factors
Testing for pre-DM should be considered in adolescents and who are overweight or obese and who have two or more additional risk factors for DM

37. A 100-gram oral glucose tolerance test (OGTT) Hemoglobin A1c
A 31-year old woman has recently found out she is pregnant for the first time. She is concerned about the possibility of developing gestational DM because she has a strong family history of type 2 DM. What is the best initial test to diagnose gestational DM?
Fasting blood glucose
Random blood glucose
A 100-gram oral glucose tolerance test (OGTT)
Hemoglobin A1c
A 50-gram glucose challenge test (GCT)

38. Answer D is incorrect: Hemoglobin A1c is not used for diagnosis of GDM
EDUCATIONAL OBJECTIVE: Learn the diagnostic tests for DM in pregnancy and GDM
Answer A B are incorrect: Fasting or Random Blood Glucose are not used to diagnose GDM
Answer C is incorrect: A 100-gram OGTT is not used for initial diagnosis of GDM, rather two strategies are adopted for diagnosis of GDM at weeks: “one-step” 75-g OGTT or “two-step” approach with a 50-g (non-fasting) screen followed by a 100-g OGTT for those who screen positive.
Answer D is incorrect: Hemoglobin A1c is not used for diagnosis of GDM
Answer E is correct: In 2013, The NIH convened a consensus development conference to establish dx’c criteria for GDM. The Panel recommended a two-step approach that used a 1Hr ( non-fasting ) 50-g glucose challenge test (GCT) followed by a 3hr ( fasting baseline ) 100g OGTT for those who screened positive. Screening with 1Hr GCT does not require fasting and is therefore easier to accomplish for many women

39. Recommendations
Test for undx’d T2DM at the first prenatal visit in those with risks factors, using standard diagnostic criteria
Test for GDM at weeks of gestation in those not previously known to have DM
Screen women with GDM for persistent DM at 6-12 weeks post-partum, using the OGTT and non pregnancy diagnostic criteria
Women with history of GDM should have lifelong screening for the development of DM or pre-DM at least q3 years
Women with a history of GDM found to have preDM should undergo lifestyle interventions or metformin to prevent DM

40. Screening for GDM
1) One-step approach:
Diagnostic 3 hr 75 gr OGTT ( fasting baseline)
2) Two-step approach:
Initial screen:
Serum glucose measures 1-hour after 50 g glucose load
Glucose threshold = or > 140 mg/dL ( ~80% sensitivity); = or >130 mg/dL (~90% sensitivity)
Diagnostic test: 100 OGTT in women who exceed initial screen threshold
Diagnosis of GDM requires 2 of the following:
Fasting = or > 95 mg/dL 1 hour: = or > 180 mg/dL
2 hour: = or > 155 mg/dL 3 hour: = or > 140 mg/dL

41. A single injection of 70/30 NPH/Regular Insulin at bedtime
A 52 year old man with type 2 DM who is your patient for the past 4 years, develops persistent hyperglycemia. He is receiving maximal doses of Metformin, Glipizide and Pioglitazone for the past 3 years. You recommend to start insulin to improve glycemic control. The patient is willing to start insulin, but is unwilling to injects himself many times a day. Which of the following insulin regimens is best for glycemic control in this patient?
A single injection of 70/30 NPH/Regular Insulin at bedtime
A bedtime injection of Insulin glargine, and up to 3 injections of short-acting insulin with meals.
A single injection of Insulin glargine at bedtime.

42. EDUCATIONAL OBJECTIVE: introducing insulin therapy for glycemic control in T2DM
Answer A is incorrect: A single injection of 70/30 NPH/Regular insulin is a valid alternative but should be given at dinner and not at bedtime
Answer B is incorrect: A bedtime injection of insulin glargine at bedtime, and up to 3 injections of short-acting insulin with meals may be necessary for T1DM, but are rarely needed for T2DM.
Answer C is correct: A single injection of glargine at bedtime. Insulin glargine has a slow release and provides a steady-state insulin levels for 24hr following one injection and is less likely to cause nocturnal hypoglycemia.
Question 6

43. Which of the following drugs is the most common hypoglycemic agent currently used in the treatment of gestational DM?
Pioglitazone
Insulin
Metformin
Repaglinide
Glyburide

44. Answer A is incorrect: There is no long-term data about the safety of Pioglitazone or Rosiglitazone as oral hypoglycemic agents for GDM.
Answer B is correct: Insulin is the preferred medication for treating hyperglycemia in GDM as it does not cross the placenta to a measurable extent.
Answer C is incorrect: Metformin may have lower risk of neonatal hypoglycemia and less maternal weight gain than insulin. However, metformin may increase slightly the risk of prematurity. Short-term trials support efficacy and safety of Metformin, but Metformin crosses the placenta and long-term data on its safety on the fetus are not known.
Answer D is incorrect: Repaniglide, the non-sulfonylurea secretagogue, is contraindicated in pregnancy because no safety data exist.
Answer E is incorrect: The concentration of Glyburide in the umbilical cord plasma is about 70% of the maternal levels. Glyburide is associated with a higher rate of neonatal hypoglycemia and macrosomia than Metformin or Insulin.
Educational Objective: Management of DM In Pregnancy
Question 7

45. Safe HTN drugs: methyldopa, labetalol, diltiazem, clonidine, prazosin
Use of common drugs in pregnancy complicated by DM, HTN and hyperlipidemia
ACEi and ARB are contraindicated ( risk of fetal renal dysplasia, oligohydramnios, intrauterine growth restriction)
Safe HTN drugs: methyldopa, labetalol, diltiazem, clonidine, prazosin
Statins are contraindicated
Indication for bariatric surgery for obesity in T2DM

46. Increase Insulin glargine Refer for bariatric surgery
A 45 yo man has type 2 DM for 5 years. His daily log book shows blood glucose levels Between 120 and 150 with weekly occurrence of hypoglycemia 50 mg/dL or below, of which the patient is not aware. His PMH includes chronic kidney disease, HTN, hyperlipidemia, GERD OSA and OA. He has followed a strict program of diet and exercise, but can only walk 15 minutes daily due to back and knee pain. He has lost 4 Kg in one year. His medications include glargine, aspart, lisinopril, carvedilol, omeprazole, aspirin and atorvastatin. On physical exam, blood pressure is 145/90, pulse rate 64. BMI is 39. Bilateral loss of microfilament and vibratory sensation on feet are present. Laboratory values show Hemoglobin A1c of 8.9 % and serum creatinine of 1.7 mg/dL Which of the following is the most appropriate therapy for this patient?
Initiate Pramlintide
Initiate Metformin
Increase Insulin glargine
Refer for bariatric surgery
Increase Insulin aspart

47. EDUCATIONAL OBJECTIVE: Learn the indications for bariatric surgery in an obese patient with T2DM
Answer A is incorrect: Pramlintide, a synthetic analogue of amylin, which is co-secreted with insulin from beta cells, can cause a modest weight loss due to the slowing of gastric emptying caused by this drug. However, it could potentially exacerbate hypoglycemia
Answer B is incorrect: Metformin is contraindicated in men with serum creatinine above 1.5 mg/dL because of the risk of lactic acidosis
Answer C and E are incorrect: Increasing insulin would exacerbate the weekly hypoglycemia events and could lead to more weight gain
Answer D is correct: Bariatric surgery should be considered in patients with a BMI between 35 and 40 with one or more comorbidities. This patient has uncontrolled T2DM with microvascular complications along with other co-morbidities associated to obesity such as HTN, HLD, OSA, GERD, OA. An attempt to lifestyle changes with diet and exercise did not results in weight loss that could improve his metabolic abnormalities.
Question 8