SG 4.3: Glucose Lowering Agents Cases

Question 1

A 49 y/o female with a history of type 2 diabetes is referred to you for her diabetes management. Nonalcoholic steatohepatitis was recently diagnosed after routine testing showed abnormal liver function. A liver biopsy revealed nonalcoholic steatohepatitis with pathologic evidence of steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis. There was no evidence of cirrhosis.

A1c is 8.5, alanin is elevated

her hepatologist suggests that you prescribe an antidiabetic agent that would improve her liver histology

which of the following would the best choice:
A. metformin

B. pioglitazone

C. dulaglutide

D. sitagliptin

E. dapagliflozin

Answer 1

B. pioglitazone

she has nonalcoholic fatty liver disease

Question 2

what are the major risk factors for nonalcoholic fatty liver disease?

Answer 2

1. central obesity
2. type II DM
3. dyslipidemia
4. metabolic syndrome

Question 3

how do you manage nonalcoholic fatty liver disease? which medication is best?

Answer 3

1. optimization of blood glucose control in those with diabetes.
2. certain antidiabetic agents have been shown to improve liver histology such as steatosis, lobular inflammation, hepatocellular ballooning, and fibrosis

compared with placebo, thiazolidinediones, specifically pioglitazone, were more likely to improve hepatic histologic parameters such as ballooning degeneration, lobular inflammation, and steatosis

Question 4

what is the MOA of pioglitazone?

Answer 4

it’s a thiazolidinedione which stimulates nuclear receptor peroxisome proliferator-activated receptor gamma

activation of PPAR-γ improves insulin sensitivity over several weeks by upregulating the transcription of adiponectin and GLUT4 glucose transporters in adipose and muscle cells

it causes weight gain, as seen in this patient, in addition to other adverse effects, such as fluid retention, exacerbation of congestive heart failure, and osteoporosis

Question 5

whats the primary physiological action of pioglitazone?

Answer 5

it’s a thiazolidinedione which increase insulin sensitivity

metformin and thiazolidinedione increase insulin sensitivity

Question 6

you plan to start your patient on pioglitazone for NASH. you will counsel your patient regarding all the following potential adverse effects except:

A. bladder cancer

B. edema

C. UTIs

D. risk of bone fracture

Answer 6

C. UTIs

most common side effect is edema but there’s also a risk of osteoporosis and balder cancer

Question 7

A 45 y/o male with no past medical history presents to his primary care physician with complaint of unintentional weight loss of about 8 lbs in the past few months history of polyuria and nocturia for the past few days. His family history includes type 2 diabetes mellitus in his paternal uncle.

On physical examination, his blood pressure is 100/70, heart rate is 72, BMI is 24 kg/m2. His examination findings are unremarkable, with no signs of an infection.

random serum glucose is 275, A1c is 8.5, normal creatinine, TSH is 2

does this patient have DM?

Answer 7

yes

random glucose is over 200 and he has symptoms like polyuria and weight loss plus his A1c is over 5.7

Question 8

what describes the MOA of the most appropriate pharmacotherapy for this patient?

A 45 y/o male with no past medical history presents to his primary care physician with complaint of unintentional weight loss of about 8 lbs in the past few months history of polyuria and nocturia for the past few days. His family history includes type 2 diabetes mellitus in his paternal uncle.

On physical examination, his blood pressure is 100/70, heart rate is 72, BMI is 24 kg/m2. His examination findings are unremarkable, with no signs of an infection.

random serum glucose is 275, A1c is 8.5, normal creatinine, TSH is 2

Answer 8

metformin which causes decreased hepatic gluconeogenesis

it also decreases glycogenolysis

binding tyrosin ekinase receptors is insulin’s action

Question 9

He is referred to you 3 months later, while he is taking metformin, 1000 mg twice daily. You review the following laboratory test results:
Random serum glucose = 230 mg/dL Hemoglobin A1c = 8.2%
C-peptide = 1.2 ng/mL (reference range: 0.9-4.3 ng/mL)

Review of his twice daily self-monitoring blood glucose log reveals most values in the range of the high 100s to low 200s mg/dL, with an average of 189 mg/dL.

which lab will provide you more information regarding the diagnosis?

Answer 9

we assume he has type I DM since metformin didn’t work so now we would want glutamic acid decarboxylase antibody (GAD65 Ab)

you dont have to do an OGTT because we already know he has DM since he presented with elevated A1c, symptoms, etc.

Question 10

if GAD65 Ab comes back elevated what is the likely diagnosis?

A. type II DM

B. CF related DM

C. Cushing’s sydnrome

D. latent autoimmune diabetes in adult

Answer 10

D. latent autoimmune diabetes in adult

Question 11

if a patient has latent autoimmune diabetes in the adult what is the best next step to manage t’his patients DM if he’s already tried metformin?

Answer 11

start insulin
‘
he’s type I and the only treatment for type i is insulin!

Question 12

what is latent autoimmune diabetes in adults?

Answer 12

LADA is a form of type 1 diabetes that may be seen in adults

it progresses to the need for insulin very slowly, over years, or more rapidly

may be present in up to 30% of patients with a clinical diagnosis of type 2 diabetes

Question 13

what is the criteria for latent autoimmune diabetes in adults?

Answer 13

the Immunology Diabetes Society has proposed following criteria:
1. age at onset of at least 30 years,

2. positive for at least one type 1 diabetes autoantibody, and
3. not requiring insulin within the first 6 months after diagnosis

compared with type 2 diabetes, LADA is generally associated with:
1. lower BMI

2. lower triglyceride
3. higher HDL cholesterol
4. lower prevalence of hypertension

Question 14

A 52 y/o male, taking metformin for 3 years, presents for advice on treatment of his diabetes.

He is obese (BMI 35), with h/o dyslipidemia, CAD, and HTN.

You decide to start him on a dipeptidyl peptidase 4 inhibitor (DPP-4 inhibitor).

will this medication help him lose weight?

Answer 14

no, it has no effect on weight!

only GLIP1 agonists do!

Question 15

what is the MOA of DPP4 inhibitors?

Answer 15

by increasing GLP1 levels it targets hepatic glucose output and b cell dysfunction

through increasing endogenous GLP-1, can lowering hepatic glucose output by:
1. stimulating glucose-dependent insulin secretion from the β cell and

2. lowering glucagon secretion

Question 16

what are the potential adverse events to counsel a patient on DPP4 inhibitors?

Answer 16

pancreatitis

does not cause hypoglycemia, thyroid cancer or UTIs

Question 17

does liraglutide cause weight loss?

Answer 17

yes

it’s a GLP1 agonist

Question 18

what side effects does liraglutide have?

Answer 18

nausea, thyroid cancer and pancreatitis

it’s a GLP1 agonist

Question 19

what is the MOA of GLP1 agonists?

Answer 19

they exert the same effects as DPP4 inhibitors and, in addition, SLOW gastric emptying and DECREASE food intake, which can promote weight loss

GLP-1 is deficient in patients with type 2 diabetes

Question 20

what are the benefits of GLP1 agonists outside of DM?

Answer 20

patients with type 2 diabetes with ASCVD or increased risk for ASCVD, the addition of liraglutide decreased major cardiovascular event (MACE) and mortality, and the closely related GLP-1 receptor agonist semaglutide also had favorable effects on CV end points in high-risk subjects

in these CV outcomes trials, liraglutide and semaglutide had
beneficial effects on composite indices of CKD.

Question 21

what is the MOA of canagliflozin?

Answer 21

sodium glucose cotransporter 2 inhibitors

lowers blood glucose by decreasing SGLT2 activity in the proximal renal tubule

lowers the threshold for glucose, thereby increasing glucose excretion in the urine and lowers the plasma glucose concentration

this may cause polyuria and glucosuria

Question 22

in addition to UTIs what other adverse effects are associated with canaglflozin?

Answer 22

DKA

Question 23

what are the side effects of SGLT2 inhibitors?

Answer 23

Develop UTIs related to glycosuria (~5% incidence)

May be associated with dysuria and polyuria

Patients are at increased risk of developing vulvovaginal candidiasis, vulvovaginal mycotic infection, vulvovaginitis, and genital fungal infection

Women usually complain of vaginal itching or discharge

Men are at increased risk of developing balanitis or balanoposthitis and genital fungal infection

Question 24

what are the benefits of SGLT2 inhibitors?

Answer 24

In people with diabetes with established ASCVD, empagliflozin decreased a composite three-point major cardiovascular event (MACE) outcome and mortality compared with placebo.

Reduced hospitalization for HF

In CV outcomes trials, empagliflozin, canagliflozin (in addition to liraglutide and semaglutide) all had beneficial effects on composite indices of CKD

Question 25

A 35-year-old woman, gravida 3, para 2, at 28 weeks’ gestation comes to the physician for a follow-up examination. One week ago, an oral glucose tolerance screening test showed elevated serum glucose levels. She has complied with the recommended diet and lifestyle modifications. Over the past week, home blood glucose monitoring showed elevated fasting and post-prandial blood glucose levels.

which drug is the best for her and what is the MOA?

Answer 25

binding of tyrosine kinase receptors = insulin

insulin is what DOC in pregnancy

Question 26

A 35-year-old woman, gravida 3, para 2, at 28 weeks’ gestation comes to the physician for a follow-up examination. One week ago, an oral glucose tolerance screening test showed elevated serum glucose levels. She has complied with the recommended diet and lifestyle modifications. Over the past week, home blood glucose monitoring showed elevated fasting and post-prandial blood glucose levels.

which drug is the best for her and what is the MOA?

Answer 26

binding of tyrosine kinase receptors = insulin

insulin is what DOC in pregnancy

Question 27

A 50-year-old woman comes to the physician because of a 6-month history of fatigue and increased thirst. She has no history of serious medical illness and takes no medications. She is 163 cm (5 ft 4 in) tall and weighs 72 kg (160 lbs); BMI is 28 kg/m2. Her fasting serum glucose concentration is 249 mg/dL. Treatment with an oral hypoglycemic drug is begun.

what drug would you give her and what is the MOA?

Answer 27

decreased hepatic gluconeogeneisis = metformin

Biguanides such as metformin decrease hepatic gluconeogenesis by inhibiting the mitochondrial glycerophosphate dehydrogenase (mGPD).
It improves insulin sensitivity, thereby increasing peripheral glucose uptake and utilization (↑ glycolysis), and slows intestinal glucose absorption.

Question 28

what are the side effects of metformin?

Answer 28

1. lactic acidosis

2. GI symptoms

Question 29

A 54-year-old man comes to the physician for a routine health maintenance examination. He was diagnosed with type 2 diabetes mellitus 1 year ago. His only medication is metformin. His serum glucose is 186 mg/dL and his hemoglobin A1C is 7.6%. The physician prescribes an additional antidiabetic drug and counsels the patient on its delayed onset of action. At a follow-up appointment 4 weeks later, the patient reports that his home blood glucose readings have improved. He also mentions that he has had a weight gain of 4kg (8.8 lbs).

the patient has been most likely been treated with which drug?

Answer 29

rosiglitazone

it’s a thiazolidinedione

Question 30

what is the MOA of thiazolidinediones?

Answer 30

Thiazolidinediones, such as rosiglitazone and pioglitazone, activatethe transcription factor peroxisome proliferator-activated receptor gamma (PPAR-γ).

Activation of PPAR-γ improves insulin sensitivity over several weeks by upregulating the transcription of adiponectin and GLUT4 glucose transporters in adipose and muscle cells.

It causes weight gain, as seen in this patient, in addition to other adverse effects, such as fluid retention, exacerbation of congestive heart failure, and osteoporosis

Question 31

A 16-year-old boy is brought to the physician for a follow-up examination. He has a 6- year history of type 1 diabetes mellitus and his only medication is insulin. Seven months ago, he was treated for an episode of diabetic ketoacidosis. He has previously been compliant with his diet and insulin regimen. He wants to join the high school soccerteam.Vital signs are within normal limits. His hemoglobin A1C is 6.3%.

what is the best recommendation at this time?

Answer 31

lower insulin doses on days of exercise
Since patients with type 1 diabetes mellitus typically have a higher drop in blood glucose during exercise than healthy individuals, they are at increased risk for hypoglycemia.

Exercise increases overall insulin sensitivity, which promotes glycolysis and inhibits gluconeogenesis.

Exercise-induced increase in body temperature and blood flow can accelerate resorption of subcutaneous insulin deposits, injection into arms or legs that are exercised should be avoided.

Insulin dosages should therefore be decreased by 1–2 units per 20–30 minutes of physical activity on days of exercise.

Furthermore, patients should be advised to closely monitor their blood glucose before, during, and after exercise, to watch out for symptoms of hypoglycemia (e.g., sweating, lightheadedness), and to eat slowly-absorbed carbohydrates after exercising to prevent delayed hypoglycemia.

Question 32

A 60-year-old man comes to the physician for evaluation of gradually worsening fatigue, increased urinary frequency, and blurry vision for 5 months. He has not seen a doctor in several years. Physical examination shows decreased vibratory sense and proprioception in the lower extremities. His hemoglobin A1C is 10.4%. Treatment for his condition with an appropriate medication is begun. In response to this drug, pancreatic islet cells being producing increasing amounts of secretory granules.

the patient was most likely treated with which drug?

Answer 32

glimepiride

it’s a sulfonylurea which timulates insulin secretion from
pancreatic β-cells

their maintarget is the ATP-sensitive K+ channels in the
pancreatic β-cell plasma membrane

inhibition of K+ channels by sulfonylureas causes depolarization of the β-cell membrane, leading to an influx of Ca2+, which stimulates exocytosis of insulin-containing secretory granules

Question 33

A 56-year-old man with type 2 diabetes mellitus comes to the physician for a follow-up examination. He reports that he has been compliant with his current antidiabetic medication regimen. His hemoglobin A1C concentration is 8.5%. The physician prescribes a drug that reversibly inhibits a membrane-bound enzyme that hydrolyzes carbohydrate bonds.

which drug was most likely added to his current regimen?

Answer 33

miglitol = alpha-glucosidase inhibitor

Miglitol inhibits alpha-glucosidase and thus prevents the hydrolysis of polysaccharides to monosaccharides

acarbose is the other alpha-glucosidase inhibitor that is available in the US.

since polysaccharides are not absorbed as easily as monosaccharides, alpha-glucosidase therapy results in a slower rise in postprandial blood glucose concentrations

adverse effects of alpha-glucosidase inhibitors are caused by impaired absorption and include flatulence, diarrhea, and early satiety

Question 34

A 56-year-old man with type 2 diabetes mellitus comes to the physician for a follow-up examination. Three months ago, the patient was started on metformin therapy after counseling on diet, exercise, and weight reduction failed to reduce his hyperglycemia.
Physical examination shows no abnormalities. His hemoglobin A1C is 8.4%. Pioglitazone is added to the patient’s medication regimen.

which cellular changes is most likely to occur in response to this new drug?

Answer 34

increased transcription of adipokines because it’s a thiazolidinediones

increased transcription of adipokines is part of the mechanism of action of thiazolidinediones (e.g., pioglitazone, rosiglitazone)

these drugs work by activating the PPAR-γ (peroxisome proliferator- activated receptor of gamma type) transcription factor, which increases the transcription of genes involved in glucose and lipid metabolism

this results in increased levels of adiponectin and other adipokines, which are decreased in patients with type 2 diabetes mellitus, and increased storage of triglycerides and subsequent reduction of products of lipid metabolism (e.g., free fatty acids) that otherwise enhance insulin resistance

in this way, glucose utilization is increased, and hepatic glucose production is reduced