Pathophysiologic abnormalities in treatment


a. Is his current therapy working? (350 words) (20 marks)

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Justify your answer by using the evidence presented in the case study.

In your answer, you should also explain the pathophysiology of any of the signs/symptoms observed.

Present universal guidelines for diabetes mellitus type 2 (T2D) management encourage preliminary changes in lifestyle (i.e., exercise and diet). Metformin is favored and prescribed as a first-line anti-diabetes treatment for diagnosed individuals who do not show contraindications to the drug. After commencing this treatment, patients glycemic targets ought to be assessed after three to six months. For suboptimal blood glucose level control (target glycated hemoglobin [HbA1c]) (Laiteerapong et al., 2019), dual combination treatment is commenced. This, or other subsequent treatment modifications, must be followed by another test of glycemic targets three months later, and regularly after that, for ascertaining whether or not therapeutic goals for the patient are being accomplished, and whether there is a need for further alteration or intensification of treatment (Davies et al., 2018).

Gliclazide can improve beta-cell results as well, when compared with other sulfonylureas, suggested by increased duration before the need for insulin therapy commencement as against treatment with glibenclamide (mean time from diabetes onset in case of gliclazide treatment: 27.7 years; 95% CI: 24.730.7; mean time in case of glibenclamide: 21.4 years; 95% CI: 18.724.2; p<0.001). Considering metformin improves insulin sensitivity as well as decreases basal production of liver glucose, and gliclazide stimulates insulin secretion, a clinical rationale exists for using combination treatment, considering their complementary action (Gottwald-Hostalek et al., 2016).

T2D represents a complicated cardiovascular/metabolic disorder accompanied by several pathophysiologic abnormalities, with the key abnormalities being ?-cell malfunction and liver/muscle insulin resistance. The former happens prematurely in T2Ds natural history and has now been recognized to be a more serious issue than considered earlier. Upper tertile IGT (impaired glucose tolerance) patients are almost maximally or maximally resistant to insulin, losing over 80 percent of ?-cell functioning. Besides ?-cells, muscle, and liver (triumvirate), GI tract (incretin resistance/deficiency), adipocytes (quicker lipolysis), brain (neurotransmitter dysregulation and insulin resistance), ?-cells (hyperglucagonemia), and kidney (greater glucose reabsorption) contribute significantly to glucose intolerance among those diagnosed with T2D. The above eight factors together are termed the ominous octet, dictating that1) there is a need for several drugs combined for correcting associated numerous pathophysiological abnormalities,2) therapy is grounded in known pathogenic defect reversal and not mere HbA1c reduction, and3) timely treatment commencement will retard or prevent progressive failure of ?-cells well-established among IGT patients (DeFronzo et al., 2013).

b. Look at Mr. Keens laboratory results. Which results should we be concerned about, and why? (200 words) (15 marks)

The blood pressure levels recorded for Mr. Keen are 162/85, suggesting Stage 2 Hypertension. (Stage 2 Hypertension is characterized by blood pressure levels of 160-179 / 100-109). Further, Mr. Keens HbA1c levels are 9.2%; the goal normally set by physicians for those diagnosed with both type 2 and type 1 diabetes is maintaining HbA1c levels below 7%, as maintenance of this level of HbA1c has been proven to retard the onset of diabetes-related complications among patients. Mr. Keens hyperglycemia levels must be monitored, as they stand at >140 mg/dl (7.8 mmol/l). Fasting blood sugar levels of 11.8 mmol/L in the patient, with a prior diabetes diagnosis, has been linked to a greater risk of mortality and complications (Corsino et al., 2017).

c. Why does insulin therapy lead to weight gain, and why would this be problematic for a patient with diabetes? (200 words) (15 marks)

Type 2 diabetics on insulin therapy gain weight, a tendency apparent in insulin-nave patients commencing insulin treatment as well as insulin users are intensifying treatment due to having poor glycemic control. The above phenomenon is extensively recorded and described. The chief weight gain related risk factor among insulin-administered patients is HbA1c or average blood sugar levels before insulin therapy commencement. Higher pre-treatment HbA1c level implies greater pre-treatment glycosuria and, consequently, more weight gain following treatment commencement. Roughly 12 months after commencing insulin therapy, insulin dosage begins to influence weight gain to some extent. However, it is found to be roughly four times less influential as compared to pre-therapy HbA1c levels. Weight gain hasnt been linked to HbA1c modification during therapy or with HbA1c levels achieved following a year of insulin therapy commencement (Swinnen et al., 2009).

Insulin treatment with traditional basal insulin and mealtime preparations has several drawbacks. Firstly, regular insulin is slowly absorbed from subcutaneous tissues, with metabolic action taking effect only some 0.5-1 hours following injection administration and peaking 23 hours later. Thus, regular insulin therapy is linked to post-meal hyperglycemia as well as greater late-postprandial hypoglycemia risks. Additionally, traditional basal NPH insulin is associated with clear peak blood sugar decreasing effects, acts for considerably lower than a day, and is variably absorbed from subcutaneous tissues. The above pharmacodynamic shortfalls tend to increase blood sugar levels before breakfast, besides triggering nocturnal hypoglycemia (Swinnen et al., 2009).

For surmounting the above challenge, insulin analogs were developed with an amended sequence of amino acids from the insulin molecule in humans. Rapid-acting aspart, lispro, and glulisine analogs get absorbed quicker as compared to regular insulin owing to lower self-association, with their action commencing within fifteen minutes of being subcutaneously injected. They also have a more profound and quicker peak action. The earliest commercially-available long-acting analog, insulin glargine, claimed, at first, to possess the peakless ideal of almost 24 hours action (Swinnen et al., 2009).

Patients who can better understand the harm of insulin therapy postponement causes underlying insulin-linked weight increases, and weight gain patterns with diverse kinds of insulin can more effectively control their therapy and condition, and be more involved and motivated in managing their treatment. It is also crucial to commit to early insulin therapy commencement for dealing with poor glycemic control as well as continuing with and intensifying therapy as required (despite the potential for weight gain). For offsetting the advantages with the disadvantages of insulin therapy, a crucial management consideration is the choice of concomitant drugs and insulin. Clinical research reveals that more recent insulin analogs provide advantages over traditional preparations of human insulin in the form of more physiological action profiles, lower weight increases, and decreased hypoglycemia risks (McFarlane, 2009).

Question 2

Q2. Complete the following table by providing a rationale for each of the changes made to his medication.

Medication Change

Rationale (10 marks each/ approximately 100 words each)

In your answer, you should:

Consider if there are any potential interactions or practice points that should be reviewed when looking at this new regime.

Consider if the suggested changes are supported by the best evidence currently available.

a. Mr. Keen should stop metformin but keep taking gliclazide and start long-acting insulin therapy. Mr. Keen should start with ten units SC after the evening meal and slowing increase until BGLs are stable.

Several people with type 2 diabetes ultmately require insulin for glycemic control maintenance when the ? cells in their pancreas begin failing. Practitioners commonly combine isophane insulin, insulin glargine, or other similar long-acting insulin with metformin, gliclazide, or other oral medication. Mealtime insulin peak levels are believed to be achieved through the impact of gliclazide on remnant pancreatic ? cells. Several people with type 2 diabetes thus controlled ultimately require either a fixed long acting-short acting insulin mixture combination or basal-bolus long acting-short acting insulin regimen when metformin treatment is ceased; however, gliclazide, a well-tolerated, affordably-priced, and safe medicine, is often continued.

b. Mr. Keen should start atorvastatin 20mg/day.

Statin treatment has been linked to significant cardiovascular endpoint declines, but there have been concerns regarding statin usage and greater diabetes risk. Several statins can now be found, having diverse drug interactions and potencies (e.g., atorvastatin, simvastatin, rosuvastatin, and pitavastatin). But researchers are yet to confirm their impact on insulin resistance and insulin levels. Some theories exist indicating a likely risk of NOD (new-onset diabetes) development or deterioration of glycemic control among people with diabetes following high-dosage statin treatment. The risk appears to be greater when atorvastatin is used (i.e., about 61 percent greater diabetes development risk) (Angelidi et al., 2018).

c. Mr. Keen should stop taking propranolol and commence valsartan 80mg/day.

The use of ?-blockers among type 2 diabetics and those with established CV (cardiovascular) risk factors have been linked to elevated risks of serious hypoglycemia and CV events. Propranolol and other ?-blockers might work protectively through lowering acute hypertension, CV events, and hypoglycemia-linked cardiac arrhythmias. But ?-blockers in themselves have the potential to increase acute hypoglycemia risks. Moreover, they can dampen initial warning signs, resulting in hypoglycemia unawareness, besides causing weight gain that can, with time, exacerbate CV event risk. Valsartan might be prescribed/administered along with other medications for heart failure. But the triple-drug combination of a mineralocorticoid receptor antagonist /? -blocker, ACE inhibitor, and valsartan is discouraged (Hackethal, 2018).

d. Mr. Keen should stop taking corticosteroids and instead start taking methotrexate 15mg once a week.

As Mr. Keen suffers from T2D, continued corticosteroid usage will probably result in increased blood sugar levels. In the case of a significant increase in blood sugar levels, Mr. Keen may have to modify or increase his medication to achieve optimal levels. MTX or methotrexate is an extraordinary medicine with an important role in managing RA (rheumatoid arthritis) at all stages of evolution. Some of its positive qualities are great general efficacy for symptoms and signs, inhibited structural harm, and function preservation with controllable and acceptable safety, yet-to-be-rivaled cost-efficacy, a large dosage-titratable range, and options for administering either parenterally or orally (Taylor et al., 2019).

e. Mr. Keen should stop taking St Johns Wort and instead seek psychotherapy for his depression.

St. Johns Wort possesses a hyperforin element, a separate part of its phytochemical and molecular structure, inducing CYP3A4. Also, the medication is a PXR (pregnane X receptor) agonist, which activates the p-glycoprotein and PXR receptor, besides modifying the pharmacokinetics of several other drugs. This point must be borne in mind as roughly three in ten liver-metabolized medications are dependent on this PRX receptor (Wick, 2016). Another efficient therapy is psychotherapy, alone, or combined with medications. Its benefits include a lasting impact that safeguards against symptoms that recur even following cessation of treatment (Rapaport et al., 2011).


Angelidi, A. M., Stambolliu, E., Adamopoulou, K. I., & Kousoulis, A. A. (2018). Is atorvastatin associated with new-onset diabetes or deterioration of glycemic control? Systematic review using data from 1.9 million patients.International journal of endocrinology,2018.

Corsino, L., Dhatariya, K., & Umpierrez, G. (2017). Management of diabetes and hyperglycemia in hospitalized patients. InEndotext [Internet]., Inc.

Davies, M. J., DAlessio, D. A., Fradkin, J., Kernan, W. N., Mathieu, C., Mingrone, G., … & Buse, J. B. (2018). Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD).Diabetes care,41(12), 2669-2701.

DeFronzo, R. A., Eldor, R., & Abdul-Ghani, M. (2013). Pathophysiologic approach to therapy in patients with newly diagnosed type 2 diabetes.Diabetes care,36 Suppl 2(Suppl 2), S127S138.

Gottwald-Hostalek, U., Schlachter, J., & Geloneze, B. (2016). Combination Therapy with Metformin plus Gliclazide in Patients with Type 2 Diabetes.J Dia Res Ther,2(3).

Hackethal, V. (2018). Beta-blockers in Type 2 Diabetes: Time to Reconsider? Retrieved April 26, 2020, from

Laiteerapong, N., Ham, S. A., Gao, Y., Moffet, H. H., Liu, J. Y., Huang, E. S., & Karter, A. J. (2019). The legacy effect in type 2 diabetes: impact of early glycemic control on future complications (the Diabetes & Aging Study).Diabetes Care,42(3), 416-426.

McFarlane, S. I. (2009). Insulin therapy and type 2 diabetes: management of weight gain.The Journal of Clinical Hypertension,11(10), 601-607.

Rapaport, M. H., Nierenberg, A. A., Howland, R., Dording, C., Schettler, P. J., & Mischoulon, D. (2011). The treatment of minor depression with St. John’s Wort or citalopram: failure to show benefit over placebo.Journal of psychiatric research,45(7), 931941.

Swinnen, S. G., Hoekstra, J. B., & DeVries, J. H. (2009). Insulin therapy for type 2 diabetes.Diabetes care,32(suppl 2), S253-S259.

Taylor, P. C., Balsa Criado, A., Mongey, A. B., Avouac, J., Marotte, H., & Mueller, R. B. (2019). How to Get the Most from Methotrexate (MTX) Treatment for Your Rheumatoid Arthritis Patient?-MTX in the Treat-to-Target Strategy.Journal of clinical medicine,8(4), 515.

Wick, J. Y. (2016). The Complex Relationship between Depression, Diabetes, and St. Johns Wort. Retrieved April 26, 2020, from

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