Page 778 - Basic _ Clinical Pharmacology ( PDFDrive )

764 SECTION VII Endocrine Drugs

on canagliflozin. It is likely that the effect on the bones is a class meal. The drug is not very useful in type 2 patients who can
effect and not restricted to canagliflozin. A modest increase in instead use the GLP-1 receptor agonists.
upper limb fractures was observed with canagliflozin therapy. It is Colesevelam hydrochloride, the bile acid sequestrant and
not known if this is due to an effect on bone strength or related cholesterol-lowering drug, is approved as an antihyperglycemic
to falls due to hypotension. Interim analysis of the Canagliflozin therapy for persons with type 2 diabetes who are taking other
Cardiovascular Assessment Study clinical trial reported an approx- medications or have not achieved adequate control with diet and
imately doubled risk of leg and foot amputations in the trial group exercise. The exact mechanism of action is unknown but pre-
assigned to Canagliflozin; in 2017 the FDA issued a drug safety sumed to involve an interruption of the enterohepatic circulation
communication regarding the association. Cases of diabetic keto- and a decrease in farnesoid X receptor (FXR) activation. FXR is a
acidosis have been reported with off-label use of SGLT2 inhibitors nuclear receptor with multiple effects on cholesterol, glucose, and
in patients with type 1 diabetes. Type 1 patients are taught to give bile acid metabolism. Bile acids are natural ligands of the FXR.
less insulin if their glucose levels are not elevated. Because type 1 Additionally, the drug may impair glucose absorption. In clini-
patients on an SGLT2 inhibitor may have normal glucose levels, cal trials, it lowered the HbA concentration 0.3–0.5%. Adverse
1c
they may either withhold or reduce their insulin doses to such effects include gastrointestinal complaints (constipation, indiges-
a degree as to induce ketoacidosis. Therefore, SGLT2 inhibitors tion, flatulence). It can also exacerbate the hypertriglyceridemia
should not be used in patients with type 1 diabetes and in those that commonly occurs in people with type 2 diabetes.
patients labelled as having type 2 diabetes but who are very insulin Bromocriptine, the dopamine agonist, in randomized placebo-
deficient and prone to ketosis. controlled studies lowered HbA by 0–0.2% compared with base-
1c
line and by 0.4–0.5% compared with placebo. The mechanism by
which it lowers glucose levels is not known. The main adverse events
OTHER HYPOGLYCEMIC DRUGS are nausea, fatigue, dizziness, vomiting, and headache.
Colesevelam and bromocriptine have very modest efficacy
Pramlintide is an islet amyloid polypeptide (IAPP, amylin) ana- in lowering glucose levels, and their use for this purpose is
log. IAPP is a 37-amino-acid peptide present in insulin secretory questionable.
granules and secreted with insulin. It has approximately 46%
homology with the calcitonin gene-related peptide (CGRP; see
Chapter 17) and physiologically acts as a negative feedback on ■ MANAGEMENT OF THE
insulin secretion. At pharmacologic doses, IAPP reduces glu-
cagon secretion, slows gastric emptying by a vagally mediated PATIENT WITH DIABETES
mechanism, and centrally decreases appetite. Pramlintide is an
IAPP analog with substitutions of proline at positions 25, 28, Diet
and 29. These modifications make pramlintide soluble, non-self- A well-balanced, nutritious diet remains a fundamental element
aggregating, and suitable for pharmacologic use. Pramlintide is of therapy for diabetes. It is recommended that the macronutri-
approved for use in insulin-treated type 1 and type 2 patients who ent proportions (carbohydrate, protein, and fat) be individualized
are unable to achieve their target postprandial blood glucose levels. based on the patient’s eating patterns, preferences, and goals.
It is rapidly absorbed after subcutaneous administration; levels Generally most patients with diabetes consume about 45% of
peak within 20 minutes, and the duration of action is not more their calories as carbohydrates; 25–35% fats; and 10–35% pro-
than 150 minutes. It is metabolized and excreted by the kidney, teins. Limiting the carbohydrate intake and substituting some of
but even at low creatinine clearance there is no significant change the calories with monounsaturated fats, such as olive oil, rapeseed
in bioavailability. It has not been evaluated in dialysis patients. (canola) oil, or the oils in nuts and avocados, can lower triglycer-
Pramlintide is injected immediately before eating; dosages ides and increase HDL cholesterol. A Mediterranean-style eating
range from 15 to 60 mcg subcutaneously for type 1 patients and pattern (a diet supplemented with walnuts, almonds, hazelnuts,
from 60 to 120 mcg for type 2 patients. Therapy with this agent and olive oil) has been shown to improve glycemic control and
should be initiated at the lowest dosage and titrated upward. lower combined endpoints for cardiovascular events and stroke.
Because of the risk of hypoglycemia, concurrent rapid- or short- Caloric restriction and weight loss is an important goal for the
acting mealtime insulin dosages should be decreased by 50% obese patient with type 2 diabetes.
or more. Pramlintide should always be injected by itself using
a separate syringe; it cannot be mixed with insulin. The major Education
adverse effects of pramlintide are hypoglycemia and gastrointes-
tinal symptoms, including nausea, vomiting, and anorexia. Since Education of the patient and family is a critical component of
the drug slows gastric emptying, recovery from hypoglycemia can care. The patient should be informed about the kind of diabetes
be problematic because of the delay in absorption of fast-acting he or she has and the rationale for controlling the glucose levels
carbohydrates. (see Box: Benefits of Tight Glycemic Control in Diabetes). Self-
Selected patients with type 1 diabetes who have problems with monitoring of glucose levels should be emphasized, especially
postprandial hyperglycemia can use pramlintide effectively to con- if the patient is on insulin or oral secretagogues that can cause
trol the glucose rise especially in the setting of a high-carbohydrate hypoglycemia. The patient on insulin therapy should understand