Endocrinology Metabolism

Pharmacologic (oral and injectable incretins) and Surgical Treatment of Diabetes

What every physician needs to know

When to initiate pharmacologic therapy in type 2 diabetes mellitus

Healthy lifestyle changes, including diet and exercise, remain the cornerstone of successful therapy for type 2 diabetes mellitus. However, in the past, initiation of pharmacologic therapy was often delayed to allow a patient to attempt those modifications. Currently, both the American Diabetes Association (ADA) and the American Association of Clinical Endocrinologists (AACE) recommend the initiation of pharmacologic therapy early on in the course of diabetes to attain faster glycemic control and prevent diabetic complications.

The choice of pharmacologic therapy depends on patient characteristics such as age, hypoglycemia risk, disease state (such as HbA1c level), presence of renal or liver disease, and life expectancy as well as other factors such as cost, effectiveness of the medication, side effects, etc. Regardless of which approach is used, it is important to reassess every 3 months the impact of the medication(s) chosen on HbA1c as well as any potential side effects until appropriate and safe control of glycemia has been achieved. It is also important not to delay the initiation of insulin when appropriate, including at the diagnosis of diabetes.

One important fact to consider is that the potential of a diabetes medication to maintain an acceptable HbA1c over the long term is low (9-13% at 10 years in the United Kingdom Prospective Diabetes Study (UKPDS).) Therefore, in most patients it will be necessary to add another agent to sustain the target HbA1c. With the increased availability of novel classes of oral hypoglycemic agents, the therapeutic options are numerous. However, due to the risks of increased side effects and decreased compliance with polypharmacy, it is recommended to keep the total number of oral hypoglycemic agents to three or fewer and consider earlier addition of insulin, especially in a basal formulation.

Oral pharmacotherapy for type 2 diabetes mellitus

Metformin

Metformin is the most commonly used medication for T2 DM and is recommended as first-line agent by both the AACE and ADA. It works by activating AMP-kinase and its primary physiologic effect is the lowering of hepatic glucose output. It combines a long track record of safety with a low cost as it has been available in generic format for more than 10 years. It is reported to decrease HbA1c by about 1.5 percentage points. Its effect on weight is generally neutral with a tendency for modest weight loss. It generally does not cause hypoglycemia when used as monotherapy.

The main side effects of metformin are gastrointestinal (GI), with nausea, abdominal cramping, and diarrhea being most common (in about 5% of patients). To minimize the GI side effects, it is recommended to start metformin at a lower dose and frequency and slowly titrate the dose upwards. If GI side effects are severe enough to warrant discontinuation, an extended-release form of metformin could be tried for better tolerability. Lactic acidosis is a much rarer complication (1 in 100,000) of metformin use and hence it should be avoided in the presence of predisposing disease states (renal insufficiency Cr >1.5 in men and >1.4 in women, liver failure, alcoholism, and low perfusion states such as shock or heart failure).

Vitamin B12 deficiency has been reported to occur while taking metformin. It is important to monitor clinically for symptoms or signs of neuropathy, measure blood cell parameters and periodically, (every 2-3 years) vitamin B12 levels. Fortunately, vitamin B12 deficiency secondary to metformin ingestion is easily treated with oral vitamin B12 supplementation and is not a reason for discontinuation of metformin.

Sulfonylureas

Sulfonylureas are secretagogues and as such increase insulin release by the pancreatic beta-cells. They act by binding to the ATP-dependent K channel (K-atp) on the cell membranes of beta cells, although some members of this class can bind to similar channels on other organs such as the heart. The net effect of binding to the K-atp channel is an increase in intracellular calcium, which in turns results in increased insulin secretion. Sulfonylureas are associated with a 1 to 1.5% lowering of HbA1c and several formulations are currently available in generic format. There is extensive clinical experience in the UKPDS study with their use in reducing microvascular events associated with the lowering of HbA1c.

The most prominent side effect of sulfonylureas is hypoglycaemia, which can be of special concern in susceptible populations such as the elderly and those with some degree of renal insufficiency due to decreased clearance. They also tend to result in weight gain. Due to the potential for earlier exhaustion of pancreatic beta-cell reserve, they are believed to have a lower durability of long-term glucose-lowering. Finally, some agents in this class may have a negative impact on myocardial ischemic preconditioning. Although there are concerns about the potential for increased cardiac risk when using these agents, the recent ADVANCE trial's use of Gliclazide, showed neither benefit nor harm in the subjects who received it compared with the other treatment arm. Due to the presence of a sulfa moiety, these agents are generally avoided in patients with a sulphonamide allergy.

Meglitinides

Meglitinides are also secretagogues but are distinct from sulfonylureas in two main aspects: they do not contain a sulfa moiety and they have shorter half-life and hence are usually taken 2-3 times a day before meals. Owing to their shorter half-life, their risk of prolonged hypoglycemia is less than with sulfonylureas but they also are slightly less effective at lowering HbA1c. They are considered an alternative to sulfonylureas in patients with sulphonamide allergies. There are two FDA approved agents in this drug class: Repaglinide, which does not need dose adjustments in renal insufficiency, and nateglinide. They are both available in generic form.

The need to take these medications before each meal may be considered a benefit, due to increased flexibility in the timing of the meals, or a disadvantage, due to the increased number of tablets that need to be taken daily.

Alpha-Glucosidase Inhibitors

These drugs act by reversibly inhibiting intestinal alpha glucosidase, with the primary effect of slowing the digestion and absorption of carbohydrates in the intestinal tract. This results in lower post-prandial hyperglycemia. They are less potent than metformin and sulfonylureas (HbA1c lowering of 0.5-0.9 percentage points) and do not cause hypoglycemia in monotherapy. Acarbose and miglitol are the main drugs in this class. Their use is severely limited by their gastrointestinal side effects leading to discontinuation of treatment (about 50% of patients experience bloating, flatulence, and loose stools). Although they are listed as first-line therapy, their use is not widespread due to the combination of lower potency and high frequency of side effects. Hypoglycemia that occurs with the concomitant use of these drugs needs to be treated with glucose due to the inhibition of the intestinal alpha glucosidase.

Dipeptidyl-Peptidase 4 (DPP-4) Inhibitors

These drugs act by inhibiting Dipeptidyl-Peptidase 4 (DPP-4), the enzyme responsible for the degradation of glucagon-like peptide-1 (GLP-1). This results in increased levels of GLP-1, an endogenous intestinal peptide produced in response to food intake that promotes insulin secretion, lowers glucagon secretion, decreases gut peristalsis and increases satiety. Due to the fact that GLP-1 is only released prandially, there is less risk of hypoglycemia during monotherapy with DPP-4 inhibitors. These medications are more costly and less potent than metformin and sulfonylureas (about 0.8 percentage point drop in HbA1c). They are, however, well tolerated with few side effects reported and can be prescribed in the presence of renal insufficiency at a time where metformin becomes contraindicated. They are considered weight-neutral and to date have no established causal association with either pancreatitis or pancreatic tumors. The currently FDA-approved DPP-4 inhibitors are sitagliptin, saxagliptin, linagliptin, and alogliptin. A recent multicenter, 5-year, prospective study in patients with Type 2 Diabetes Mellitus and preexisting cardiovascular disease showed no increase in cardiovascular events (especially cardiovascular mortality, nonfatal myocardial infraction and stroke and hospitalizations from heart failure) in patients receiving sitagliptin compared to placebo.

Thiazolidinediones

Thiazolidinediones act by activating the nuclear transcription factor PPAR gamma, leading to the sensitization of peripheral tissues to the action of insulin. They result in a decrease of HbA1c by about 1-1.5 percentage points. They do not cause hypoglycemia in monotherapy but are associated with fluid retention and weight gain, especially when used in combination with insulin. As such, they are contraindicated in NYHA-III and IV heart failure. Due to controversy about increased cardiovascular risk associated with the use of rosiglitazone, the FDA had included them in the Risk Evaluation and Mitigation Strategy (REMS) category. The reanalysis of the RECORD trial data lead to the removal of the REMS restrictions due to lack of evidence of increased cardiovascular risk. Pioglitazone has favorable effects on LDL cholesterol that are not seen with rosiglitazone. While a meta-analysis indicated a slight increase in risk for bladder cancer in patients taking pioglitazone, 10-year epidemiologic post-marketing data appear to show no effect of the drug on bladder cancer risk.

Bile Acid Sequestrant

Colesevelam is a bile-acid sequestrant that increases hepatic bile acid production. It improves glycemic control through an unclear mechanism. Its reported effect on HbA1c was a 0.5 percentage point reduction. Its side effects include constipation and higher triglycerides. It is recommended for use only as add-on therapy for glycemic control. Long-term studies on its glycemic effect are not currently available.

Dopamine Agonists

Bromocriptine is the only member of this class currently approved for the treatment of type 2 diabetes. It is different from the drug traditionally used for the control of hyperprolactinemia as it is a quick-release formulation and must be taken within 2 hours of awakening. The mechanism of action is through the dopaminergic neurons, impacting the regulation of metabolism by the hypothalamus. This leads to decreased postprandial glucose values through several possible mechanisms. Its advantages are low to no risk of hypoglycemia and a potential cardiovascular benefit seen in one large 52-week phase 3 trial. It results in a small decrement in HbA1c (0.5%) with nausea, vomiting, rhinitis, and fatigue as major side effects. It is weight neutral and there are no generic formulations available to date.

Sodium-Glucose Co-Transporter 2 (SGLT-2) inhibitors

Bromocriptine is the only member of this class currently approved for the treatment of type 2 diabetes. It is different from the drug traditionally used for the control of hyperprolactinemia as it is a quick-release formulation and must be taken within 2 hours of awakening. The mechanism of action is through the dopaminergic neurons, impacting the regulation of metabolism by the hypothalamus. This leads to decreased postprandial glucose values through several possible mechanisms. Its advantages are low to no risk of hypoglycemia and a potential cardiovascular benefit seen in one large 52-week phase 3 trial. It results in a small decrement in HbA1c (0.5%) with nausea, vomiting, rhinitis, and fatigue as major side effects. It is weight neutral and there are no generic formulations available to date.

SURGICAL THERAPY FOR DIABETES

Besides the obvious reduction in weight, weight loss surgery has been shown to decrease mortality in some individuals as well as decrease or cause remission of diabetes and its complications. Whether the improved glycemic control is solely due to weight loss or to other beneficial hormonal changes associated with bariatric surgery remains to be established. Recent studies highlighted that bariatric surgical procedures are effective not only in patients with diabetes and body mass index (BMI) above 35 but also in those who are overweight or have class 1 obesity.

Different surgical techniques are available, including gastric bypass, sleeve gastrectomy, and gastric banding. In one study, 37-42% of the patients who had a gastric bypass or a sleeve gastrectomy had a HbA1c of 6.0% or less 12 months after the start of the study compared with only 12% of the medically managed patients. It is interesting to note that the two procedures used in this study (gastric bypass and sleeve gastrectomy) had similar results even though they presumably work by different mechanisms in terms of weight loss. These effects were sustained after a median follow-up of 6 years. Further data will need to be collected to assess the long-term durability of the diabetes "remission".

Complications of surgical therapy include early mortality even though data suggest long-term improvements in survival with surgery. Other issues can occur that are more problematic: short-term infections at the incision sites, and pneumonia, venous thromboembolism, and leaks at staple lines. Long-term complications include ulcers at anastomosis sites, hernias, stomal strictures, dehydration, and nutritional deficiencies leading to anemia, neurologic complications, kidney stones, and bone disease. Some individuals may also experience hypoglycemia that requires medications or surgical treatment to resolve.

Key Laboratory and Imaging Tests

Non-insulin injectable pharacotherapy for diabetes

Incretins are a class of hormones naturally produced by the L cells of the intestine in response to meal ingestion. Their mode of action includes promoting satiety, decreasing gut peristalsis, increasing prandial insulin secretion, and decreasing glucagon secretion. GLP-1 is a naturally occurring incretin that is rapidly degraded by the enzyme DPP-4. GLP-1 receptor agonists are pharmacologic compounds that are not degraded easily by DPP-4 and include exenatide, exenatide extended release, liraglutide, and albiglutide. They are all currently available as subcutaneous injections. Since their effects are mostly prandial, they have a lower risk of hypoglycemia when compared with secretagogues.They lower HbA1c by about 1% and can be used in combination with most oral therapies for diabetes. They have a favorable effect on weight, with about 1 to 3 kg mean weight loss reported.

Their side effects include mainly nausea, vomiting, and diarrhea. Pancreatitis has been reported in patients on GLP-1 analogues although a clear cause and effect relationship has not been established to date because of the overall increased incidence of pancreatitis in patients with type 2 diabetes. In addition, concerns about increased risk of medullary thyroid cancer in animal studies have precluded the prescription of GLP-1 analogues in patients with a personal or family history of medullary carcinoma of the thyroid or multiple endocrineneoplasia Type 2.

Management and Treatment of the Disease

There is limited clinical trial data on the sequence of addingmedications for the treatment of diabetes. The ongoing GRADE trial,(Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) will be assessing the long term impact of the addition of various hypoglycemic agents to metformin. Many organizations have suggested guidelines for the pharmaceutical management of diabetes based on the currently available evidence as well as expert opinions. It is important to note that the full effect of the oral medications on glucose control may take weeks to months. Self-blood-glucose monitoring and HbA1c should be used to assess the success of glucose-lowering therapy. Monitoring of side effects is also essential as side effects, frequency of administration, and cost are significant factors that impact patient adherence.

The most accepted first agent in patients who do not need to start on insulin immediately is metformin. It should be started either once a day in the regular or extended release form and uptitrated slowly as long as it is well tolerated. If HbA1c is not controlled on metformin therapy, an additional agent may need to be added to control the diabetes. If it is determined that insulin is not needed, the selection of the next agent for therapy is driven by a variety of factors.

If cost of the medications is a major factor, then the sulfonylureas are most likely the agents of choice.

If cost is not a factor, then agents can be selected by different variables: risk of hypoglycemia, weight gain or loss, degree of lowering of HbA1c, and side effects as described in the previous section. Since the FDA has a mandatory evaluation of diabetes drugs for cardiovascular outcomes, this may lead to selection of agents based on cardiovascular advantages seen in these clinical trials once the studies are completed.

Surgical intervention should be considered for any patient who meets the criteria for weight loss surgery and has gone through appropriate screening for suitability for surgery. Not every candidate who meets the BMI requirements for surgery is eligible for surgery due to operative risk, behavioural issues, and ability to safely modify food intake after surgery.

What’s the evidence?

Garber, AJ, Abrahamson, MJ, Barzilay, JI, Blonde, L, Bloomgarden, Z, Bush, M. "American Association of Clinical Endocrinologists' Comprehensive Diabetes Management Algorithm 2013". Consensus Statement EndocrPract. vol. 19(Suppl 2). 2013.

(Revised algorithm from AACE illustrating the need to initiate pharmacotherapy for type 2 DM early on; offers a decision tree on which agent to use based on HbA1c.)

Qaseem, A, Humphrey, LL, Sweet, DA, Starkey, M, Shekelle, P. "Oral pharmacologic treatment of type 2 diabetes mellitus: a clinical practice guideline from the American College of Physicians". Ann Intern Med. vol. 156. 2012. pp. 218-31.

(A good review of the current evidence and comparative effectiveness of available oral agents for type 2 diabetes.)

Nisal, K, Kela, R, Khunti, K, Davis, M. "Comparison of efficacy between incretin-based therapies for type 2 diabetes mellitus.". BMC Medicine. vol. 10. 2012. pp. 152.

(A recent review of incretins and their use in the treatment of diabetes.

Green, JB, Bethel, MA, Armstrong, PQ. "Effect of Sitagliptin on Cardiovascular Outcomes in Type 2 Diabetes.". N Engl J Med. vol. 373. 2015. pp. 232-242.

(A recent publication establishing cardiovascular safety of sitagliptin use in patients with Type 2 DM)

Schauer, PR, Kashyap, SR, Wolski, K, Brethauer, SA, Kirwan, JP, Pothier, CE. "Bariatric surgery versus intensive medical therapy in obese patients with diabetes". N Engl J Med. vol. 366. 2012. pp. 1567-76.

Maggard-Gibbons, M, Maglione, M, Livhits, M, Ewing, B, Maher, AR, Hu, J. "Bariatric surgery for weight loss and glycemic control in nonmorbidly obese adults with diabetes: a systematic review.". JAMA. vol. 309(21). 2013. pp. 2250-61.

(Two articles presenting the latest evidence regarding the effects of bariatric surgery on diabetes and its complications.)

Inzucchi, SE, Bergenstal, RE, Buse, JB, Diamant, M, Ferrannini, E, Nauck, M. "Management of hyperglycemia in type 2 diabetes: a patient-centered approach: Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)". Diabetes Care. vol. 35. 2012. pp. 1364-79.

(The first official consensus statement on the management of diabetes from the American Diabetes Association and the European Association for the Study of Diabetes.)

Ismail-Beigi, F. "Glycemic management of type 2 diabetes mellitus". N Engl J Med. vol. 366. 2012. pp. 1319-27.

(A general review of diabetes therapies.)
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