Century of Evolution of Non-Insulin Therapeutic Options in Management of Diabetes

First recognized by the ancient Egyptians, the presentation and treatment of diabetes have dramatically evolved over the centuries [1]. Though the discovery of insulin 100 years ago changed the management of diabetes forever, most patients today are not insulin deficient, but overweight with a combination of insulin resistance and impaired insulin secretion [1]. While lifestyle changes can be very effective in improving glucose control, in the long-term most patients will eventually require medications to achieve adequate diabetic control [2]. For decades options for oral glucose lowering medications were limited, but in the past 25 years many more options have become available. The purpose of this article is to provide an overview of the existing oral and injectable (non-insulin) pharmacologic options available for the treatment of patients with type 2 diabetes.


Sulfonylureas
Sulfonylureas were first introduced in the 1950s, but the hypoglycemic effects of synthetic sulfur compounds were first observed in 1937 by Ruiz and colleagues [3] [4]. The hypoglycemic effect of sulfur compounds was later confirmed in 1942 by Janbon and his colleagues, when noting hypoglycemia as a complication in the treatment of typhoid patients with para-amino-sulfonamide-isopropylthiodiazole [4]. In 1946 Loubatieres and colleges confirmed aryl sulfur drugs stimulated the release of insulin from pancreatic beta cells and therefore required some Beta cell function be present to have any effect on glucose levels [3] [4].
The first commercially available sulfonylurea was tolbutamide and was introduced in 1956 in Germany [3]. Other first generation sulfonylureas such as acetohexamide, chlorpropamide and tolazamide were quickly release. Nearly 25 years later, the more commonly known second generation sulfonylureas such as glyburide, glipizide and glimepiride were developed. These compounds were found to have a higher affinity for the targeted cellular receptor sites and thus proved to be far more potent compounds at lower doses [2]. Sulfonylureas mainly lower blood glucose levels by directly stimulating pancreatic beta cells to secrete insulin, but have other secondary effects that may also play a role in lowering blood glucose levels. These secondary effects include decreasing hepatic clearance of insulin, inhibiting glucagon secretion from pancreatic alpha-cells, and enhancing insulin sensitivity within the peripheral tissues [2]. Sulfonylureas are generally safe, inexpensive, and widely used as monotherapy or in combination with any other class of oral diabetic medications except meglitinides [2] [4].
The primary use limiting side effect is hypoglycemia. Since most sulfonylureas are metabolized in the liver and to some extent excreted by the kidney, hepatic and/or renal impairment can further increase the risk for hypoglycemia [2].
Overtime, patients on sulfonylureas may require the addition of other medications to maintain adequate glucose control. This secondary failure or lack of du-

Biguanides
French lilac or goat's rue (Galega officinalis) an herb was used in Southern and Eastern Europe during Medieval times as a folk remedy for the treatment of diabetes [3] [4]. The herb was found to contain quanadine, a compound with hypoglycemic properties but too toxic for clinic use [3]. Two synthetic diguanides were synthesized from this compound and used in the 1920s to treat diabetes, but were soon discontinued due to their hepatotoxic nature [3]. Interest in the biguanides continued and in the 1950s three biguanides were introduced: metformin, phenformin, and buformin [3]. Phenformin was widely studied in the United States, while metformin was studied in France, and buformin in Germany [4]. An increased incidence of lactic acidosis associated with phenformin and buformin, led to the withdrawal of these drugs from the market in most countries [4]. Metformin continued to be used in Europe, being reintroduced to the U.S. market in 1995 after 20 years of proven safe and efficacious use in Europe [3]. Metformin is the only clinically significant biguanide in use today and has become the most widely prescribed oral agent for the treatment of type 2 diabetes in the world [2]. Metformin is recommended as initial therapy for patients with type 2 diabetes by both the American Diabetes Association and the European Association for the Study of Diabetes [2]. Metformin works to reduce blood sugar levels mainly by decreasing hepatic glucose production and modestly increasing peripheral insulin-mediated glucose uptake [3] [4]. Typical reduction in A1c with metformin therapy is in the range of 1% -2% [2] [3]. Metformin is contraindicated in patients with advanced renal and hepatic disease.
Both chronic conditions increase risk for the development of lactic acidosis [2].
In 2016 the US Food and Drug Administration changed recommendations for metformin use in chronic kidney disease from should be avoided in patients with a creatinine level greater than 1.4 mg/dL in women and 1.5 mg/dL in men to contraindicated at eGFR less than 30 ml/min/1.73m 2 and not recommended to be started in patients with an eGFR less than 45 ml/min/1.73m 2 [5]. The most common side effect is gastrointestinal (GI). Nausea, diarrhea, and/or abdominal discomfort may occur in up to 50% of patients [2] [3]. These side effects are usually dose related and slow titration may help reduce occurrence. Prescribing immediate release metformin three times a day with food may also reduce GI related side effects. Extended release metformin causes fewer GI side effects and can improve tolerability in those patients who do not tolerate the immediate release formulation [2]. Long term metformin use has also been associated with vitamin B12 deficiency. Periodic testing of vitamin B12 levels should be considered, particularly in the setting of macrocytic anemia or neuropathy symptoms [6].

Meglitinides
Mechanism of action is similar to the sulfonylureas in that these medications stimulate insulin release from pancreatic beta cells. This class of drugs has a rapid onset of action, short duration of action and is glucose dependent [2] [4].
Their pharmacokinetics make meglitinides particularly useful drugs in patents who eat erratically or have a need to specifically lower postprandial glucose levels [2]. Secondary to the rapid onset and short duration, meglitinides are administered up to 30 minutes prior to meals and maybe omitted if the patient is planning on skipping that particular meal. A1c reduction from meglitinides is approximately 1% -1.5% [3]. Also similar to sulfonylureas, meglitinides can cause weight gain and hypoglycemia, but given their short duration of action, the risk for severe hypoglycemia is less [2]. However, meglitinides are metabolized in the liver and should be used cautiously in patients with impaired liver function or in combination with drugs that inhibit the cytochrome P450 enzymes, thus increasing the risk for hypoglycemia [2]. The first agent in this class, repaglinide was approved in 1997 and the second nateglinide in 2000 [4]. Repaglinide has shown to be slightly more effective in lowering A1c levels over nateglinide and is safe to use in patients with renal failure [7]. Neither has been shown to have a beneficial effect on cardiovascular outcomes [7].

Thiazolidinediones (TZDs)
Thiazolidinediones are peroxisome proliferator activated receptor gamma agonists, promoting adipogenesis, tissue glucose uptake and insulin sensitivity [8]. Activation of these receptors leads to a decrease in fat accumulation within the liver, muscle and pancreas resulting in the reduction of insulin resistance and hepatic glucose production [2] [4] [8]. Troglitazone was the first thiazolidinedione to be approved for clinical use in 1997, but was quickly withdrawn from the market in 2000, due to idiosyncratic hepatic failure [3] [4]. Two other TZDs, rosiglitazone and pioglitazone were released in 1999. Both pioglitazone and rosiglitazone have each been linked to issues unrelated to glycemic control. Both agents have been linked to fluid retention and should be used cautiously in patients at increased risk for congestive heart failure [4] [7] [8].
Restrictions placed on rosiglitazone in 2010 over concerns regarding its cardiovascular safety were lifted in 2013 when reanalysis of the RECORD study concluded that patients treated with rosiglitazone did not have an increased risk of cardiovascular death, myocardial infarction, or stroke compared to patients taking other oral antihyperglycemic medications [4] [7] [8]. Pioglitazone has also been associated with a possible increased risk for bladder cancer [3] [4].
Though the data do not definitively support that pioglitazone significantly increases the risk of bladder cancer, the FDA recommends that pioglitazone not be used in patients with active bladder cancer or a history of bladder cancer [2].
A number of observational studies and randomized controlled trials have noted that long term treatment with TZDs decreased bone density, nearly doubling the  [8]. Though the onset of action may be more gradual, the durability of glycemic control with TZDs is more prolonged than either with metformin or sulfonylureas [2]. The glucose lowering efficacy of TZDs, along with potential benefits on blood pressure and lipids should be weighed against the potential disadvantages of edema, congestive heart failure and osteoporosis [2].

α-Glucosidase Inhibitors (AGIs)
AGIs work locally at the brush border of the small intestine by inhibiting α-glucosidase enzymes, which prevents the breakdown of disaccharides and oligosaccharides into monosaccharides [

Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists
The greater insulin stimulatory response to oral glucose in comparison to intravenous administration of glucose, is known as the "incretin effect". The majority of the incretin effect is due to two gastrointestinal hormones: glucose dependent insulinotropic peptide (GIP) and glucagon like peptide-1 (GLP-1) [2]. It wasn't until the 1980s when the incretin-insulin pathway was fully understood and the (GLP-1) was first studied in patients with type 2 diabetes [4]. In two key trials, patients with type 2 diabetes were injected with native GLP-1 and demonstrated a significant increase in insulin response with reversal of hyperglycemia [4]. Enhanced understanding of the incretin effect and the clinical findings in these initial trials led to the development of a drug class that utilized this mechanism by increasing GLP-1 production [4].
GLP-1 is a hormone secreted from the small intestine within minutes of a carbohydrate or fat containing load [3]. then native GLP-1 hormone [3]. Exenatide is available in two injectable formulations, a twice daily injection (Byetta) as well as a once weekly injection (Bydureon) [7]. Short acting GLP1 agonists include twice daily exenatide and lixisenatide [2]. Lixisenatide is administered as a once daily subcutaneous injection with the first meal of the day.
Long acting GLP1 agonists include weekly exenatide (Bydureon), liraglutide, dulaglutide and semaglutide [2]. Liraglutide was approved for use in 2010 and is approved for patients ≥10 years of age with type 2 diabetes [7]. Liraglutide is the only long acting GLP1 agonist that is a once daily injection [2]. Dulaglutide and semaglutide are both long acting GLP-1 agonists available as once weekly injections [2]. Semaglutide is also unique in that it has been recently released as an oral formulation (Rybelsus) [7]. It is important to note that exenatide and lixisenatide are contraindicated in patient with renal dysfunction  [12]. Exenatide was determined to be non-inferior to placebo with respect to cardiovascular safety, nor was it superior in efficacy in reducing risk among patients with Type 2 diabetes with or without previous cardiovascular disease [12]. Simply put, exenatide was determined to be a safe addition to conventional therapy but offers no additional benefit in reduction of major cardiovascular events [12].
The effects of lixisenatide on cardiovascular outcomes in patients with type 2 diabetes were studied over 25 months and included over 6000 patients [13]. Lixisenatide was compared to placebo in patients who had recently (within 180 days) suffered a myocardial infarction or been hospitalized with unstable angina [13]. It was determined that lixisenatide, when added to conventional therapy, was not associated with a significant difference in rates of adverse cardiovascular events as compared to conventional therapy plus placebo [11] [13]. There were no significant differences in rate of hospitalization for heart failure, or the rate of death [13]. Lixisenatide was found to be noninferior to placebo when evaluating cardiovascular safety and thus is an effective adjunct to conventional hyperglycemic therapy [13].
The cardiovascular effects of semaglutide were studied over 2 years and included over 3000 patients [14]. Once weekly semaglutide was compared to placebo to determine effects on cardiovascular death, nonfatal MI and nonfatal stroke [14]. Patients with type 2 diabetes treated with once weekly semaglutide were found to have statistically significantly lower rates of cardiovascular death, nonfatal MI, and nonfatal stroke when compared to placebo [14]. Other indirect cardiovascular benefits included reduction in A1c, body weight and systolic blood pressure, which may have contributed to the positive outcomes [14].
The cardiovascular effects of dulaglutide were studied over a five-year period and included more than 9000 patients [15]. Dulaglutide has been shown to reduce blood glucose concentration, blood pressure, weight and albuminuria which lead to investigative trials regarding possible cardiovascular benefits [15].
When compared to placebo, dulaglutide reduced the risk of cardiovascular outcomes including cardiovascular death, nonfatal MI and most significantly nonfatal stroke [15]. Thus in summary, dulaglutide can be safely added to treatment regimen for patients with type 2 diabetes and may have the additional benefit of cardiovascular risk factor reduction [15].
Of the available GLP-1 agents in the United States, both semaglutide and dulaglutide seem to have the added benefit of decreasing the incidence of major adverse cardiac events in diabetic patient, while exenatide and lixisenatide dem-

Dipeptidyl Peptidase-4 (DPP-4) Inhibitors
The agonists, they do not result in delayed gastric emptying or increased satiety but also avoid the nausea and vomiting associated with the initial onset of therapy [8].
The first DPP-4 inhibitor to be FDA approved was sitagliptan in 2006 [4]. Interestingly, when compared to placebo in one trial, patients who were treated with saxagliptin were more likely to be admitted to the hospital with heart failure early in the treatment course, however no differences were noted after 12 months [2] [17]. Due to a similar effect observed with alogliptin, this has prompted the FDA to issue a warning regarding heart failure risk, especially in patients with cardiovascular and renal disease [11]. The impact of DPP-4 inhibitors on cardiovascular outcomes has been studied in five major trials including over 50,000 patients [11]. The conclusion from these multiple trials has shown this class of drugs as not increasing major adverse cardiovascular events (MACE), but they have also not shown any added cardiovascular benefits [11].

Sodium-Glucose Transport Protein 2 (SGLT-2) Inhibitors
SGLT-2 Inhibitors block glucose transporter, SGLT-2, which is responsible for  [4]. SGLT-2 Inhibitors decrease renal glucose reabsorption and increase urinary glucose excretion reducing fasting and postprandial blood glucose levels [7]. These agents can be used as monotherapy, in patients where metformin was not tolerated, in addition to other glucose lowering agents including insulin [8]. As these medications function at the renal tubule, their effectiveness is dependent on renal filtration of glucose and thus should not be initiated in patients with an eGFR <60 ml/min/1.73m 3 [8].
One of the benefits of SGLT-2 Inhibitors is the ability to lower blood glucose levels independent of insulin action and therefore their effectiveness is not affected by insulin levels or insulin resistance [2] [8].

Amylin Agonists
Amylin, an endogenous neuroendocrine hormone was first discovered in 1987 [3] [4]. Amylin is co secreted with insulin by the pancreatic beta cells in response to food intake [19].

Bromocriptine
Bromocriptine is a dopamine agonist that has been used for many years in the

Colesevelam
Colesevelam or Welchol is a bile-acid sequestrant primarily used to lower LDLcholesterol was secondarily noted to also have a favorable effect on glucose le- lam is also contraindicated in patients with plasma triglyceride levels greater than 500 mg/dL or history of hypertriglyceridemia induced pancreatitis [2].