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Health Protocols

Diabetes and Glucose Control

Treatment Of Type 2 Diabetes

Goals of Treatment

Many conventional sources agree on diabetes treatment priorities. A self-management and self-care program that includes an understanding of home glucose monitoring, lifestyle changes, and medication is critical. Diet and exercise are emphasized in order to help bring blood sugar under control and allow the patient to lose weight, if necessary. Stopping smoking is universally recommended. Metformin treatment is typically initiated immediately upon diagnosis. All these measures have the goal of minimizing complications and improving the diabetic patient’s overall quality of life. Ultimately, their purpose is to bring blood sugar under control and control blood sugar- and insulin-derived damage to the heart, small and large blood vessels, and other tissues (Whitlatch 2015; O'Connor 2015; Inzucchi 2012b; Fonseca 2013).

Achieve blood sugar goals. Blood sugar control (as assessed by the HbA1C test) is the primary goal of diabetes treatment (Delamater 2006; ADA 2014c; Inzucchi 2012b; Whitlatch 2015; Fonseca 2013). HbA1C is a test that reflects average blood sugar over 2‒3 months. Specifically, it measures glycated hemoglobin. Hemoglobin is the oxygen-carrying component of red blood cells; glycated hemoglobin is irreversibly bound to glucose, forming an AGE. HbA1C testing should be performed routinely as part of continuing care to monitor how well blood glucose is being managed (Bozkaya 2010; ADA 2014a).

  • Conventional glycemic control goals. The American Diabetes Association recommends diabetic patients attempt to achieve an HbA1C level of 7% or less (ADA 2015f). Fasting glucose levels alone are not generally relied upon to follow blood sugar control (O'Connor 2015). The International Diabetes Foundation recommends a post-meal glucose upper limit of 140 mg/dL (IDF 2007).
  • Life Extension optimal goals for health and longevity. The following are suggested target levels for variables related to glycemic control. Note: it may be difficult for patients with long-standing type 2 diabetes to achieve these goals. Risks of hypoglycemia should be discussed with a healthcare provider, especially among individuals who attempt intensive glucose control using drugs that stimulate insulin secretion (eg, sulfonylureas) or insulin itself.
    • Hemoglobin A1C: <5.6% = good; <5.0% = optimal (Adams 2009; Jorgensen 2004)
    • Fasting glucose: 70‒85 mg/dL (Bjornholt 1999; Kato 2009; Muti 2002; Nichols 2008; Simons 2000; Meigs 1998; Tirosh 2005; Gerstein 1999; Coutinho 1999)
    • Glucose: 125 mg/dL or less 2 hours after a meal (or no more than 40 mg/dL above baseline fasting level) (Gerstein 1999)
    • Fasting insulin: 5 µIU/mL or less

Risks of Intensive Glucose Control in Long-Standing Diabetes and the Need for Individualized Targets

The risk-benefit equation of intensive glycemic control may progressively shift in favor of less-intensive control as diabetes progresses. This is because the risk of hypoglycemia and associated complications inherently increases with the medications and dosages needed to maintain lower glucose and HbA1C levels in late-stage type 2 diabetes (Unger 2011).

During healthy metabolic conditions, the body regulates insulin secretion in response to blood glucose levels, avoiding hypoglycemia risk. However, as glucose metabolism becomes increasingly perturbed with advancing diabetes, tight glucose and HbA1C control may require treatment intensification by adding or increasing the doses of insulin or insulinogenic drugs such as sulfonylureas. These drugs increase insulin levels independently of glucose levels, thus posing serious risk of hypoglycemia if dosage is excessive or if glucose levels are not frequently monitored (Unger 2011).

Intensive glycemic management in patients with long-standing and advanced type 2 diabetes not only increases hypoglycemia risk, but has also been associated with increased risk of death from any cause and no reduction in cardiovascular risk in studies (ACCORD Study Group 2008; Gerstein 2011; Duckworth 2009; Inzucchi 2012d; Chokrungvaranon 2011). Although the reasons for these findings remain unclear, weight gain triggered by the use of these medications, complex medication regimes, and hypoglycemia itself are suspected contributors to the increased risk of death and lack of cardiovascular benefit (Inzucchi 2012d). In addition, sulfonylureas, which are frequently used as part of intensive glycemic control regimens, do not reduce, and may even increase, cardiovascular risk (Shimoda 2016).

The glycemic targets described as optimal in this protocol may not be suitable for individuals with long-standing diabetes. Individuals with long-standing diabetes should work closely with their healthcare provider to optimize their treatment plan and closely monitor their glucose levels to avoid hypoglycemia. Patients with late-stage type 2 diabetes may be able to significantly improve their glycemic control through motivated dietary and lifestyle changes coupled with diligent medication usage, but a brute force approach via treatment intensification with insulin or insulin secretagogues (eg, sulfonylureas) aimed at achieving the glycemic goals described in this protocol may pose greater risk than benefit. A comprehensive glycemic management plan for diabetes must take into account several variables including age, cardiovascular health, duration of diabetes, kidney function, hypoglycemia risk, and potential for medication interactions (Inzucchi 2012d; Chokrungvaranon 2011).

Reduce cardiovascular complications. Controlling blood pressure and lipids is an important part of diabetes treatment (Fonseca 2013; Whitlatch 2015; Inzucchi 2012b; O'Connor 2015). Conventional recommendations for blood pressure targets in diabetes range from less than 130/80 mm Hg to less than 140/90 mm Hg, while recommendations for statin medications are based on individualized cardiovascular risk assessment and LDL cholesterol levels (Whitlatch 2015; O'Connor 2015).

Strategies for reducing cardiovascular risk are reviewed in the Atherosclerosis and Cardiovascular Disease protocol.

Dietary and Lifestyle Considerations

Diet. Dietary changes are essential in treating type 2 diabetes. Increasing consumption of vegetables, nuts and seeds, whole grains, legumes, and fruit, as reflected in the Mediterranean dietary pattern, is an effective approach. Avoiding highly processed foods, fast food, and junk food can help reduce “empty calories” in the diet. Avoiding high-heat cooking methods can reduce exposure to dangerous dietary AGEs. Sugar-sweetened beverages, including sodas and drinks made with high-fructose corn syrup, should be eliminated. Also, eating a balanced diet can help prevent blood sugar surges, as protein, fat, and fiber may help slow glucose absorption (AHA 2014; ADA 2015a; JDC 2011; Moghaddam 2006). Typical recommendations are that low-glycemic, high-fiber carbohydrates should comprise 45–60% of total caloric intake, fats should provide about 20–35%, and protein about 15–20% (Dworatzek 2013; Hung 1989; Bazzano 2008; Vlassara 2014; Xi 2014; ADA 2015a; Esposito 2014; Takahashi 2012; Carter 2013; Odegaard 2012). Specific dietary strategies include:

  • Mediterranean diet. Mediterranean-type diets are primarily characterized by abundant quantities of legumes, whole grains, vegetables, fruits, and nuts, and light-to-moderate alcohol consumption, with olive oil as a primary dietary fat (Tognon 2014). The Mediterranean diet includes moderate amounts of fish and dairy products, and low amounts of poultry, meat, highly processed foods, and refined sugars. A rigorous analysis of 10 studies involving over 136 000 participants found highest (versus lowest) compliance with the Mediterranean dietary pattern was associated with a 23% reduction in type 2 diabetes risk (Koloverou 2014). The Mediterranean diet is associated with a lower risk of multiple degenerative conditions associated with advancing age and diabetes, including cardiovascular disease, cancer, obesity, lung disease, and cognitive decline (Gotsis 2015).

  • Caloric restriction. Caloric restriction, which has multiple health benefits, is an effective strategy in diabetes prevention and treatment. Calorie restriction has been shown to significantly improve several measures of glucose metabolism and diabetic complication risk (Colman 2009; Wing 1994; Soare 2014; Lefevre 2009; Bales 2013; Rizza 2014). The benefits of caloric restriction, and how to approach this dietary regimen, are presented in the Caloric Restriction protocol.

  • Low-glycemic-index and low-glycemic-load diet. Glycemic index and glycemic load are estimates of the impact foods have on postprandial blood sugar. Glycemic index is a numerical value that reflects the blood sugar response to a given food in comparison with the response to a specific amount of a pure glucose solution and of white bread (Sheard 2004; Barclay 2008; Juanola-Falgarona 2014; Derdemezis 2014; Afaghi 2012; Higdon 2009). Glycemic load is determined by both glycemic index as well as the total amount of carbohydrate in a food. A low glycemic load denotes a smaller expected postprandial glucose elevation than a high glycemic load (Bhupathiraju 2014; Venn 2007).

    Beans, fruits, vegetables, and unsweetened dairy products are generally low-glycemic-index foods, while rice and grains (whole and refined), breads, and breakfast cereals can be high- or low-glycemic index foods, depending in part on how they are prepared. Fiber-containing foods usually have a lower glycemic index and load (Atkinson 2008; Sheard 2004; ADA 2014b; AHA 2014).

    A comprehensive analysis of observational studies found that, compared with the lowest glycemic index and glycemic load diets, the highest glycemic index and glycemic load diets were associated with significantly higher risk of developing type 2 diabetes, heart disease, gallbladder disease, and other diseases. Intervention trials using low glycemic index and glycemic load diets have shown improved metabolic parameters in diabetics and overweight or obese subjects. The American Diabetes Association endorses the use of glycemic index and glycemic load as an adjunct to counting carbohydrates for controlling blood glucose (ADA 2014b; Sheard 2004; Atkinson 2008; Barclay 2008; Juanola-Falgarona 2014; Afaghi 2012).

Diets high in animal protein and fat—potential long-term risks

Low-carbohydrate, high-protein diets containing relatively large amounts of animal products, protein, and fat are sometimes suggested for diabetics (Klonoff 2009). In short-term studies, lower-carbohydrate diets have shown some beneficial effects (Masharani 2015; Jonsson 2009; Boers 2014; Gower 2015). Their long-term effects on health, however, may be negative. Low-carbohydrate diets have been associated with decreased insulin sensitivity and increased risk of death from all causes, and are usually considered inadvisable in diabetes (Noto 2013; Li, Flint 2014; Fung 2010; Sheard 2004; Handa 2014). Higher intake of animal protein may account for a portion of the risk associated with this type of diet. Two large population studies found that a high-vegetable, low-carbohydrate diet was associated with lower overall mortality, whereas a low-carbohydrate diet high in animal products increased risk of death from any cause, cardiovascular death, and cancer death (Li, Flint 2014; Fung 2010).

Importantly, the concepts of “low-glycemic-index” and “low-carbohydrate” do not mean the same thing, nor do they necessarily call for reliance on proteins and fats (Mayo 2016). A whole-food, plant-based diet low in animal products, such as the Mediterranean diet, is well-known to help control blood sugar metabolism, but is not necessarily low in carbohydrates (Esposito 2014). Unrefined plant-based carbohydrates are typically paired naturally with fiber, and thus whole plant foods (eg, whole grains, vegetables, fruits, and beans) generally have less impact on glucose levels than refined, processed plant-based foods (eg, white bread, white rice) (UOS 2015).

Self-monitoring. Self-monitoring of blood glucose levels with a glucose meter is an important part of diabetes management (Benjamin 2002). Keeping a log of blood glucose readings can help patients recognize patterns and fluctuations in their blood sugar levels in relation to diet, lifestyle, and medications (Kishore 2014; Benjamin 2002; ADA 2015b). Effective self-monitoring, as part of a comprehensive treatment plan, has been shown to reduce diabetic complications; and greater frequency of self-monitoring is associated with lower HbA1C levels (ADA 2015f). Glucose meters are available for purchase over the counter, and even people who are not diabetic should consider obtaining a glucose meter and periodically monitoring their fasting as well as postprandial glucose levels.

Weight loss. For individuals with diabetes who are overweight, even relatively modest weight loss has been shown to improve glycemic control and cardiovascular risk markers (Wing 1987; Wing 2011). Potential benefits include improvements in HbA1C, increased HDL cholesterol, decreased triglycerides, and lower blood pressure (ADA 2015a). Moreover, for those who are not diabetic but are overweight, losing 7% of body weight, or 15 pounds for individuals weighing 200 pounds or more, reduces the risk of developing type 2 diabetes by 58% (Diabetes Prevention Program (DPP) Research Group 2002; NIDDK 2012). Several strategies to promote healthy weight loss are reviewed in the Weight Loss protocol.

Physical activity. Regular exercise improves blood glucose control, lowers risk of cardiovascular disease, aids in weight loss, and improves overall health. It may also prevent development of diabetes in those at high risk. In adults with diabetes, 150 minutes per week of moderate-intensity aerobic exercise (to 50‒70% max heart rate) or 90 minutes per week of vigorous aerobic exercise (to >70% max heart rate) is generally recommended. Additional strength training is also beneficial. Adults over 65 or those with disabilities for whom this level of activity is not possible should be as physically active as possible. Sedentary time should be minimized (ADA 2015a). Moderate exercise, such as rapid walking for 30 minutes per day, five days per week, has been shown to substantially lower the risk of type 2 diabetes (Colberg 2010). Methods to maximize the benefits of exercise are described in Life Extension’s Exercise Enhancement protocol.

Oral Glucose-Lowering Agents

Several classes of oral medications are used in the management of diabetes. In many cases, patients take oral drugs from more than one different class at a time. This is called polypharmacy and can increase risk of side effects and treatment non-compliance, especially in older patients (Emslie-Smith 2003; Noale 2016). 

Biguanides. Biguanides are a class of drugs that lower levels of blood glucose largely by reducing glucose production in the liver (ADA 2015d).

  • Metformin. Chemically, metformin resembles naturally occurring biguanide molecules in the French lilac, a plant used in traditional medicine for hundreds of years (Witters 2001). Metformin, the only biguanide medication currently available for the treatment of diabetes, is considered the first-line drug for type 2 diabetes (Misbin 2004; Kajbaf 2016). The primary reason is that the glucose-lowering action of metformin, when used alone, is at least as effective as that of any other oral glucose-lowering drug, without promoting weight gain and only rarely causing excessively low blood sugar. Also, metformin can be safely used with other drugs, including insulin. According to the American Diabetes Association and the European Association for the Study of Diabetes, metformin therapy, together with lifestyle intervention, should be initiated at the time of diagnosis of type 2 diabetes. Metformin was selected as first-line treatment because of its record of safety and efficacy, as well as its low cost (Gold Standard 2015c). Worldwide, metformin is prescribed to over 100 million patients annually (Inzucchi 2012c; Rena 2013; Scheen, Paquot 2013).

    Metformin lowers blood glucose by several different mechanisms (Viollet 2012). Its main modes of action are suppressing glucose production in the liver, mostly through inhibition of gluconeogenesis, and opposing the activity of the hormone glucagon (Kishore 2014; Pernicova 2014). Metformin also functions as an insulin sensitizer, and it decreases intestinal glucose absorption (Gold Standard 2015c). Unlike other antidiabetic drugs that cause the pancreas to secrete more insulin, metformin makes the body’s tissues more sensitive to insulin, thus reducing insulin resistance (Nasri 2014). Side effects of metformin may include gastrointestinal distress or a slight taste disturbance, usually a metallic taste. Rarely, metformin may cause potentially serious lactic acidosis, a buildup of lactic acid in the blood (Diabetes.co.uk 2016).

    The health benefits of metformin extend far beyond diabetes. In particular, abundant evidence indicates metformin has significant anti-cancer activity. In a large, rigorous review of over 50 studies involving more than one million patients, metformin use in patients with type 2 diabetes was associated with a 35% reduction in risk of death from cancer, and a 27% reduction in risk of any cancer (Franciosi 2013). In a study of over 1000 breast cancer patients with diabetes, those taking metformin had an almost 24% lower mortality risk compared with controls, whereas those not taking metformin had an almost 71% higher mortality risk (Hou 2013). Numerous epidemiologic and observational studies have also found metformin use is associated with dramatically reduced risk of developing cancer (Morales 2015). Clinical trials are investigating metformin as an anti-cancer therapy in breast, prostate, endometrial, and pancreatic cancers (Dowling 2011). In addition to its benefits in diabetes and cancer, metformin has been shown to promote weight loss and protect against cardiovascular disease, Alzheimer disease, and non-alcoholic fatty liver disease (Forouzandeh 2014; Blagosklonny 2009; Gupta 2011; Mazza 2012; Berstein 2012; Miles 2014).

    In fact, metformin shows such great promise as an anti-aging drug (Martin-Montalvo 2013; Anisimov 2013; Violett 2012; Blagosklonny 2009; Greer 2007) that the US Food and Drug Administration (FDA) approved a large-scale clinical trial—the Targeting Aging with Metformin (TAME) trial—to test its effects on biological aging (AFAR 2016).

    One underlying reason for metformin’s many benefits is thought to be its ability to activate AMPK—a critical enzyme that functions as a key regulator of energy balance in the body (Coughlan 2014; Boyle 2010). AMPK (adenosine monophosphate-activated protein kinase) is a major hub for a network of cell signaling that, when activated, keeps the metabolism running smoothly (Ruderman 2013). Activation of AMPK, for example, signals cells to burn glucose and fatty acids for energy rather than store them as body fat. Exercise and calorie restriction are proven methods to boost AMPK activity. However, the body’s response to AMPK signaling becomes blunted with age. Disturbances in AMPK signaling and overall energy balance lead to chronic inflammation, obesity, and the development of age-related diseases (Lee 2013; Lee 2006; Rana 2015). AMPK even helps control the aging process itself by inducing several known longevity factors (such as SIRT1) that have been shown to extend lifespan in many organisms (Salminen 2011).

    Since metformin is a prescription medication, people without diabetes may have difficulty accessing it. Fortunately, medicinal plants, such as Gynostemma pentaphyllum, may activate AMPK and provide some of the same metabolic benefits as metformin (Yoo 2016).

    Another explanation for metformin’s wide-ranging benefits has recently gained recognition: its ability to impact the gut and the intestinal microbial community (microbiome) (McCreight 2016; Pryor 2015). The intestinal microbiome is increasingly thought to be a crucial factor in the development of obesity and diabetes (Palau-Rodriguez 2015; Hur 2015), and a growing body of laboratory, animal, and human research indicates metformin may normalize the disturbed microbial balance associated with abnormal glucose metabolism (Pryor 2015; Forslund 2015; McCreight 2016).

    In a pilot study, 12 diabetic subjects being treated with metformin were examined as they discontinued and then re-started their metformin treatment. Tests showed that, within one week of stopping metformin, bile acid metabolism was altered such that total bile acid levels were increased, and levels of GLP-1, which is derived from intestinal cells, were decreased. Both of these changes point to alterations in digestive system functioning. In addition, significant individual changes in the composition of the intestinal microbiome were seen. These effects were reversed when metformin was reintroduced (Napolitano 2014).

    Findings from a two-part study add to evidence that the gut is an important site of metformin’s action. In the first phase, 20 overweight but otherwise healthy individuals were treated with four distinct metformin preparations, each for one day. Metformin (immediate release, extended release, and two doses of delayed release) were used. The delayed-release preparations, designed to deliver metformin to the lower small intestine, were found to be poorly absorbed, resulting in lower metformin blood levels than the other preparations. In the second phase, 240 subjects with type 2 diabetes were treated with a placebo; delayed-release metformin with breakfast at doses of 600 mg, 800 mg, or 1000 mg; or extended-release metformin with evening meals at doses of 1000 or 2000 mg for 12 weeks. At all doses, the delayed-release metformin preparation had a significant effect on blood glucose and HbA1C levels versus placebo. Delayed-release metformin was about half as bioavailable as immediate-release or extended-release metformin, but was about 40% more potent than extended-release metformin in reducing fasting plasma glucose. Based on this research, it appears a significant proportion of metformin’s action could be attributed to its effect on the lower digestive tract (Buse 2016).

Metformin and Vitamin B12

Metformin is the preferred first-line drug for type 2 diabetes. It is one of the few antidiabetic agents associated with reduced risk of cardiovascular disease and cancer, and does not cause weight gain or hypoglycemia. Metformin, however, does interfere with absorption of vitamin B12, increasing the risk of vitamin B12 deficiency. Low B12 levels, in turn, may contribute to elevated concentrations of homocysteine—an independent risk factor for cardiovascular disease (Strack 2008; Davidson 1997; Kasznicki 2014; de Jager 2010). In a 2015 review, 15 of 22 studies showed a significant decrease in serum vitamin B12 in people taking metformin (Niafar 2015). Duration of metformin usage has been tied to risk of B12 deficiency, with risk rising about 13% for each additional year of usage (Aroda 2016).

Regular testing of serum B12 and plasma homocysteine levels in patients on long-term metformin therapy is advised, and those taking metformin should supplement with vitamin B12 (de Jager 2010; Mahajan 2010).

Alpha-glucosidase inhibitors. Drugs referred to as “starch blockers” belong to a drug group called alpha-glucosidase inhibitors. These drugs lower glucose by blocking breakdown of starches and slowing absorption of sugar and carbohydrates (ADA 2015d).

  • Acarbose. Acarbose is the most researched and widely used of the alpha-glucosidase inhibitors (Josse 2006). In China, the country with the largest diabetic population, acarbose is one of the most commonly prescribed oral glucose-lowering medications (Standl 2014; Gu 2015). Like metformin, acarbose is effective as a first-line drug for type 2 diabetes insufficiently controlled by diet alone, and does not stimulate insulin secretion or cause hypoglycemia or weight gain. Acarbose blocks the intestinal enzyme alpha-glucosidase needed to digest complex carbohydrates (eg, starches) into simple sugars such as glucose that can be easily absorbed into the bloodstream. As a result, acarbose helps reduce after-meal blood sugar levels (Campbell 1996; Hanefeld 1998; Gu 2015; Joshi 2014; Derosa 2012).

    In a rigorous review of 19 randomized controlled trials that enrolled type 2 diabetics, acarbose was found to significantly reduce HbA1C levels when given alone or as add-on treatment with other antidiabetic drugs (Derosa 2012). In an international trial involving over 500 patients with impaired glucose tolerance, treatment with acarbose significantly improved glucose tolerance, and reduced the risk of progression to diabetes by 25% over 3.3 years (Chiasson 2002).

    The mechanism of action of acarbose is complementary to that of metformin. While metformin primarily controls fasting blood sugar, acarbose regulates postprandial glucose levels. Combination therapy with acarbose and metformin has been demonstrated, in multiple studies, to be more effective for the control of blood glucose than treatment with either drug alone (Mooradian 1999; Johnson 1993; Joshi 2014; Jayaram 2010; Wang 2013).

    In a study in diet-treated diabetic patients, even a single mixed meal of 450 Calories caused immediate and significant impairment in endothelial function, a key early step in the development of atherosclerosis. Prior treatment with acarbose markedly reduced the postprandial rise in blood glucose and associated endothelial dysfunction (Steyers 2014; Shimabukuro 2006).

    In a review of seven long-term placebo-controlled studies in type 2 diabetics, acarbose reduced the risk of any cardiovascular event by 35% and the incidence of heart attack by 64% (Hanefeld 2004). The ongoing Acarbose Cardiovascular Evaluation (ACE) trial, which has enrolled 7500 patients with coronary heart disease and impaired glucose tolerance, will test whether acarbose treatment can prevent heart attacks, strokes, or death from these events. Results are expected in 2018 (DTU 2015).

    Side effects of acarbose treatment are generally mild, and tend to be short-lived. Gastrointestinal effects such as flatulence and diarrhea are most common (Coniff 1995; Joshi 2014; Derosa 2012; Standl 2014).

    Since acarbose is a prescription medication, some individuals who wish to use it to control post-meal glucose elevations but are not diabetic may have difficulty obtaining the drug. Fortunately, natural products such as white mulberry leaf extract and brown seaweed extract also inhibit the alpha-glucosidase enzyme and help reduce postprandial hyperglycemia (Lordan 2013; Zhang 2007; Yatsunami 2008; Hansawasdi 2006).

Table 1: Other Oral Medications for the Treatment of Type 2 Diabetes
Class Examples Mechanism Benefits Risks
Thiazolidinediones (TZDs) pioglitazone, rosiglitazone Increased insulin sensitivity and activation of PPAR-gamma Lower HbA1C; improved lipid levels; may preserve beta cell function and be anti-inflammatory Heart failure, heart attack, stroke, bladder cancer, fractures, may cause weight gain
SGLT2 Inhibitors dapagliflozin, canagliflozin Causes excess glucose to be excreted by kidney Lower HbA1C; weight loss; decreased blood pressure Increase glucose in urine; fungal and urinary tract infections; decreased kidney function; breast and bladder cancer
Dipeptidyl peptidase-4 (DPP-4) Inhibitors sitagliptin,
saxagliptin
Prolongs action of GLP-1 and GIP by inhibiting their breakdown Lower HbA1C; low risk of hypoglycemia; no weight gain; cardiovascular protection Constipation; upper respiratory and urinary tract infections; headache; possible association with pancreatitis or pancreatic cancer; some concerns about heart failure risk, but more evidence is needed
Bile acid sequestrants Colesevelam Binds bile acids to lower cholesterol; blood sugar lowering mechanism unclear Lower HbA1C; decreased LDL cholesterol Constipation; indigestion
Sulfonylureas Glimepiride,
glipizide,
glyburide
Stimulates insulin secretion Lower HbA1C Weight gain; hypoglycemia; permanent neurologic disability; exhaustion of beta cell function; death
Meglitinides (Glinides) Repaglinide, nateglinide Stimulates insulin release Lower HbA1C Hypoglycemia; weight gain; upper respiratory infection; headache; numerous drug interactions

(Kishore 2014; ADA 2015d; NLM 2009; Gold Standard 2013; Gold Standard 2014; Inzucchi 2012b; Fonseca 2013; O'Connor 2015; Whitlatch 2015; Drucker 2006; Vilsbøll 2012; Fadini 2011; Patil 2012; Scheen 2013; Ryder 2013; Nauck 2013; Peng 2016)

Injectable or Other Glucose-Lowering Agents

Insulin. Lifelong insulin therapy is generally required for individuals with type 1 diabetes, and should be started as soon as possible after diagnosis (Vimalananda 2014; Kishore 2014; Galli-Tsinopoulou 2012). Insulin is also commonly prescribed for type 2 diabetics who cannot adequately manage their condition with diet and oral medications (Inzucchi 2012c).

Insulin cannot be taken orally because it would be degraded by stomach acid. Insulin is almost always injected subcutaneously (into the fat under the skin). Replacement insulin therapy attempts to mimic normal release patterns by using two types of insulin (ADA 2015c; Vimalananda 2014):

  1. long-acting insulin (detemir, glargine) or intermediate-acting insulin (neutral protamine hagedorn [NPH]) to provide a steady basal effect of up to 12‒24 hours;
  2. rapid-acting insulin (lispro, aspart, insulin glulisine) to be used at mealtime to cover after-meal spikes in blood glucose.

Potential Concerns with Inhaled Insulin

In 2014, the FDA approved a new, rapid-acting inhaled insulin (Afrezza) for adults with diabetes as an alternative to injectable insulin for mealtime use. However, the long-term risks of this treatment have not been conclusively determined (FDA 2014; Fleming 2015; Al-Tabakha 2015).

Insulin is a mild growth factor itself, but high concentrations of insulin in tissues can lead to overstimulation of other, more potent growth factors such as insulin-like growth factor-1 (IGF-1), which in turn can promote the growth and spread of cancer (Draznin 2011; Stattin 2007; NPG 2012; Humpert 2008; Kaaks 2004; Hiraga 2012; Bahr 2005). Compared with normal cells, cancer cells have more receptors for insulin and IGF-1, making them much more responsive to hormone stimulation (Ouban 2003; Belfiore 2011; Godsland 2009; Aleem 2011).

Powdered inhaled insulin comes in contact with tissues of the upper respiratory tract on its way to the lungs (von Kriegstein 2007; Graff 2005), which may increase risk of tumors in the respiratory tract. Since only 25% of insulin reaching the lungs is absorbed, most of the insulin builds up in the lungs. In fact, prior to Afrezza’s approval, Exubera—the first inhaled insulin drug developed—was linked to lung cancer and withdrawn from the market (Al-Tabakha 2015; Neumiller 2010; FDA 2009; von Kriegstein 2007; Heinemann 2008).

Apart from cancer, other health risks of insulin inhalation therapy include respiratory tract irritation, exacerbation of asthma symptoms, and adverse effects in people with pre-existing respiratory diseases (Fleming 2015; Selam 2008; Schaafsma 2007; Henry 2003; Siekmeier 2008; Mudaliar 2007).

Pramlintide. Pramlintide (Symlin) is an injectable drug used along with insulin when after-meal hyperglycemia cannot be controlled with insulin alone (Cohen 2013). Pramlintide is a synthetic version of the hormone amylin, which is normally secreted along with insulin by pancreatic beta cells after a meal. Amylin slows gastric emptying and helps control postprandial glucose spikes (Schmitz 2004). Pramlintide is associated with severe hypoglycemia and weight loss. Also, due to the fact that it delays emptying of the stomach, it can delay absorption of drugs taken at the same time (Cohen 2013).

Glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 receptor agonists (eg, exenatide, liraglutide) increase insulin secretion while inhibiting glucagon release, but only when blood glucose is high, thus reducing the risk of hypoglycemia. They reduce body weight and lower systolic blood pressure in type 2 diabetics, and increase after-meal satiety. These drugs are administered by subcutaneous injection. Adverse effects associated with GLP-1 agonists include nausea, diarrhea, and vomiting; development of antibodies against the drug; and reactions at the injection site (Garber 2011; Trujillo 2015). Some evidence suggests GLP-1 receptor agonists may be associated with a small increase in risk of pancreatitis or pancreatic cancer, but research thus far has been inconclusive and proven cardiovascular benefits likely outweigh the risks (Drucker 2006; Vilsbøll 2012; Ryder 2013; Nauck 2013; Peng 2016).

Incretin-Based Drugs and Pancreatic Disease

Incretin-based drugs, which include dipeptidyl peptidase-4 (DPP-4) inhibitors, also referred to as gliptins, and GLP-1 receptor agonists, are among the newest blood glucose-lowering medications for treating type 2 diabetes. Despite the growing body of evidence for their favorable effects on HbA1C, body weight, and possibly cardiovascular risk, as well as their low risk of hypoglycemia as a side effect, questions remain about their possible connections with acute pancreatitis and pancreatic cancer (Azoulay 2015; Suarez 2014). Findings from animal research suggest a high-fat diet may increase risk of pancreatic harm from these medications (Williams 2016).

Pancreatic cancer. Observational studies examining the relationship between incretin-based medications and pancreatic cancer have had mixed findings; furthermore, they have been hampered by challenges such as confounding risk factors, a long latency between treatment initiation and cancer diagnosis, and low frequency of occurrence of pancreatic cancer (de Heer 2014; Azoulay 2015). Three of the most recent studies are detailed as follows:

  • One new study used data collected by the FDA Adverse Event Reporting System (FAERS) database from 1968–2013. Based on the FAERS standard for identifying potential relationships, an association between the use of DPP-4 inhibitors and pancreatic cancer was identified (Nagel 2016).
  • A recent study analyzed data from 182 428 individuals and compared those using incretin-based drugs to individuals using other non-insulin anti-diabetes drugs and people not being treated for diabetes. The participants were followed for an average of 4.1 years. When diabetes severity was taken into account, there was no difference in pancreatic cancer risk between incretin-based drug users, other anti-diabetes drug users, and untreated subjects with diabetes; however, an unexplained two-fold increase in risk was seen in new users of incretin-based drugs, though this effect leveled out with longer use (Knapen 2016).
  • The largest study to date included data collected at six sites in three countries, and represented medical information from 972 384 patients initiating medical treatment for diabetes and followed for an average of 1.3–2.8 years. Using patients taking sulfonylureas as the control group, the analysis found no increase in pancreatic cancer rates among those taking incretin-based drugs (Azoulay 2016).

Acute pancreatitis. Evidence linking incretin-based drugs and acute pancreatitis is also conflicting, and determining the nature of the relationship appears to be confounded by the impact of diabetes severity on pancreatitis risk (Chou 2014). Findings from one study suggest the risk of DPP-4 inhibitor-induced pancreatitis may be higher in females and in the elderly (Lai 2015).

A recent analysis of available research found the overall occurrence of pancreatitis in diabetics using incretin-based drugs is low, and deemed the evidence too weak to support the notion of a cause and effect relationship (Li, Shen 2014); another study analyzed results from three recent large trials and concluded that incretin-based drugs were associated with an 82% increased risk of acute pancreatitis compared with other anti-diabetes drugs (Roshanov 2015). Based on current information, the FDA and the European Medicines Agency (EMA) continue to advise caution until definitive evidence emerges (Egan 2014); therefore, it is recommended that incretin-based drugs should be discontinued in patients with suspected acute pancreatitis and should not be initiated in diabetics with a history of acute pancreatitis (de Heer 2014).

Metabolic Surgery

Researchers and physicians have known for many years that one of the benefits of weight loss (bariatric) surgery in many cases is rapid and profound improvements in glucose metabolism among diabetics (Singh 2015; Pories 1995). In fact, beta cells of type 2 diabetic patients who undergo weight loss surgery often regain function following the procedure (Su 2016). Recently, the term “metabolic surgery” has been widely adopted, given that benefits of bariatric surgery extend well beyond weight loss alone (Lee, Almulaifi 2015; Cordera 2016).

In a large, often-cited clinical study, 191 patients who had impaired fasting glucose or type 2 diabetes underwent laparoscopic Roux-en-Y gastric bypass surgery and were followed-up for a mean of 19.7 months. Oral antidiabetic drug use decreased by 80% after surgery, and insulin use decreased by 79%. Also, subjects lost an average of 60% of their excess body weight (Schauer 2003).

Considering this and other compelling data, in early 2016, 45 worldwide medical and scientific societies have endorsed new guidelines that recommend metabolic surgery in type 2 diabetics with a BMI ≥40 kg/m2, and in type 2 diabetics with a BMI of 35–39.9 whose hyperglycemia is not adequately controlled by lifestyle and medical therapy. These guidelines, put forth at the 2nd Diabetes Surgery Summit (DSS-II), also suggest metabolic surgery be considered in type 2 diabetic patients with a BMI of 30–34.9 and inadequately controlled hyperglycemia. The team of 48 international clinicians and scholars who developed the recommendations concluded that “Although additional studies are needed to further demonstrate long-term benefits, there is sufficient clinical and mechanistic evidence to support inclusion of metabolic surgery among antidiabetes interventions for people with T2D and obesity” (Rubino 2016).

The mechanisms behind the benefits of metabolic surgery are still being investigated. Aside from benefits that stem from the obvious reduction in caloric intake that follows these procedures (Pories 1995), several other changes may promote healthy metabolic function. These include changes in bile acid metabolism, altered nutrient sensing and glucose utilization in the gastrointestinal tract, and changes in the intestinal microbiome (Batterham 2016).