Even as lifestyle interventions in IGT have a status similar to their status in the management of type 2 diabetes, it remains to be seen whether the intensive lifestyle interventions employed in clinical trials can be transferred successfully from the highly structured and disciplined environment of a trial to the more routine, day-to-day management in a primary care set-up. It would therefore seem prudent to introduce pharmacological interventions to prevent type 2 diabetes in the ‘at-risk’ population. The history of pharmacological interventions for prevention goes a long way back to a small trial published in 1980, with 49 subjects, which demonstrated that the sulfonylurea tolbutamide was effective in blocking the progression of IGT to type 2 diabetes over a 10-year follow-up period, compared to a 29% incidence among control patients.[21
Since then we have come a long way in terms of understanding the disease process and the interventions that may block it at various levels.
Keeping in view the multimodal pathophysiological basis for type 2 diabetes, it is not necessary that these interventions be targeted at hyperglycemia alone. Other agents that do not primarily target hyperglycemia may also reduce the risk of type 2 diabetes. The use of orlistat for use of orlistat for managing obesity, RAS blockade with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBS), and recently the use of vitamin D and bromocriptine are all different approaches toward the common goal.
Metformin has been found to be useful in the prevention of development of diabetes in many large, well-powered trials. It has been shown to lower fasting blood glucose in individuals at risk for type 2 diabetes, without causing hypoglycemia. In addition, it has a favorable action on cardiovascular risk factors, which are often present in these individuals. It helps in maintaining diet-induced weight loss and lowers fasting plasma insulin concentrations, total and low density lipoprotein-cholesterol, and free fatty acids. These effects make metformin a first-line agent for the prevention of type 2 diabetes as recommended by the ADA.[16
The Diabetes Prevention Program (DPP) was a multicenter clinical trial, aimed at finding the effect of modest weight loss through dietary changes and increased physical activity or treatment with metformin for the prevention or delay in the onset of type 2 diabetes in pre-diabetes, overweight subjects.[22
] The trial found that both lifestyle interventions and metformin were effective in slowing the progression of IGT to diabetes. For participants in the lifestyle intervention group, the risk-reduction for type 2 diabetes was to the tune of 58%, while it was about 31% in the metformin group. In the lifestyle intervention group, around 5% developed diabetes / year, compared to 7.8% in the metformin group, and 11% in the placebo group.
On similar lines, the Indian Diabetes Prevention Program (IDPP) reported a 28.5% reduction in the incidence of type 2 diabetes with lifestyle modifications and 26.4% reduction with metformin in comparison to placebo, in subjects with IGT.[23
The Chinese Diabetes Prevention Program (CDPP) evaluated the preventive effect of diet and exercise, acarbose, and metformin on the progression to diabetes mellitus in 321 subjects with IGT.[24
] The subjects were divided into the control, diet plus exercise, acarbose, and metformin groups. The glycemic control deteriorated in the control group with elevations in both fasting and postprandial plasma glucose at the end of study period. In the diet and exercise groups, the fasting plasma glucose increased slightly and postprandial plasma glucose levels were reduced. The other two groups demonstrated significant reductions in the two glycemic indices. Annual diabetes incidence was 11.6, 8.2, 2.0, and 4.1% in the control, diet and exercise, acarbose, and metformin groups, respectively.
The Early Diabetes Intervention Trial (EDIT) gave insights into the use of therapeutic agents for the prevention of type 2 diabetes in 631 patients with IFG. At three years, there was an 8% risk reduction with acarbose and 37% with metformin, compared to placebo.[25
] Although there was no difference in the relative risk for diabetes with acarbose or metformin at the six year follow-up, it was observed that for subjects with IGT at baseline the relative risk reduction was significant with acarbose (0.66), but not with metformin (1.09), implying that there could be differences in the ability of the therapies, to reduce the risk of diabetes in subjects with IGT or IFG.[26
Metformin has also been found to be effective in pregnant females with gestational diabetes and polycystic ovarian syndrome (PCOS). In a study by Begum et al
] the two main outcome measures in this trial were development of gestational diabetes and the fetal outcome. The occurrence of gestational diabetes was significantly lower in the metformin group with only one subject (3.44%) developing gestational diabetes. On the other hand, nine of 30 pregnant (30%) subjects developed diabetes in the control group. Of note was the observation that all the babies in the metformin group had an average birth weight, while four babies in the control group were large for date. Another study of GDM prevention in PCOS patients with the use of metformin by Gluek et al
] yielded similar results.
Even as metformin has been found to be useful in preventing the progression to type 2 diabetes, the topic has also raised questions on certain issues. One of the more important issues is whether the effect of metformin to reduce the incidence of diabetes during DPP is true prevention or simply a masking of diabetes, as the post-trial washout period is very short for testing that distinction. It is suggested that the very rapid effect of metformin to increase insulin sensitivity can similarly dissipate rapidly as well. These effects of metformin on insulin sensitivity may disappear two weeks after stopping metformin. The available data does not provide direct measures of insulin sensitivity; it also remains uncertain whether the glucose levels are stabilized or still rise two weeks after discontinuing metformin. With the current understanding of the effects of metformin on carbohydrate metabolism, it is possible that only a part of the effects are due to beta-cell protection, while another part is simply a masking due to the acute glucose-lowering effects of metformin; it will probably be difficult to estimate the proportion of these two effects.
The alpha-glucosidase inhibitors acarbose, miglitol, and voglibose act by competitively inhibiting the alpha-glucosidase enzymes present in the intestines and are involved in carbohydrate digestion. They decrease both postprandial hyperglycemia and hyperinsulinemia, and may improve insulin sensitivity and diminish the stress on pancreatic beta-cells.[29
] These compounds have a good safety profile and do not cause hypoglycemia, although gastrointestinal side effects are commonly observed and may lead to a reduced long-term compliance.
The Study TO Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM) was a multicenter, international, double-blind, placebo-controlled study to evaluate the effects of acarbose in delaying the progression of IGT to type 2 diabetes in 1418 subjects with IGT.[30
] The primary endpoint was the development of type 2 diabetes, based on an oral glucose tolerance test. There was a 25% relative risk reduction of progression to type 2 diabetes in the acarbose group compared to the placebo group. Acarbose significantly increased the reversion of IGT to normal glucose tolerance.
Voglibose has also been found to be useful in the prevention progression of IGT to type 2 diabetes. In a clinical trial by Ryuzo Kawamori et al
] voglibose was seen to improve glycemic parameters in 1780 Japanese subjects with IGT. The patients treated with voglibose had a significantly lower risk of progression to type 2 diabetes compared to the placebo group. A significantly higher number of subjects in the voglibose group achieved normoglycemia than those in the placebo group. Voglibose was approved by the Japanese Ministry of Health, Labor, and Welfare, in the year 2009, for the prevention of new-onset type 2 diabetes, in patients with impaired glucose tolerance.
Pioglitazone, a PPAR-gamma agonist, is a member of the thiazolidinedione class (which also includes troglitazone and rosiglitazone). Pioglitazone is primarily expressed in the adipose tissue and has a favorable influence on systemic insulin resistance.[32
Troglitazone in Prevention of Diabetes (TRIPOD)[33
] was a randomized, placebo-controlled trial of 266 women with recent gestational diabetes, with 126 completing the treatment of 3.6 years, with an eight-month, post-drug washout period. A 55% reduction in the incidence of diabetes was observed, with persistent protection from diabetes for eight months post the drug, and stable glucose and beta-cell function for 4.5 years, in women who did not get diabetes during the troglitazone treatment. The study was terminated prematurely when troglitazone was withdrawn from the market.[33
The Pioglitazone in Prevention of Diabetes (PIPOD)[34
] study with pioglitazone was an open-label follow-up of 89 women from TRIPOD. The results were similar to the TRIPOD study, and a comparison of changes in beta-cell compensation for insulin resistance in both the studies showed that pioglitazone halted the decline in the beta-cell function that was seen with the placebo treatment in the TRIPOD study, and also maintained the stability of the beta-cell function that occurred in the TRIPOD with troglitazone treatment. Together, these two studies demonstrated that prevention of type 2 diabetes is possible with thiazolidinediones providing beta-cell rest.
The Actos Now for the prevention of diabetes (ACT NOW) study,[35
] was a randomized, double-blind, placebo-controlled trial conducted to examine the effectiveness of pioglitazone in the prevention of type 2 diabetes in 602 subjects with IGT. The annual incidence rate of type 2 diabetes was 2.1% in the pioglitazone group compared to 7.6% in the placebo group. The hazard ratio of conversion of type 2 diabetes was 0.28 (95% CI 0.16 – 0.49 p < 0.001)
The diabetes reduction approaches with ramipril and rosiglitazone medications (DREAM)[36
] study evaluated the efficacy of rosiglitazone in the prevention of type 2 diabetes. The trial randomized 5269 subjects with IGT and / or IFG to either rosiglitazone or ramipril versus placebo. More subjects regained normoglycemia on rosiglitazone (50.5%) than on placebo (30.3%). The ramipril therapy had no effect on the incidence of diabetes or death, but was more effective than placebo in achieving normoglycemia (42.5 vs. 38.2%, for ramipril vs. placebo). Importantly, rosiglitazone reduced the incidence of diabetes by 60% relative to the placebo and was effective in subjects with IFG and IGT.
Although each of these drugs has been found to be useful in preventing the progression from prediabetic to the diabetic stage, these drugs have been mired by issues of safety. Troglitazone was banned following its hepatotoxic effects. The United States Food and Drug Administration (USFDA) has restricted the use of Rosiglitazone, due to its increased risk for cardiac morbidity and mortality. USFDA recently (June 2011) issued a safety announcement on the use of pioglitazone, stating that taking pioglitazone for more than one year may be associated with an increased risk of bladder cancer. Although the Endocrine Society, the American Association of Clinical Endocrinologists, and the American Diabetes Association have appealed to patients to continue taking their prescribed medications, unless instructed otherwise by their healthcare provider, one must address the issue of pioglitazone-use in the light of the fact that the highest risk of bladder cancer was noted among patients who had been on pioglitazone for the longest durations and had received higher doses.[37
Orlistat, a specific inhibitor of gastrointestinal lipases (gastric and pancreatic), is responsible for the hydrolysis of ingested triglycerides into fatty acids and monoglycerides. Orlistat also increases postprandial glucagon-like peptide 1 (GLP-1) levels, thereby enhancing the insulin secretory response to a meal and blunting the postprandial glucose surge in obese diabetics. This probably leads to decreased food intake, and may also contribute to weight loss.[38
] Orlistat has been shown to lower plasma insulin levels versus the placebo in clinical trials.[39
] Heymsfield et al
., conducted a post hoc analysis of orlistat therapy in 675 obese adults with IGT, from three randomized, placebo-controlled trials.[41
] Orlistat was found to reduce the progression of IGT to diabetes versus placebo (3 vs. 7.6%). Seventy-two percent of the subjects on orlistat achieved fasting glucose values in the normal range, compared to 49%, in the placebo group.
The XENical in the prevention of Diabetes in Obese Subjects (XENDOS) study[42
] led to the confirmation of results from previous studies.[41
] This prospective multicenter, randomized, double-blind, placebo-controlled, parallel group study investigated the effectiveness of orlistat along with lifestyle changes compared with lifestyle modifications alone in 3305 subjects. Over four years of therapy, orlistat led to a risk reduction of 37.3% in the cumulative incidence of diabetes versus placebo. Despite intensive lifestyle modifications in both the groups, weight loss was greater in the orlistat group versus the placebo group (– 6.9 vs. – 5.8 kg, respectively). Orlistat treatment led to a significant reduction in visceral adipose tissue.
The use of certain oral hypoglycemic agents has been known to cause weight gain and this constitutes an important risk factor for diabetes; there is an incremental risk of 9% for every kilogram increase in body weight.[43
] Incretin-mimetics like exenatide have been shown to address this issue as their use has been found to be associated with significant weight loss. Exenatide acts through multiple mechanisms, the net result of which is improved glycemic control. The effects have been categorized as immediate effects — glucose dependent insulin secretion, suppression of post-prandial high glucagon levels, and delayed gastric emptying and delayed effects — with weight loss and improvement in beta cell mass and function.[44
Exenatide plus lifestyle modification have been shown to reduce caloric intake, produce weight loss, and improve glucose tolerance in nondiabetic obese subjects with both IGT and IFG.[44
] In a study of 152 obese subjects with and without pre-diabetes, IGT or IFG normalized in 77 and 56% of exenatide- and placebo-treated subjects, respectively, at the end of the study. Exenatide-treated subjects had a significantly higher weight loss of 5.1 kg versus 1.6 kg for placebo. Subjects on exenatide treatment also consumed a lower number of calories. In summary the data available so far suggests that exenatide produced beneficial effects on insulin sensitivity and islet function .
Summary of clinical trials on the risk of new onset Type 2 diabetes with oral hypoglycemic agents
Statins are commonly prescribed for the prevention of cardiovascular disease in patients with diabetes and even pre-diabetes. As statins have variable and complex effects on glucose metabolism, the risk of diabetes remains an area of controversy. In experimental studies statin lipophilicity as well as the potential to inhibit 3-hydroxy-3-methylglutaryl-coenzyme-A reductase are considered prognostic factors of an adverse impact of statin treatment on carbohydrate metabolism. Other factors like hypotriglyceridemic capacity, increase in islet blood flow, anti-inflammatory properties, and the ability to alter circulating levels of several adipokines are known to affect glucose homeostasis. Among the various drugs in this class, pravastatin appears to possess beneficial effects on glucose metabolism and also reduces the risk of diabetes. In general, the hydrophilic statins pravastatin, rosuvastatin, and pitavastatin are preferable to the lipophilic agents atorvastatin and simvastatin.[46
A large body of evidence has demonstrated that the risk of new-onset type 2 diabetes may be increased by certain agents and a list of some of the statin trials and their results are given in . The risk may also be related to the duration and the dose of the individual statin used. Having said this, it is also true that their benefits far outweigh any potential risk in populations where statin-use has proven benefits.
Summary of clinical trials on the risk of new-onset type 2 diabetes with statin therapy
Renin angiotensin system blockade
A large body of evidence suggests that RAS blockade may reduce the incidence of new-onset type 2 diabetes in the at-risk population, with or without hypertension.[54
] The reduction in the incidence of new-onset diabetes by ACE inhibitors or ARBs can be explained by hemodynamic effects like improved delivery of insulin and glucose to the skeletal muscle, and by non-hemodynamic effects, including direct effects on glucose transport and insulin signaling pathways; factors that contribute to reducing insulin resistance. RAS blockers help in maintaining a critical beta cell mass by blocking the effect of angiotensin II. It has also been found that these drugs delay or prevent the development of insulin resistance through novel mechanisms. provides the results from some of the trials where these agents have been found to be useful.
Summary of clinical trials on the risk of new-onset type 2 diabetes with Renin Angiotensin System blocking drugs
All these trials taken together involved a large number of non-diabetic subjects and demonstrated that ACE inhibitors or ARBs produced a significant 25% reduction in the incidence of new-onset diabetes. Although these trials differed in their methods and only few had the development of diabetes as a pre-specified end point,[62
] it could be inferred that the interplay of hypertension, hyperglycemia, and dyslipidemia worked as a cardiovascular risk factors and the RAS blockade had a positive effect on the metabolic milieu. Clinically, the inhibition of RAS improved insulin sensitivity and decreased the incidence of type 2 diabetes.
Vitamin D has been receiving attention for its potential role in preventing cardiovascular disease and type 2 diabetes mellitus. Epidemiological studies have suggested that individuals with low blood levels of vitamin D have increased risks of heart disease, stroke, hypertension, and diabetes. Vitamin D receptors are present in most cells and tissues where they stimulate the nuclear transcription of various genes to alter cellular function. Vitamin D, appears to have an effect on numerous disease states and disorders, including osteoporosis, chronic musculoskeletal pain, diabetes (types 1 and 2), multiple sclerosis, cardiovascular disease, and various cancers.[64
As calcium is necessary for insulin secretion, it has been suggested that vitamin D may contribute to maintaining insulin secretion. Many mechanisms are known, whereby, hypovitaminosis D may be involved in the causation of hyperglycemia, type 2 diabetes, and metabolic disorders like an increase in insulin resistance, reduction in insulin secretion, and an increase in damage to pancreatic islets.
In a recent trial of 12,719 non-diabetic participants, lower serum levels were associated with pre-diabetes after adjusting for a variety of factors such as age, sex, and race.[65
This is another group of agents that has been recently postulated to be involved in the development of insulin resistance and a variety of other deleterious effects. It is being increasingly recognized that there is interplay between the gut flora, energy homeostasis, and inflammation, and that these have a role in the pathogenesis of obesity-related disorders. Several mechanisms have been considered to play a role in this interplay: increased energy from diet, altered fatty acid metabolism, and composition of the adipose tissue and liver are some of them.[66
] Chronic low-grade endotoxemia, has also been postulated as a link between gut microbial flora and obesity. This low-grade endotoxemia further induces chronic inflammation. In summation, endotoxemia may play a key role in the pathogenesis of an obesity-associated inflammatory state and the type of food may affect the endotoxin levels.[66
There is evidence to suggest that there may be quantitative and qualitative differences in the gut microbial flora among lean and obese, and between diabetic and non-diabetic subjects.[67
] Modification of the gut flora and / or its biochemical capacity by dietary or pharmacological interventions may favorably affect host metabolism. Short-term clinical trials have shown the benefit of prebiotics and probiotics on insulin sensitivity, inflammatory markers, postprandial incretins, and glucose tolerance.
The fascinating role of gut flora on metabolic disease opens new avenues in the treatment of obesity, insulin resistance, and type 2 diabetes.
Concerns of safety
Even as the preventive aspect of diabetes may appear as a tremendous opportunity at all levels including those of the population, physician, and planners, in clinical practice, it is limited by the occurrence of a variety of therapy-related side effects, which limit the usefulness. Certain agents are also known to cause serious adverse effects during long-term use.
Another problem area is of long-term adherence to these pharmacological interventions. While a majority of clinical trials demonstrate the benefits of appropriate therapy, they also highlight the issue of non-compliance. In the STOP-NIDDM[30
] and XENical in the prevention of Diabetes in Obese Subjects (XENDOS)[42
] trials, 30 and 48% of subjects, respectively, did not complete the active intervention. Adherence to therapy has been around 70% in the DPP[24
] and DREAM[36
] trials. This is probably explained by the lack of tangible benefits for an asymptomatic subject with pre-diabetes, who has to constantly live with obvious adverse effects and the fear of developing frank diabetes.
Drugs causing hyperglycemia
Even when focusing on the preventive aspects of diabetes with the use of drugs one should not forget that there are certain drugs that can cause alter the glucose-insulin homeostasis through a variety of mechanisms, some of which are not fully understood. As hyperglycemia is one component of the metabolic changes, it is often seen that a patient already taking some medication for another component like hypertension or dyslipidemia is subsequently found to have an impaired glucose tolerance or frank diabetes. Diuretics and beta-blockers used for the treatment of hypertension, certain statins like rosuvastatin, and many other agents can cause hyperglycemia. Other agents include corticosteroids, niacin, and pentamidine.[68
] A list of drugs that commonly cause hyperglycemia is given in .
Medications causing hyperglycemia